Download Dynamics of sensory thalamocortical synaptic networks during

Progress in Neurobiology 74 (2004) 213–247
www.elsevier.com/locate/pneurobio
Dynamics of sensory thalamocortical synaptic networks
during information processing states
Manuel A. Castro-Alamancos*
Department of Neurobiology and Anatomy, Drexel University College of Medicine,
2900 Queen Lane, Philadelphia, PA 19129, USA
Received 29 April 2004; accepted 8 September 2004
Abstract
The thalamocortical network consists of the pathways that interconnect the thalamus and neocortex, including thalamic sensory afferents,
corticothalamic and thalamocortical pathways. These pathways are essential to acquire, analyze, store and retrieve sensory information.
However, sensory information processing mostly occurs during behavioral arousal, when activity in thalamus and neocortex consists of an
electrographic sign of low amplitude fast activity, known as activation, which is caused by several neuromodulator systems that project to the
thalamocortical network. Logically, in order to understand how the thalamocortical network processes sensory information it is essential to
study its response properties during states of activation. This paper reviews the temporal and spatial response properties of synaptic pathways
in the whisker thalamocortical network of rodents during activated states as compared to quiescent (non-activated) states. The evidence shows
that these pathways are differentially regulated via the effects of neuromodulators as behavioral contingencies demand. Thus, during activated
states, the temporal and spatial response properties of pathways in the thalamocortical network are transformed to allow the processing of
sensory information.
# 2004 Elsevier Ltd. All rights reserved.
Contents
1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1. The vibrissae thalamocortical network . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2. Activated versus quiescent states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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2.
Primary sensory lemniscal pathway . . . . . . . . . . . . . . . . .
2.1. Morphology of lemniscal synapses . . . . . . . . . . . . .
2.2. Electrophysiology of lemniscal synapses . . . . . . . . .
2.3. Effects of neuromodulators on lemniscal synapses . .
2.4. Sensory responses mediated by lemniscal synapses. .
2.4.1. Temporal response properties. . . . . . . . . . .
2.4.2. Spatial (receptive field) response properties .
2.5. Functional relevance during behavior . . . . . . . . . . .
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Corticothalamic pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Morphology of corticothalamic synapses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: BRF, brainstem reticular formation; VPM, ventroposterior medial thalamus; POm, rostral sector of the posterior complex; nRt, thalamic
reticular nucleus; CO, cytochrome oxidase; EPSP, excitatory postsynaptic potential; IPSP, inhibitory postsynaptic potential; GABA, gamma-aminobutyric acid;
LTP, long-term potentiation; LTD, long-term depression; CSD, current source density analysis; TTX, tetrodotoxin; VL, ventrolateral nucleus of the thalamus
* Tel.: +1 215 991 8287; fax: +1 215 843 9082.
E-mail address: [email protected].
0301-0082/$ – see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.pneurobio.2004.09.002
214
M.A. Castro-Alamancos / Progress in Neurobiology 74 (2004) 213–247
3.2.
3.3.
3.4.
Electrophysiology of corticothalamic synapses . . . . . . . . . . . . .
Effects of neuromodulators on corticothalamic synapses . . . . . .
Corticothalamic responses during information processing states .
3.4.1. Temporal response properties. . . . . . . . . . . . . . . . . . .
3.4.2. Functional relevance during behavior . . . . . . . . . . . . .
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4.
Thalamocortical pathway . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. Electrophysiology of thalamocortical synapses . . . . . . . .
4.2. Effects of neuromodulators on thalamocortical synapses .
4.3. Thalamocortical responses during information processing
4.3.1. Temporal response properties. . . . . . . . . . . . . .
4.3.2. Spatial (receptive field) response properties . . . .
4.3.3. Functional relevance during behavior . . . . . . . .
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5.
Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1. Dynamics of the thalamocortical network during an ascending input . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2. In conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
242
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
Understanding how the brain acquires, analyzes, stores
and retrieves sensory information is one of the most
compelling questions in neuroscience. Central to information processing, are neural networks that interconnect the
thalamus and the neocortex. Rather than being static, these
neural pathways are highly dynamic and modifiable on a
moment to moment basis. These dynamic changes occur in
response to behavioral demands to allow information
processing. The neocortex is the most highly evolved area
in the brain; it is the location where the most complex brain
activities take place, such as perception and consciousness.
The thalamus is the gate to the neocortex; all sensory
information, excluding olfaction, must pass through the
thalamus before reaching the neocortex. It is widely
accepted that the main function of the thalamus is to
control the flow of sensory information to the neocortex
during different behavioral states (Singer, 1977; Sherman
and Koch, 1986; Steriade and McCarley, 1990; Steriade,
1993; McCormick and Bal, 1994; Sherman and Guillery,
1996; Steriade et al., 1997). The thalamus and neocortex are
highly organized and complex structures that work in
concert with each other. The importance of their relation is
evident in that they are recurrently and extensively
interconnected with one another, the neocortex accesses
information about the external world primarily via the
thalamus, and the largest input to the thalamus arrives from
the neocortex. I will refer to the system of different pathways
that interconnect the thalamus and cortex as the thalamocortical network.
The goal of the present review is to describe the
properties of pathways in the sensory thalamocortical
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states .
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network using rodent vibrissae as a model system; reference
will also be made to studies from other sensory modalities
and species when necessary. A number of reviews and books
exist on the properties of the thalamocortical network (e.g.
Sherman and Guillery, 1996, 2001; Steriade et al., 1997;
Jones and Diamond, 1995). The present review focuses on
the basic properties of the three major pathways in the
thalamocortical network, and particularly on how they are
modified by behavioral state. The pathways are: (1) the
primary sensory thalamic afferents that originate in the
trigeminal nucleus and via the medial lemniscus tract
innervate cells in the ventroposterior medial thalamus
(VPM); for simplicity, termed here the lemniscal pathway;
(2) the massive corticothalamic pathway that originates in
layer VI of neocortex and innervates VPM; and (3) the
thalamocortical pathway originating in VPM cells. The role
of the lemniscal pathway is to provide direct sensory
information from the peripheral receptors, while the
thalamocortical pathway relays that information to the
neocortex. The role of the corticothalamic pathway is less
understood but among other things it is thought to regulate
sensory inputs. The main interest here is to describe how
these pathways operate during information processing states
(see below Section 1.2).
The underlying theme of this review is that the properties
of the inputs to the thalamus (corticothalamic and lemniscal)
and its output (thalamocortical) are differentially regulated
via the effects of neuromodulators as behavioral contingencies demand. In other words, neuromodulators change
the properties of these pathways during behavior to allow
effective information processing. Understating how a
pathway operates requires intimate knowledge of the
intrinsic membrane properties of the pre- and postsynaptic
M.A. Castro-Alamancos / Progress in Neurobiology 74 (2004) 213–247
cells forming the pathway, and particularly of the synaptic
connections that those cells produce. There is an ample
literature on the intrinsic membrane properties of neurons in
the thalamocortical network. However, the properties of
synapses in this network have been less intensely studied.
Deciphering the properties of these synapses is vital for
understanding the thalamocortical network. Both, intrinsic
membrane and synaptic properties contribute to the fact that
the excitability of the thalamocortical network is not static
but highly dynamic. The pioneering studies of thalamocortical responsiveness were carried out by Morison and
Dempsey over 60 years ago (Dempsey and Morison,
1942a,b, 1943; Morison and Dempsey, 1942, 1943). Their
work showed that pathways in the thalamocortical network
are highly sensitive to frequency (for review see CastroAlamancos, 1997; Castro-Alamancos and Connors, 1997b).
An important subject is to understand how these temporal
properties are involved in sensory information processing
during different behavioral states.
1.1. The vibrissae thalamocortical network
The thalamocortical network discussed here is the
representation of vibrissae in rodents (Woolsey and Van
der Loos, 1970; Bernardo and Woolsey, 1987). This system
shares many properties with the other major models used to
study sensory processing, such as the visual system (Miller
et al., 2001). Most rat strains have relatively poor visual
abilities, and instead use their whiskers to navigate and to
locate and identify objects (Carvell and Simons, 1990; GuicRobles et al., 1989; Brecht et al., 1997). The tactile skills of
their whiskers are in some ways comparable to primates
using their fingertips (Carvell and Simons, 1990; Simons,
1995), employing active touch strategies common throughout mammalian sensory/motor systems (Simons, 1995). For
a whisker deflection that drives a mechanoreceptor on the
sensory axon of a trigeminal (V) ganglion cell there are three
levels of processing up to the neocortex. The first level
occurs in the trigeminal complex (i.e. trigeminal (V)
brainstem nuclear complex), where groups of cells
representing primarily one whisker form cell clusters, called
barrelettes (Henderson and Jacquin, 1995). The axons of
these trigeminal cells produce the lemniscal pathway that
innervates clusters of cells in VPM, called barreloids (Land
et al., 1995), which represent the same principal whisker.
Finally, the axons of these VPM cells produce a
thalamocortical pathway that innervates clusters of cells
in layer IV called barrels (Woolsey and Van der Loos, 1970),
which also represent the same principal whisker. By
definition the whisker thalamocortical network consists of
the pathways received and produced by VPM cells,
including lemniscal, corticothalamic and thalamocortical
(see Fig. 1).
Notably, the number of corticothalamic fibers is one order
of magnitude larger than the number of thalamocortical
axons (Sherman and Guillery, 1996), and cortical afferents
215
are the most abundant input to the thalamus (Guillery, 1971).
In the vibrissae somatosensory network, primary and
secondary thalamic nuclei can be distinguished based on
the characteristics of the sensory information that they
process (Diamond, 1995). The primary thalamic nucleus is
the VPM, and the secondary nucleus is the rostral sector of
the posterior complex (POm). In addition, there are two
types of corticothalamic pathways (see Fig. 1) that differ in
the layer of cortex from where they originate (for review
Guillery, 1995). One pathway originates in layer VI and
sends reciprocal connections to both primary and secondary
thalamic nuclei, leaving collateral fibers in the thalamic
reticular nucleus (nRt) (Zhang and Deschenes, 1997). The
nRt sends inhibitory fibers (GABAergic) to VPM and POm.
The other pathway originates in layer V, from neurons whose
axons run toward the brainstem and give rise to collaterals
that enter the thalamus and terminate exclusively in
secondary thalamic nuclei, such as POm (Bourassa et al.,
1995), and thus avoid the nRt and VPM. The corticothalamic
fibers that originate in layer VI and innervate VPM produce
glutamatergic synapses that act on distal dendrites (for
review Guillery, 1995; Deschenes et al., 1998; Sherman and
Guillery, 1996). The VPM receives its primary sensory input
from the principal trigeminal nucleus through the lemniscal
pathway (for review Diamond, 1995). Lemniscal terminals
form glutamatergic synaptic contacts with the soma and
proximal dendrites of VPM neurons (Spacek and Lieberman, 1974; Williams et al., 1994b). Thus, corticothalamic
synapses contact distal dendrites, while lemniscal synapses
occur more proximal to the cell body of thalamocortical
neurons (Liu et al., 1995a; Spacek and Lieberman, 1974;
Williams et al., 1994b; Erisir et al., 1997a), and
corticothalamic fibers have smaller diameters than lemniscal
fibers and consequently conduct slower (Sherman and
Guillery, 1996; Robson, 1983). In conclusion, VPM
thalamocortical neurons are contacted close to their somata
by principal trigeminal nucleus fibers (lemniscal pathway)
and by nRt fibers (inhibitory pathway), and at distal portions
of their dendrites by fibers from neurons in layer VI of
neocortex (corticothalamic pathway). Moreover, VPM
thalamocortical neurons lack recurrent axon collaterals
between them, and are not innervated by local interneurons
since these do not exist within rodent ventrobasal thalamus
(Ohara and Lieberman, 1993).
There are different types of thalamocortical pathways
(for review Castro-Alamancos and Connors, 1997b), but the
main thalamocortical pathway we will discuss here is the
primary thalamocortical pathway that originates in VPM
and innervates the barrel cortex. Thalamocortical cells in
VPM project to the neocortex via the thalamic radiation and
as they do, they leave collateral fibers in the nRt and in upper
layer VI of neocortex before arriving at their destination in
layer IV (Jensen and Killackey, 1987). In addition, the POm
also generates a thalamocortical pathway, usually termed
secondary thalamocortical pathway, which is much sparser
and innervates different cortical regions and layers than the
216
M.A. Castro-Alamancos / Progress in Neurobiology 74 (2004) 213–247
Fig. 1. Schematic representation of major synaptic connections in the thalamocortical network. Left: Ascending projections in the thalamocortical network
depicting the lemniscal fibers to VPM and POm, and the thalamocortical fibers originating in those nuclei that give rise to primary and secondary
thalamocortical pathways, respectively. The primary pathway originating in VPM leaves fiber collaterals in the nRt, upper layer VI and terminates in layer IV in
barrel cortex. The secondary pathway originating in POm leaves fiber collaterals in nRt and innervates layers V, III and I in the septa or non barrel cortex.
Middle: Corticothalamic projections originating in a barrel column. Layer V cells project to the brainstem and on their way leave a collateral fiber that enters
POm, but not nRt or VPM. Cells in upper layer VI that presumably receive direct thalamocortical input from VPM, project back to VPM and leave a fiber
collateral in nRt. In contrast, cells in lower layer VI of the barrel column project to POm leaving fiber collaterals in nRt. Right: Corticothalamic projections
originating in cortical septa between barrel columns and in non-barrel cortex. Like in barrel columns, layer V cells of septa project to the brainstem and on their
way leave a collateral fiber in POm, but not in nRt or VPM. Cells in upper layer VI project to either VPM or Pom leaving collaterals in nRt. Like in barrel
columns, cells in lower layer VI of septa project to POm leaving fiber collaterals in nRt. Note that the connections depicted are those of cell populations and not
the connections made by individual cells. The white box in cortex represents a barrel in layer IV, while the adjacent cortical area represents non-barrel cortex or
septa (see text for references).
primary thalamocortical pathway (Koralek et al., 1988; Lu
and Lin, 1993).
1.2. Activated versus quiescent states
Several decades ago (Moruzzi and Magoun, 1949), it was
shown that electrical stimulation of the brainstem reticular
formation (BRF) transforms the slow and large amplitude
electroencephalographic activity typical of anesthetized or
sleeping animals into the fast and low amplitude activity
typical of activated or aroused states. Indeed, the activity
measured extracellularly in the neocortex and thalamus
during states of vigilance, alertness and attention (i.e.,
behavioral arousal) is very similar from that observed after
BRF stimulation in anesthetized animals, and we use the
term activation to refer to this activity. This contrasts with
the activity measured during sleep or quiescent states, which
is very similar to that observed in anesthetized animals not
subjected to BRF stimulation. Commonly, these two distinct
states are referred to as desynchronized and synchronized
states, respectively. However, these terms should be avoided
since during activated states cell activity may be more
tightly synchronized than during non-activated (quiescent)
states. For example, cortical neurons responding to a sensory
input may do so more tightly synchronized during activated
states than during quiescent states (Munk et al., 1996). Thus,
the use of the term desynchronized to refer to activated states
seems inaccurate. Instead, we commonly use the terms
activated and quiescent states to refer to these two distinct
states of electrographic activity. Thus, to further clarify these
terms, it should be noted that activation is the electroencephalographic sign of behavioral arousal, which can be
produced in anesthetized animals by BRF stimulation, and
that behavioral arousal per se can only be studied in
behaving un-anesthetized animals.
The thalamocortical network serves a basic function, to
acquire, analyze, store and retrieve sensory information; a
process called information processing. Sensory information processing mostly occurs during behavioral arousal, a
state characterized by vigilance, alertness and attention.
During arousal the discharge rate of cells in several
brainstem neuromodulatory systems (e.g. norepinephrine,
acetylcholine) increases significantly (Aston-Jones et al.,
1991, 1994; Steriade et al., 1990; Buzsaki et al., 1988), and
since these systems project to the thalamocortical network
(Hallanger et al., 1990; Simpson et al., 1997; Bennett-
M.A. Castro-Alamancos / Progress in Neurobiology 74 (2004) 213–247
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Fig. 2. Effects of activation caused by BRF stimulation on field potential and single-unit activity recorded simulatensouly from VPM and barrel cortex. The
activity of two cortical cells from layers IV-III and a VPM cell are shown before, during and after activation or arousal caused by BRF stimulation (100 Hz, 1 s;
gray box) in a urethane anesthetized rat. During activation the VPM cell (cell 3) robustly enhanced its firing rate, which is typical of all VPM cells. Meanwhile
the simultaneously recorded cortical cells either suppressed (cell 1) or enhanced their spontaneous firing rate (cell 2). Also, the high amplitude slow activity
characteristic of field potentials during quiescent sates is transformed into low amplitude fast activity during activation. Based on Castro-Alamancos and
Oldford (2002).
Clarke et al., 1999; Liu et al., 1995b) the levels of these
neuromodulators increase during arousal (Williams et al.,
1994a). In general, neuromodulators can affect the
response properties of isolated synapses (Thompson et
al., 1993; McGehee and Role, 1996; Wu and Saggau, 1997;
Miller, 1998), they can alter the intrinsic properties of
neurons (McCormick, 1992; Steriade et al., 1993), or they
can act at multiple sites in a neural network producing
complex effects. There is an ample literature on the effects
of these neuromodulators on the intrinsic membrane and
firing properties of thalamic neurons. Briefly, application
of a variety of neuromodulators to thalamocortical cells
results in their depolarization. In contrast, nRt cells are
differentially affected by neuromodulators, so that norepinephrine depolarizes these cells while acetylcholine
hyperpolarizes them (for review McCormick, 1992;
Steriade et al., 1997). In neocortex, neuromodulators have
been shown to have different effects depending on the cell
type (McCormick and Prince, 1985; Xiang et al., 1998).
Interestingly, many of the effects produced in the thalamus
and neocortex by neuromodulators released during arousal
in behaving animals can be reproduced in anesthetized
animals by using BRF stimulation. For example, electrical
stimulation in the area of the laterodorsal and pedunculopontine tegmentum in rats (termed here BRF stimulation), which are the main source of cholinergic inputs to the
thalamus from the brainstem (Hallanger et al., 1987),
transforms thalamocortical activity similarly to application
of acetylcholine in the thalamus (Castro-Alamancos,
2002a). Moreover, since neuromodulatory activating
systems in the brainstem and basal forebrain are
interconnected, electrical stimulation of one of those
systems is likely to recruit other neuromodulatory systems,
which may also occur during behavior.
Fig. 2 shows a typical example of simultaneously
recorded field potential and single-unit activity in VPM
and in the barrel cortex before and immediately after BRF
stimulation in an anesthetized rat (Castro-Alamancos and
Oldford, 2002). Note the large amplitude field potential
activity in the thalamus and neocortex during the quiescent
state preceding the BRF stimulation and the low amplitude
fast activity observed during the activated state that follows.
In addition, the three cells recorded in thalamus and cortex
show distinct effects. The thalamocortical cell (cell 3)
increases its firing rate consistent with a depolarization,
while one of the cortical cells (cell 1) decreases its firing
consistent with a hyperpolarization. Notably, the other
cortical cell (cell 2) also behaves like the thalamic cell
increasing its firing rate (Castro-Alamancos and Oldford,
2002), and these differences surely reflect distinct cell types
in neocortex. Evidently, the response properties of pathways
in the thalamocortical network should be different during
these distinct states (i.e., quiescent and activated). The
present review will describe those differences.
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One way to conceive the functioning of thalamocortical
cells with regards to the transmission of sensory information is like an electrical relay, in which the primary sensory
inputs from the lemniscal pathway are regulated by the
other afferents, such as the fibers from the nRt and from
BRF. Electrical relays allow the transmission of a signal
when another current activates the relay at a different input,
thus regulating the output of the relay. This seems to be
the operation of thalamocortical cells. Thus, the main role
of thalamocortical neurons is to relay sensory inputs to
the neocortex according to the regulations dictated by
behavioral state. These regulations are imposed by
neuromodulators that are released in the thalamus mainly
by afferents from the BRF. Traditionally, the statedependent relay of sensory information to the neocortex
through the thalamus has been studied within the context of
two firing modes of thalamocortical cells, the bursting mode
and the tonic mode (Steriade et al., 1997; Sherman and
Guillery, 1996). The bursting mode is mainly associated
with states of slow-wave sleep (Guido and Weyand, 1995)
and deep anaesthesia (although its relevance during awake
states is also hotly debated (Sherman, 2001; Steriade,
2001)). In contrast, the tonic-firing mode is mainly
associated with waking and alertness. The significant work
that has lead to establishing the dichotomy between bursting
and tonic firing as modes of thalamocortical relay function
has placed little relevance on the properties of thalamic
and cortical synapses. Nevertheless, computational
studies indicate that synaptic properties (e.g., short-term
plasticity) are crucial in determining the mode of processing
in neural networks (Tsodyks et al., 1998; Abbott et al.,
1997). In fact, while thalamocortical cells are in the tonicfiring mode synaptic mechanisms may be essential to set the
thalamocortical network in different information processing modes.
In the last few years we have studied how the different
connections of the thalamocortical network are affected by
the state of the subject, and in particular how they are
affected by activated states. In the long term, the major
question to decipher is what differences exist in the thalamic
and neocortical pathways between being awake and being
attentive. An initial question is how the different pathways in
the thalamocortical network are affected by activation and
behavioral arousal. This review discusses recent work
illustrating the changes in temporal and spatial response
properties that take place during transitions between
quiescent and information processing states in the three
main pathways received or produced by thalamocortical
neurons of the rodent vibrissae system: lemniscal, corticothalamic and thalamocortical pathways.
medial lemniscus tract. In addition, the spinal trigeminal
nucleus also sends a projection to the thalamus (Spacek and
Lieberman, 1974; Feldman and Kruger, 1980; Chiaia et al.,
1991a; Williams et al., 1994b; Diamond, 1995; Veinante and
Deschenes, 1999; Veinante et al., 2000). Between 70 and
90% of the axons originating in the principal trigeminal
nucleus innervate the upper two thirds of VPM. The other
10–30% of fibers originating in the principal nucleus
innervates POm and the colliculus. Cells in the three spinal
trigeminal nuclei (i.e. oralis, interpolaris and caudalis) also
project to the whisker thalamus. Few axons from oralis
innervate the thalamus, and those that do go to POm. Two
types of axons originate in interpolaris; fast conducting
thick axons go to POm while slowly conducting thin axons
go to VPM. The caudalis nucleus also produces axons
projecting to VPM that are similar to the slow conducting
axons of interpolaris. Interestingly, despite the fact that the
principal trigeminal nucleus and two of the spinal nuclei
(interpolaris and caudalis) project to VPM, these axons do
not overlap so that there seems to be no convergence of
principal and spinal information in the VPM as discussed
ahead.
Cytochrome oxidase (CO) staining in VPM reveals rodlike structures that transverse the dorsal part of the nucleus
and are called barreloids (Land et al., 1995). Retrograde
labeling of thalamic barreloids by tracer injections in a
single cortical barrel reveals rod-like structures consisting of
a core, which corresponds to the rod structures revealed with
CO staining, plus a tail that extends ventrolaterally in VPM
and is lightly CO stained (Saporta and Kruger, 1977). The
principal trigeminal nucleus projects mainly to the
dorsomedial portions of VPM, to the core of barreloids,
while spinal axons project to ventrolateral portions of VPM,
to the tails of barreloids, where projections from the
principal nucleus are sparse (Williams et al., 1994b; Pierret
et al., 2000; Veinante et al., 2000). Thus, in the core of a
thalamic barreloid, a VPM neuron receives its sensory input
primarily from cells in the principal trigeminal nucleus and
this VPM cell projects to a corresponding barrel in cortex. In
contrast, the spinal projection to VPM forms a parallel
stream because it does not innervate cells in the core of a
barreloid; instead these axons contact a population of cells in
the tail of a barreloid. Moreover, the thalamocortical cells in
these barreloid tails do not project to a cortical barrel;
instead they project sparsely to areas outside a barrel column
(i.e. dysgranular zones or septal regions) and more heavily to
the secondary somatosensory area (Pierret et al., 2000). The
present review deals with the properties of lemniscal
synapses contacting VPM cells in barreloid cores, which are
formed by fibers that originate in the principal trigeminal
nucleus.
2. Primary sensory lemniscal pathway
2.1. Morphology of lemniscal synapses
The rodent whisker thalamus receives its primary sensory
input from the principal trigeminal nucleus through the
Lemniscal terminals form glutamatergic synaptic contacts with the soma and proximal dendrites of VPM
M.A. Castro-Alamancos / Progress in Neurobiology 74 (2004) 213–247
Fig. 3. Schematic representation of lemniscal synaptic glomeruli based on
Spacek and Lieberman (1974). D, dendrite; E, excrescences; A, axon; R,
release sites; F, synapses with flattened vesicles possibly from nRt cells; G,
glia; M, mitochondria.
neurons (De Biasi et al., 1994; Williams et al., 1994b). At
the electron microscope level, lemniscal synapses form
complex synaptic connections called synaptic glomeruli
(Fig. 3) consisting of a synaptic arrangement in which
axonal and dendritic components are ensheathed by glial
cell processes (Spacek and Lieberman, 1974). Several
elements are involved (see Fig. 3): (1) a postsynaptic
dendrite (D) which produces prominent excrescences (E)
or protrusions; (2) a large axon terminal (A) deeply
invaginated by the excrescences that contains spherical
synaptic vesicles and makes multiple synaptic contacts or
release sites (R) on the dendritic excrescences but no
synaptic contacts with the dendritic shaft; (3) a small
number of synaptic terminals (F) that contained flattened
synaptic vesicles and make contacts with the dendritic
shafts at the periphery and immediately adjacent to the
glomerulus, which likely consist of inhibitory inputs from
the nRt and modulatory inputs from the brainstem reticular
formation; (4) the postsynaptic excrescences-presynaptic
lemniscal fiber complex is surrounded by glial processes
(G), which may serve to limit the spread of glutamate and
may also limit the influence of other neurotransmitters on
lemniscal synapses. A fully reconstructed glomerulus of
the rat somatosensory thalamus was found to be 5 mm in
diameter, in which two dendrites produced a total of 10
excrescences receiving a total of 44 synaptic contacts
(Spacek and Lieberman, 1974). Thus, each lemniscal
219
Fig. 4. EPSPs evoked in VPM neurons by stimulating lemniscal fibers in
slices. (A) All or none events evoked at threshold intensity. The event either
occurs, indicating the effective stimulation of the lemniscal fiber, or does not
occur, indicating it was not stimulated. When the lemniscal fiber is
stimulated the probability of triggering one of these events is 100%.
(B) Lemniscal EPSPs depress at frequencies above 2 Hz. Upper: Sample
trace of the response produced in a VPM cell by four lemniscal stimuli at
20 Hz in a slice preparation. Lower: Percent change in amplitude of the
lemniscal EPSP as a function of stimulation frequency. Shown is the
amplitude of the response to the fourth stimulus in a train. Based on
Castro-Alamancos (2002b).
synaptic glomerulus forms a large number of closely
spaced synaptic contacts or release sites. This, in
combination with the proximal location on the dendrite,
combines to produce a very powerful synaptic input.
2.2. Electrophysiology of lemniscal synapses
Lemniscal synapses of adult rodents studied in vitro (Fig.
4) produce short latency, fast-rising, large amplitude, highly
secure all-or-none EPSPs, which depress in response to
repetitive stimulation at frequencies above 2 Hz (CastroAlamancos, 2002b). Although further work is needed
to decipher the reasons why lemniscal synapses present
these specific properties, current knowledge of synaptic
transmission and lemniscal synapses suggests the following
scenario:
1) The short latency of lemniscal EPSPs is likely due to fast
conducting large-caliber myelinated lemniscal axons,
and also presumably due to the optimization of the
molecular steps responsible for fast synaptic transmission at these synapses.
2) The rise time of the EPSP for synapses that are
electrotonically close to the soma, such as lemniscal
synapses, is a function of the rate of rise of
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neurotransmitter concentration and the activation
kinetics of the receptor channels (Jonas and Spruston,
1994). Thus, the fast rise time of lemniscal EPSPs may be
related to the fast kinetics of the AMPA receptor subunits
expressed at these synapses, and the possibility that
lemniscal synaptic glomeruli favor a fast rise of
neurotransmitter concentration.
3) The landmark work of Katz on synaptic transmission
(Katz, 1969) has established the principles that determine
the response characteristics of synaptic connections. The
efficacy of a synaptic connection is determined by the
product of the probability of release, the number of
release sites and the size of the postsynaptic response to a
single quantum of neurotransmitter. Thus, the large
amplitude EPSPs evoked by a single lemniscal fiber
correlates well with the observation at the morphological
level that lemniscal synapses contain many release sites.
It also relates well with the fact that evoked lemniscal
EPSPs are highly secure, occurring invariantly on almost
every stimulus trial at low frequencies, which indicates
that this synapse has a high release probability (CastroAlamancos, 2002b). Although the amplitude of the
response to single quantum has not been determined for
lemniscal synapses, the other two factors defining
synaptic efficacy (large number of release sites and high
release probability) agree that lemniscal synapses should
produce large amplitude EPSPs.
4) Synapses display a wide range of activity-dependent
response properties. At many synapses, when two action
potentials depolarize a presynaptic terminal in rapid
succession, the second action potential releases more
neurotransmitter than the first producing synaptic
facilitation (Zucker, 1989). In contrast, other synapses
display decreased efficacy with repeated use that lasts
from several hundred milliseconds to seconds, called
short-term synaptic depression (Zucker, 1989). The
mechanisms by which synapses produce short-term
depression are not entirely elucidated, and different
synapses may have different mechanisms involved, such
as inhibition of Ca2+ channels through metabotropic
receptors (Takahashi et al., 1996), depletion of docked
vesicles (Stevens and Tsujimoto, 1995), and desensitization of postsynaptic receptors (Trussell et al., 1993).
Repetitive stimulation of lemniscal fibers at frequencies
above 2 Hz produces robust frequency-dependent
depression of lemniscal EPSPs (Castro-Alamancos,
2002b). The depression of lemniscal synapses may be
related to their high release probability. In fact, several
lines of evidence suggest that this may be the case. First,
evidence from other systems indicate that synapses with
high release probability tend to display synaptic
depression (Zucker, 1989; Debanne et al., 1996;
Castro-Alamancos and Connors, 1997a; Gil et al.,
1999). Second, the structure of synaptic terminals
usually correlates with release probability, so that the
volume of the presynaptic terminal correlates with the
size and number of its active zones, docked vesicles and
release probability (Korn and Faber, 1991; Pierce and
Lewin, 1994; Schikorski and Stevens, 1997). As
described above, lemniscal synapses form large size
terminals with numerous closely spaced release sites
(Spacek and Lieberman, 1974), which is suggestive of a
high release probability. As discussed below, these
specialized properties of lemniscal synapses serve to
endow the lemniscal pathway with useful mechanisms
for the transmission of sensory inputs through the
thalamus.
2.3. Effects of neuromodulators on lemniscal synapses
Neuromodulators are involved in a broad range of
brain functions. They have been implicated in the control
of arousal states and they may be important for attentive
and memory processes (e.g. Buzsaki et al., 1988; Singer,
1977; Aston-Jones et al., 1991; Sillito et al., 1983; Steriade
et al., 1997; Hasselmo and Bower, 1993; Bakin and
Weinberger, 1996). Apart from the excitatory glutamatergic
synaptic connections in the thalamus (corticothalamic and
lemniscal), there are several major regulatory systems.
Among them are the noradrenergic and cholinergic fibers
originating in the brainstem (Simpson et al., 1997; Hallanger
et al., 1987; Satoh and Fibiger, 1986), and the GABAergic
fibers originating in the nRt (Ohara and Lieberman, 1985).
GABA is released in the VPM by the nRt terminals and
produces well-characterized postsynaptic effects. Receptor
proteins corresponding to different neuromodulatory systems have been found on these pathways (Vidnyanszky et
al., 1996; Broide et al., 1995; Vogt et al., 1992), providing a
site for neuromodulation.
A recent study found that lemniscal synapses are
insensitive to acetylcholine and norepinephrine (CastroAlamancos, 2002b). That is, application of these neuromodulators, or the respective receptor agonists, do not affect the
amplitude of lemniscal EPSPs evoked in thalamocortical
cells that are recorded with intracellular solutions used to
block the postsynaptic actions of these neuromodulators. On
the other hand, activation of GABAB receptors seems to
depress lemniscal synapses (Emri et al., 1996). Although the
site of GABA effects (pre- or postsynaptic) has not been
established, these observations suggest that lemniscal inputs
are quite selective about the neuromodulators that affect
them. Despite the apparent absence of presynaptic effects,
neuromodulators such as norepinephrine and acetylcholine
have profound effects on the efficacy of the lemniscal
pathway because of the postsynaptic actions produced by
these neuromodulators on thalamic cells. Thus, the
postsynaptic depolarization produced by these neuromodulators influences how effective lemniscal EPSPs are in
driving thalamocortical neurons. This depolarization allows
the relay of lemniscal inputs at high-frequency rates by
bringing the depressed lemniscal EPSPs close to firing
threshold (Castro-Alamancos, 2002b), which has important
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221
consequences for the transmission of sensory information in
vivo as discussed below.
2.4. Sensory responses mediated by lemniscal synapses
Fig. 5. Schematic diagram depicting two VPM cells located in two different
thalamic barreloids representing different whiskers. The intracellular
responses of the cells to whisker stimulation of one of those whiskers
during quiescent states are shown below. Stimulation of the whisker
produced large amplitude EPSPs followed by strong recurrent IPSPs from
the nRt in the cell representing the stimulated whisker (cell 1). The
lemniscal EPSPs and also the IPSPs sharply depress with frequency until
reaching a steady state. In cell 2, which is located in a different barreloid
(barreloid 2) that does not represent the stimulated whisker, the response
consists solely of recurrent IPSPs from the nRt. The source of this crossinhibition may be dendrites extending into adjacent barrel oids, or the spread
of activity in nRt. Based on Castro-Alamancos (2002a).
The properties displayed by lemniscal EPSPs in slices
(Castro-Alamancos, 2002b) are also present in vivo (CastroAlamancos, 2002a). Intracellular recordings in vivo reveal
that whisker stimulation produces a short latency, fastrising, large amplitude EPSP followed by a longer latency
GABAergic IPSP in some VPM cells, and only an IPSP in
other VPM cells (see Fig. 5) (Castro-Alamancos, 2002a;
Brecht and Sakmann, 2002). In rodent VPM, the IPSPs are
generated by feedback inhibition from the nRt because
there seem to be no inhibitory interneurons within the
ventrobasal thalamus of rodents (Spacek and Lieberman,
1974; Barbaresi et al., 1986; Harris and Hendrickson, 1987;
Ohara and Lieberman, 1993). The EPSP–IPSP sequence
occurs in cells that are contacted directly by lemniscal fibers
representing the stimulated whisker, while the IPSP-alone
responses correspond to cells that are in a different barreloid
and are not directly innervated by the lemniscal fibers for
the stimulated whisker but that receive recurrent inhibition
from nRt (cross-inhibition) as a consequence of the whisker
stimulation. nRt cells seem to project to VPM in a closedloop pattern, meaning that they project back to the barreloid
from where they receive excitation (Desilets-Roy et al.,
2002). Thus, nRt axons entering adjacent barreloids do not
seem to provide the source for cross-inhibition between
barreloids. However, VPM cells extend their dendrites into
adjacent barreloids where they can sample recurrent
inhibition evoked by adjacent whiskers and this may well
be a substrate for cross-inhibition (Varga et al., 2002;
Lavallee and Deschenes, 2004). In addition, it is likely that
the excitation received by a population of nRt cells from a
barreloid spreads within nRt by means of intra-nRt
connections (Sohal and Huguenard, 2003; Shu and
McCormick, 2002) and gap junctions (Landisman et al.,
2002), leading to the stimulation of nRt cells that project to
other barreloids, which could also explain cross-inhibition
between barreloids and, thus, between whiskers.
Generally, whisker stimulation evokes few large amplitude unitary lemniscal events (2) on a given VPM neuron,
suggesting that VPM neurons are contacted by few
lemniscal fibers (Castro-Alamancos, 2002a,b; Deschenes
et al., 2003). These events usually have a slight difference in
latency and sum to produce a larger composite lemniscal
EPSP that very effectively drives a VPM neuron during low
frequency stimulation. The characteristics of lemniscal
EPSPs endow the lemniscal pathway with a powerful
capacity to drive thalamocortical neurons, so that in deeply
anesthetized animals receiving low frequency stimuli
(<2 Hz), the principal whisker is able to drive a VPM cell
on 80% of trials. Interestingly, during activated states
caused in anesthetized animals by BRF stimulation or by the
application of neuromodulators to the thalamus, the same
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sensory stimulus is able to drive the thalamocortical cell on
100% of the trials (Castro-Alamancos, 2002a; CastroAlamancos and Oldford, 2002). Differences in sensory
transmission through the lemniscal pathway during different
behavioral states are more dramatic for the transmission of
high frequency sensory inputs, as described ahead.
2.4.1. Temporal response properties
In anesthetized rats, thalamocortical neurons follow high
frequency whisker stimulation with great difficulty; thalamocortical neurons are low-pass filtered. Only low
frequency inputs are relayed to the neocortex in anesthetized
rats. This process is also called rapid sensory adaptation and
it is a property shared by other sensory systems, such as for
example the visual system (Nelson, 1991a). However, there
are significant differences among studies regarding the cutoff frequency for this low-pass filter or sensory adaptation.
Some studies report strong frequency-dependent depression
at frequencies above 5 Hz (Diamond et al., 1992b; Lee et al.,
1994b), others at 2 Hz (Ahissar et al., 2000), while others
report the ability to follow frequencies of up to at least 12 Hz
(Simons, 1985; Simons and Carvell, 1989; Hartings and
Simons, 1998). In urethane-anesthetized rats, thalamic
neurons are low-pass filtered so that whisker stimulation
above 2 Hz is not relayed to neocortex (Castro-Alamancos,
2002a). However, when the thalamus of anesthetized rats is
aroused by BRF stimulation or by applying acetylcholine to
the thalamus, the lemniscal low-pass filter is significantly
opened allowing the relay of sensory inputs at much higher
frequencies. Indeed, during activated states VPM cells can
follow whisker stimulation fairly efficiently at frequencies
of up to 40 Hz, and even 100 Hz (Fig. 6). Thus, during
activated states of the thalamus typical of information
processing, the low-pass filtering of sensory inputs is largely
eliminated (Castro-Alamancos, 2002a).
The underlying cause of this low-pass filter during
quiescent states has been studied in the VPM both in vivo
and in vitro. Intracellular recordings in vivo in urethane
anesthetized rats revealed that lemniscal synapses present
robust frequency-dependent depression, so that whisker
stimulation at frequencies above 2 Hz depresses lemniscal
EPSPs (Castro-Alamancos, 2002a,b). The activity-dependent synaptic depression is translated into the low-pass
filtering of sensory inputs through the thalamus (CastroAlamancos, 2002a). Sensory inputs at frequencies above
2 Hz reduce the efficacy of lemniscal synapses, which drives
the lemniscal EPSP away from the discharge threshold of the
cell resulting in a low probability of firing for thalamocortical cells. These properties are likely shared by other
primary sensory afferents in the thalamus, such as retinogeniculate synapses (Turner and Salt, 1998), and the sensory
adaptation observed in the visual thalamus may also be
caused by the activity-dependent synaptic depression of
retino-geniculate synapses.
Fig. 6. Effects of acetylcholine on whisker evoked responses in VPM neurons. (A), Upper plots correspond to counts per 2-ms bins evoked by 15 whisker
stimuli (30 trials) at different frequencies during quiescent states in urethane-anesthetized rats. Lower plots correspond to the same stimuli during application of
acetylcholine in VPM. Note the strong low-pass filtering of VPM responses at frequencies above 2 Hz, but not during application of acetylcholine. (B) Example
of whisker stimulation delivered at 66 Hz and at 100 Hz during acetylcholine. Notice that the cell is able to follow these high frequencies during application of
acetylcholine in VPM. (C) Population data showing a spectrum analysis of whisker evoked responses in VPM neurons before and during the application of
acetylcholine. Based on Castro-Alamancos (2002a).
M.A. Castro-Alamancos / Progress in Neurobiology 74 (2004) 213–247
The reason why this low-pass filter is eliminated during
activated states could be that the activity-dependent
depression of lemniscal EPSPs (i.e., synaptic depression)
is eliminated by neuromodulators that are released during
arousal. This hypothesis was examined using thalamic slices
in vitro. As discussed above (see Section 2.3), lemniscal
EPSPs are insensitive to the effects of acetylcholine and
norepinephrine, and thus this hypothesis is not supported
(Castro-Alamancos, 2002b). However, these modulators
have well recognized postsynaptic actions on thalamocortical neurons; they depolarize thalamocortical neurons
(McCormick, 1992; Steriade et al., 1997). The postsynaptic
depolarization of thalamocortical neurons produced by these
neuromodulators is sufficient to eliminate the effect of
synaptic depression on the relay of high frequency inputs
(Fig. 7). Indeed, synaptic depression is effective at
suppressing the transfer of lemniscal inputs when neurons
are sufficiently hyperpolarized within the tonic firing mode.
In contrast, if the neuron is depolarized closer to its firing
threshold it can overcome the depression and relay sensory
inputs at high frequency. Thus, because of synaptic
depression the relay of sensory information through the
lemniscal pathway requires sufficient postsynaptic depolarization to overcome synaptic depression (Castro-Alamancos,
Fig. 7. Voltage-dependency of the low-pass filtering of lemniscal inputs
within the tonic firing mode in slices. Four lemniscal stimuli are applied at
10 Hz. The neuron is placed at different membrane potentials in the bursting
mode (bottom trace) or in the tonic mode (upper traces). Note that due to
lemniscal synaptic depression the cell only responds with an action potential
to the first stimulus unless the cell is sufficiently depolarized within the tonic
firing mode. Based on Castro-Alamancos (2002b).
223
2002b). When these two events coincide (lemniscal release
and postsynaptic depolarization) the relay of sensory
information is warranted for high frequency inputs. This
interaction between synaptic depression and postsynaptic
depolarization was also demonstrated in vivo using whisker
stimulation (Castro-Alamancos, 2002a). These results serve
to explain why in anesthetized rats some studies have shown
that thalamocortical neurons can follow whisker stimulation
up to 12 Hz (Simons, 1985; Simons and Carvell, 1989;
Hartings and Simons, 1998), while other studies report
strong frequency-dependent depression at frequencies above
5 Hz (Diamond et al., 1992b) or 2 Hz (Ahissar et al., 2000).
These discrepancies are explained by the anesthetic state of
the preparation, and in particular the membrane potential of
thalamocortical neurons. The more efficient frequency
following of lemniscal sensory inputs during activated
states as compared to quiescent states would result from
the depolarization of thalamocortical neurons caused by
the release of neuromodulators in the thalamus, which
serves to bring depressed lemniscal EPSPs close to firing
threshold.
It is worth mentioning that, in anesthetized cats, lateral
geniculate nucleus (LGN) cells have been reported to show a
strong paired-spike facilitation to fast incoming retinal
inputs (Usrey et al., 1998). That is, when two retinal spikes
arrive in close succession the second one discharges the
LGN cell with high probability. This phenomenon seems to
occur when the first retinal spike generally fails to discharge
the LGN cell and when the second retinal spike occurs
rapidly after the first retinal spike (<30 ms). This time
course reflects the time constant of the EPSP produced by
primary sensory afferents (lemniscal or retinal-geniculate)
(Castro-Alamancos, 2002b; Turner and Salt, 1998). In this
case, the first retinal spike produces a large EPSP in the LGN
cell that is just subthreshold for spike generation, and a
second EPSP caused by the second retinal spike will be
strongly depressed due to synaptic depression, but because it
arrives during the time course of the first EPSP (temporal
summation) both sum and reach firing threshold only in
response to the second retinal spike. This phenomenon
might be less common during activated states, when
thalamic cells respond with very high reliability to
stimulation of their receptive fields, and thus would be
unlikely to fail to the first retinal spike.
Thalamocortical cells operate mainly in two different
firing modes: bursting and tonic firing (Steriade et al., 1997;
Sherman and Guillery, 1996). In the bursting mode, neurons
respond robustly to low frequency lemniscal stimuli with a
burst of action potentials (see Fig. 7) but are unable to follow
at frequencies above 2 Hz. In contrast, in the tonic mode, the
firing of thalamic neurons is highly reliable for every
stimulus delivered at frequencies up to 100 Hz (Fig. 6).
Thus, in the tonic mode, lemniscal inputs seem to be able to
overcome synaptic depression because the membrane
potential is placed close to firing threshold. Thalamocortical
neurons are unable to follow high frequency lemniscal
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inputs in the burst mode because of the properties of the
currents involved in burst generation (McCormick and
Feeser, 1990; Sherman, 1996). It is important to note that the
suppression of high frequency lemniscal inputs does not
require thalamocortical neurons to be in the bursting mode.
Indeed, synaptic depression is effective at suppressing the
transfer of lemniscal inputs when neurons are sufficiently
depolarized so they are not in the bursting mode (CastroAlamancos, 2002b). Within the tonic mode, the suppression
of lemniscal inputs is expressed when the neuron is
sufficiently hyperpolarized so that the depressed lemniscal
EPSPs do not reach action potential generation threshold.
When the neuron is depolarized closer to the firing threshold
it can overcome the depression and relay sensory inputs at
high frequency (Fig. 7). Within the tonic firing mode, the
relay of sensory information through the lemniscal pathway
requires sufficient postsynaptic depolarization to overcome
synaptic depression. Thus, neuromodulators play an
essential role in the transmission of inputs through the
lemniscal pathway by setting the level of postsynaptic
depolarization within the tonic firing mode.
Since IPSPs mediated by the nRt follow lemniscal EPSPs
(Castro-Alamancos, 2002a; Brecht and Sakmann, 2002), an
important issue relates to the role played by the nRt in the
relay of high-frequency sensory inputs. The long duration of
IPSPs may affect the responses to trains of stimuli delivered
at relatively high frequencies. This is supported by finding
that lesions of nRt (Lee et al., 1994a) or blocking GABA
receptors in the thalamus (Lee et al., 1994b; CastroAlamancos, 2002a) alter the responses of VPM neurons to
sensory inputs. Hence, the nRt must play an important role in
defining the response properties of VPM neurons. nRt
neurons produce responses to sensory stimuli that are
different from those of VPM neurons; nRt neurons respond
to a single whisker deflection (Fig. 8) with a stronger and
longer lasting response than VPM neurons (Hartings et al.,
2000). VPM neurons respond weakly to sustained deflections, and responses to maintained deflections are only
unmasked in VPM by the application of GABA receptor
antagonists (Hartings and Simons, 2000).
Recent work has also shown that the responses of nRt
neurons to sensory stimuli during tonic and burst firing
Fig. 8. Responses of an nRt cell to whisker stimulation delivered at different frequencies during quiescent states in a urethane-anesthetized rat, and the
corresponding IPSPs recorded intracellularly in a VPM cell during the same state. Upper plots correspond to a single-unit recording of an nRt cell displayed as
counts per 2-ms bins evoked by whisker stimulation at different frequencies. The lower traces correspond to intracellular recordings from a VPM neuron of a
different experiment but recorded under the same experimental conditions and state. The left trace corresponds to 10 whisker stimuli at 10 Hz, while the right
trace corresponds to a pair of stimuli delivered at 2 Hz. Action potentials are truncated.
M.A. Castro-Alamancos / Progress in Neurobiology 74 (2004) 213–247
modes are somewhat, but not exceedingly, different
(Hartings et al., 2003). In burst mode, nRt responses to a
single stimulus consist of large spike counts (5–6 spikes)
that occur with a slow rise time (15 ms) followed by a slow
decay (35 ms), exhibiting an accelerando-decelerando
pattern typical of these cells in the burst mode. While in
tonic firing mode, nRt cells also respond with large spike
counts but with a very fast rise time (1.5 ms), which in this
case is also followed by a long decay similar to the pattern
seen during burst mode. It is likely that these subtle
differences in the discharge of nRt neurons to sensory inputs
may affect the flow of sensory inputs through VPM. For
instance, if the duration and strength of IPSPs from nRt is
strong lemniscal EPSPs may be shunted, and inhibition
would be a contributing factor to frequency adaptation in the
thalamus. Intracellular recordings in vivo recently revealed
this contribution (Castro-Alamancos, 2002a); under certain
circumstances postsynaptic depolarization alone of thalamocortical neurons is not sufficient to overcome the lowpass filtering of lemniscal inputs. For instance, in deeply
anesthetized rats, postsynaptic depolarization of VPM
neurons alone produced by current injection is insufficient
to completely overcome frequency adaptation as a
consequence of the presence of IPSPs from the nRt.
Interestingly, during deep anesthesia these hyperpolarizations could last for up to one second and are caused by the
oscillatory activity of nRt neurons (Fig. 8). Thus, a single
whisker deflection causes nRt neurons to oscillate at the
spindle oscillation frequency (10 Hz). Consequently,
VPM neurons are bombarded by IPSPs at 10 Hz for
500–1000 ms after a single whisker stimulus (Fig. 8).
These IPSPs can successfully filter successive sensory inputs
arriving during the initial 800 ms after the first stimulus,
even if the VPM neuron is depolarized by current injection.
This indicates that during quiescent states, in which nRt
neurons respond to a sensory stimulus with a spindle
oscillation, subsequent sensory input at high frequencies
(the interval corresponding to the duration of the spindle
sequence) can be shunted by feedback inhibition from the
nRt. This, together with lemniscal synaptic depression, may
well serve as a mechanism that disconnects thalamocortical
neurons from high frequency sensory activity in the external
world during quiescent states and certain stages of sleep,
while still allowing a low frequency communication line
with the external world.
Notably, the robust and sometimes oscillatory feedback
IPSPs from the nRt only occur during deep anesthesia and
not during activated states (Fig. 9). During activated states,
such as those caused by BRF stimulation, IPSPs are strongly
reduced but not absent (Castro-Alamancos, 2002a). This is
caused by several factors: (1) nRt neurons change their state
from burst to tonic firing, resulting in the consequent
reduction in IPSP amplitude and duration (Kim and
McCormick, 1998); (2) GABAergic IPSPs are suppressed
in the ventrobasal thalamus by acetylcholine (Fig. 9) and
norepinephrine (Castro-Alamancos, 2002b); (3) Certain
225
Fig. 9. nRt-mediated IPSPs are suppressed during arousal. IPSPs evoked in
VPM cells by whisker stimulation in vivo or by stimulating nRt fibers in
slices are reduced by BRF stimulation or by application of acetylcholine,
respectively. Based on Castro-Alamancos (2002a) and Castro-Alamancos
(2002b).
neuromodulators such as acetylcholine hyperpolarize nRt
neurons (Ben Ari et al., 1976; McCormick and Prince,
1986), and thus would inhibit their discharge. Thus, the
amplitude and duration of feedback IPSPs is strongly
reduced during activated states and consequently, they do
not oppose the relay of sensory inputs by lemniscal EPSPs
during arousal. The changes in response properties of nRt
neurons (Hartings et al., 2003) and the change in size and
duration of evoked IPSPs in VPM work favorably for the
relay of sensory inputs through VPM. When this occurs the
only obstacle for sensory transmission of high frequency
sensory inputs to the neocortex is lemniscal synaptic
depression, which can be overcome by postsynaptic
depolarization of VPM neurons caused by the release of
neuromodulators during arousal. Thus, the sharper IPSPs
that occur during activated states may well serve to sharpen
the excitatory response and allow the transmission of high
frequency sensory inputs.
2.4.2. Spatial (receptive field) response properties
Recent studies in vivo and in slices indicate that VPM
neurons are contacted by few (1–3) lemniscal fibers (CastroAlamancos, 2002a,b; Deschenes et al., 2003), each of them
giving rise to a large amplitude EPSP with the properties
described above. Early studies that recorded from VPM
neurons in anesthetized rats indicated that they respond
solely to a single whisker (e.g. Chiaia et al., 1991a; Rhoades
et al., 1987; Waite, 1973; Shosaku, 1985). However, more
recent work has revealed that under light anesthesia VPM
cells respond to deflections of multiple whiskers (Arm-
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strong-James and Callahan, 1991; Diamond et al., 1992a;
Friedberg et al., 1999; Simons and Carvell, 1989; Minnery et
al., 2003). Indeed, the size of the receptive field (i.e. the
number of whiskers that stimulate a VPM neuron) can be
dramatically modified by the level of arousal, so that during
non-activated states VPM neurons respond only to one
whisker, while during activated states (caused by either
application of neuromodulators, BRF stimulation or by
reducing the anesthetic dosage), the same VPM neuron
responds to a principal whisker and also to a large number of
adjacent whiskers (Aguilar and Castro-Alamancos, unpublished observations). Moreover, responses to adjacent
whiskers occur at longer latencies than responses to the
principal whisker (Minnery et al., 2003; Brecht and
Sakmann, 2002), and therefore may be especially susceptible to a modulation by feedback IPSPs from the nRt.
The origin of the principal whisker responses in VPM
cells is the principal nucleus of the trigeminal complex, but
the origin of the longer latency adjacent whisker responses is
less clear. There are several possible sources for the origin of
adjacent whisker responses found in VPM during activated
states:
1) One explanation may be that the dendrites of VPM
neurons, which extend beyond the area of a single
barreloid (Chiaia et al., 1991b; Varga et al., 2002; Harris,
1986; Ohara and Havton, 1994) integrate information
from lemniscal inputs arriving at adjacent barreloids. The
major problem with this hypothesis is that recent work
has revealed that lemniscal synapses are absent on extrabarreloid dendrites (Varga et al., 2002).
2) Corticothalamic feedback may contribute to adjacent
whisker responses in VPM. A large percentage of
adjacent whisker responses occur at latencies that would
allow for the signal to travel to cortex and return to
thalamus via corticothalamic fibers (Minnery et al.,
2003). The major problem with this hypothesis is that
recent work indicates that corticothalamic feedback
seems to form a closed loop somatotopically-precise
barrel-to-barreloid connectivity (Temereanca and
Simons, 2004), which cannot account for the origin of
adjacent responses because according to this connectivity scheme VPM neurons primarily receive cortical
information from the whisker they represent.
3) Several studies have proposed that the longer latency
adjacent whisker responses in VPM reflect an input from
the spinal trigeminal nucleus, and in particular, from the
subnucleus interpolaris (Armstrong-James and Callahan,
1991; Friedberg et al., 1999; Lee et al., 1994a; Rhoades et
al., 1987). It is well established that cells in the
subnucleus interpolaris project to VPM (Chiaia et al.,
1991b; Erzurumlu and Killackey, 1980; Pierret et al.,
2000; Veinante et al., 2000; Williams et al., 1994b), have
multiwhisker receptive fields (Jacquin et al., 1989, 1986)
and have slower conducting axons than those originating
in the principal trigeminal nucleus (Veinante et al.,
2000). However, the major problem with this hypothesis
is that, as discussed above (see Section 1.1), the spinal
and principal trigeminal inputs to VPM do not overlap
(Pierret et al., 2000; Williams et al., 1994b). Inputs to
VPM from the subnucleus interpolaris are sparse and
target the tails of barreloids in the ventral lateral region of
VPM, while inputs from the principal nucleus target the
core of barreloids in the dorsomedial portion of VPM.
Thus, a direct pathway from the spinal nucleus to VPM is
unlikely the origin of multiwhisker receptive fields in
most VPM neurons.
4) Recent work has demonstrated that, in lightly anesthetized rats, cells in the principal trigeminal nucleus have
multiwhisker receptive fields just like cells in VPM
(Minnery and Simons, 2003), and that principal nucleus
responses can fully account for the multiwhisker
receptive fields found in VPM (Minnery et al., 2003).
Thus, the question now becomes what is the origin of
multiwhisker receptive fields in the principal trigeminal
nucleus? Morphological studies have identified a dense
plexus of intersubnuclear connections linking the
different spinal trigeminal subnuclei with the principal
trigeminal nucleus (Jacquin et al., 1990). It is possible
that these connections provide the substrate for multiwhisker responses in the principal trigeminal nucleus,
and recent evidence indicates that this is the case
(Timofeeva et al., 2004).
A related question is: why do multiwhisker responses
emerge in VPM during activated states? A major problem
with answering this question is that there are no studies
comparing the responses of principal trigeminal nucleus
neurons and those of VPM neurons during different behavioral states. Thus, it is not currently possible to ascertain
if the large receptive fields of VPM neurons arise during
activated states as a consequence of thalamic mechanisms
or because those same receptive fields also appear in the
trigeminal nucleus during activated states and are absent
during non-activated states. One possibility is that principal trigeminal receptive fields respond to one whisker
during quiescent states and only during activated states do
multi-whisker receptive fields arise. Alternatively, multiwhisker receptive fields may be present in the principal
trigeminal cells during both quiescent and activated states,
with little changes between these states. In this case, the
origin of large receptive fields in the VPM would be caused
by thalamic mechanisms that suppress multiwhisker responses during quiescent states while enhancing them during activated states. Further work should explore these
issues.
Feedback inhibition mediated by the nRt should affect
thalamocortical receptive fields. In particular, these long
latency IPSPs are well suited to modulate the longer latency
adjacent whisker responses. A recent study performed
intracellular recordings from VPM cells of urethaneanesthetized young rats (P16–24) and mapped their
M.A. Castro-Alamancos / Progress in Neurobiology 74 (2004) 213–247
subthreshold receptive fields (Brecht and Sakmann, 2002).
Under these conditions, VPM neurons respond to a principal
whisker with action potentials while the surrounding
whiskers produced either subthreshold excitatory or
inhibitory responses. One possibility is that the excitatory
responses of adjacent whiskers are strongly shunted by
inhibition, and so a mechanism of recurrent inhibition would
lead to single whisker receptive fields.
In lightly anesthetized animals, when VPM cells respond
to multiple whiskers, recurrent inhibition from the nRt is
also present in VPM as determined using single-unit
extracellular recordings but it is a weak phenomenon that
does not seem to counteract excitation (Minnery et al.,
2003). This may be due to the fact that during activated
states, VPM IPSPs driven by whisker deflections are
strongly reduced (Fig. 9) both in vivo and in vitro
(Castro-Alamancos, 2002a,b). One possible scenario is that
during quiescent states, strong recurrent IPSPs serve to
suppress adjacent whisker responses by shunting EPSPs
from adjacent whiskers. During activated states, because of
the postsynaptic depolarization and the reduction of
inhibition, the excitatory responses of adjacent whiskers
would remain unchallenged and receptive fields would
consequently enhance. Further work should explore this
possibility.
2.5. Functional relevance during behavior
These results indicate that synaptic depression of
lemniscal EPSPs and the level of depolarization of
thalamocortical neurons work together in thalamic primary
sensory pathways to suppress high-frequency sensory
inputs during non-activated (quiescent) states while
permitting the faithful relay of high-frequency sensory
information during activated (processing) states. Work
conducted in awake behaving animals indicates that this in
fact occurs during behavior. Poggio and Mountcastle
(1963) demonstrated that the capacity for frequency
following of tactile stimuli is dramatically different for
thalamic cells in the waking as compared to the
anesthetized monkey. More recent work in the freely
behaving rat using electrical stimulation of the infraorbital
nerve has shown that pairs of stimuli delivered at
frequencies above 10 Hz were suppressed during quiescent
states, but not during active exploration (Fanselow and
Nicolelis, 1999). In unanesthetized rabbits, arousal
measured as increased hippocampal theta has been shown
to markedly facilitate the sustained responses of LGN
neurons to constant stimulation of the center of the
receptive field (Swadlow and Weyand, 1985). If the
reduction of the sustained responses is caused by retinogeniculate depression, then these results could also
indicate the elimination of retino-geniculate depression
during arousal.
Taken together, these results suggest that one way the
thalamus gates the flow of sensory inputs to the neocortex is
227
by filtering high-frequency sensory inputs during quiescent
states, while allowing them to flow through during activated
states. It is noteworthy that this gating occurs during the
tonic-firing mode of thalamocortical neurons. In the tonic
mode, the interaction between postsynaptic depolarization
(within the membrane potential range of tonic firing) and
synaptic depression serves to regulate the flow of sensory
inputs through the thalamus. On a speculative note, this
mechanistic interaction occurring within the tonic firing
mode could underlie the differences between being awake
and being attentive. In the bursting mode, during deep sleep
and deep anesthesia, low frequency sensory inputs trigger
low-threshold calcium spikes in thalamocortical neurons
that either completely fail to discharge the cell or trigger a
burst of action potentials, while high frequency sensory
inputs are unable to trigger repetitive bursting because of
both synaptic depression and the properties of the currents
involved in generating low-threshold calcium spikes.
3. Corticothalamic pathway
The thalamus receives a massive input from the neocortex
via corticothalamic fibers. The number of corticothalamic
fibers is one order of magnitude larger than the number of
thalamocortical axons, and cortical afferents to the thalamus
largely outnumber the primary sensory input from peripheral
receptors (Guillery, 1969; Sherman and Guillery, 1996;
Steriade et al., 1997). Considering the massiveness of the
corticothalamic pathway it must serve an important
function. However, detailing a clear role for corticothalamic
activity has been difficult. In fact, most studies have found
small effects on thalamic responsiveness when the neocortex
was inactivated (e.g., Baker and Malpeli, 1977). As
discussed later, this may be due to the frequency-dependent
properties of the corticothalamic pathway; this pathway is
expressed strongly only when high frequency activity flows
through it. Some processes believed to be mediated by
corticothalamic activity are: (1) corticothalamic activity
could serve as a modulatory system that serves to change the
firing rate, mode, and excitability of thalamic neurons. For
instance, glutamate released by corticothalamic fibers may
serve to shift the firing between burst and tonic modes of
firing by affecting the membrane potential of thalamic
neurons (Sherman, 1996; McCormick and von Krosigk,
1992). It is also possible that corticothalamic activity
regulates the firing of thalamocortical cells by activating the
nRt, resulting in a tonic inhibition of TC cells via
feedforward inhibition; (2) corticothalamic activity may
specifically affect the spatial and temporal properties of
thalamocortical receptive fields (e.g. Murphy et al., 1999;
Singer, 1977; Diamond et al., 1992a; Yuan et al., 1985;
Krupa et al., 1999). For instance, there is evidence that
corticothalamic activity serves to spatially focus thalamocortical receptive fields, presumably by enhancing the
inhibitory surround through activation of the nRt and/or by
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enhancing the excitatory center (Murphy and Sillito, 1987;
Temereanca and Simons, 2004; Ergenzinger et al., 1998).
There is also evidence that the gain and timing of thalamic
sensory responses may be affected by corticothalamic
activity (reviewed in Sherman and Koch, 1986; Singer,
1977). In the somatosensory system, thalamocortical cells
follow more effectively repetitive stimulation in the
presence of corticothalamic activity (Yuan et al., 1985).
In the visual system, corticothalamic activity may also serve
to synchronize thalamocortical cells in the LGN as cells
respond to single elongated stimuli (Sillito et al., 1994).
There is no doubt that further work is required to clarify the
functional role of corticothalamic activity.
3.1. Morphology of corticothalamic synapses
Corticothalamic pathways arise from pyramidal cells in
layers V and VI of neocortex (Fig. 1). Corticothalamic fibers
originating from layer V consist of fiber collaterals from
long range axons projecting to the brainstem and/or spinal
cord. These collaterals do not contact the nRt or VPM.
Instead they project to intralaminar and higher order
associational nuclei, such as POm in the vibrissa system,
where they form small clusters of large terminals
(Deschenes et al., 1998; Sherman and Guillery, 1996).
The large terminals innervate proximal dendrites of thalamic
neurons and form complex synaptic glomeruli that are
similar to those formed by primary sensory (lemniscal)
synapses (Jones and Powell, 1969; Li et al., 2003b). In
contrast, the corticothalamic fibers originating from layer VI
leave a fiber collateral in the nRt on their way into VPM (i.e.,
primary sensory nuclei) where they produce small terminals
that innervate the distal dendrites of thalamic neurons
(Robson, 1983; Li et al., 2003b; Bourassa et al., 1995; Zhang
and Deschenes, 1997; Erisir et al., 1997b; Jones and Powell,
1969). The small terminals formed by layer VI corticothalamic fibers have a small postsynaptic density that is
consistent with the presence of a single release site. On nRt
cells, these synapses are formed in more or less equal
numbers over proximal and distal dendrites, while on
thalamocortical cells they occur preferentially at distal
dendrites (Jones, 2002). On nRt cells, as many as 70% of all
the synapses are corticothalamic, while the remaining 30%
are about equally distributed between GABAergic synapses
and synaptic collaterals of thalamocortical cells; synapses
from the brainstem and basal forebrain form a very small
number of contacts (Liu and Jones, 1999). In primary
thalamic nuclei, approximately 44% of the synapses are
corticothalamic, while about 16% originate from primary
sensory afferents and the rest correspond primarily to
inhibitory synapses from the nRt plus a portion of
neuromodulatory afferents from the brainstem (Liu et al.,
1995a; Erisir et al., 1997b).
It has been estimated that about half of the pyramidal
cells in layer VI project to the thalamus (Eyding et al., 2003),
and there seems to exist two distinct populations of
corticothalamic cells within layer VI. In the barrel cortex,
cells in the upper part of layer VI of a barrel column project
exclusively to VPM where they form rod-like terminal fields
in a thalamic barreloid. Thalamocortical cells in VPM and
upper layer VI cells in a barrel form closed-loops for the flow
of information between a thalamic barreloid and a cortical
barrel column (Bourassa et al., 1995). In contrast, the
corticothalamic cells located in deep layer VI exclusively
innervate large sectors of secondary thalamic nuclei and
intralaminar thalamic territories such as POm in the vibrissa
system (Deschenes et al., 1998). A similar segregation
between upper and lower layer VI cells has been found in the
visual cortex of monkeys; upper layer VI cells project to the
parvocellular LGN layers, while lower layer VI cells project
to the magnocellular LGN layers (Lund et al., 1975).
Recent work has also found differences between the
corticothalamic projections depending on the type of sensory
cortex from where the corticothalamic fibers originate (Fig.
1), so that granular and dysgranular fields project differentially to the thalamus (Killackey and Sherman, 2003). The
major difference is that the dysgranular zones of the barrel
cortex (e.g. the area between the barrel columns) project from
upper layer VI to the secondary thalamic nucleus (i.e. POm),
while the granular zone (barrel area) does not, projecting only
to the primary thalamic nucleus (i.e. VPM). This indicates
that for the primary sensory thalamus recurrent loops with the
neocortex only occur in the granular (barrel) zones of the
sensory cortex within the upper part of layer VI. While for the
secondary thalamic nuclei (POm), recurrent loops (not
necessarily monosynaptic) with the dysgranular (non-barrel)
zones of the sensory cortex involve pathways from all three
thalamic projecting layers (i.e. layer V, upper layer VI and
lower layer VI). Thus, the primary sensory thalamocortical
network would consist of a barrel column and its
corresponding barreloid in VPM, while a secondary sensory
or higher order thalamocortical network would involve a nonbarrel area or septa and POm (Killackey and Sherman, 2003).
In addition to these recurrent closed loop circuits, corticothalamic fibers form open loop connections that could serve
to link different cortical and thalamic areas. For example,
layer V and lower VI cells of barrel columns project to POm
(but not to VPM), providing a potential mechanism for
cortico-cortical communication (Guillery, 1995; Killackey
and Sherman, 2003). By means of these pathways,
information from a cortical area could arrive at a different
cortical area via the thalamus.
Since the main types of corticothalamic connections
originate from distinct cell types in neocortex and project in
a different pattern, it is quite feasible that the type of
information they carry, and thus their functional roles, are
quite distinct. It has been proposed that layer V corticothalamic fibers provide the primary driving input to cells in the
secondary (higher order) thalamic nuclei (Sherman and
Guillery, 1996), much like the primary sensory afferents do
in the primary thalamic nuclei. The function of this powerful
input originating in layer V would be to provide a way for
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229
cortico-cortical communication via the thalamus (Guillery,
1995). Here we will focus on the properties of the
corticothalamic fibers that originate from layer VI and
innervate the primary thalamic nuclei, such as VPM.
Reference will also be made to the layer V corticothalamic
pathways when appropriate for comparison purposes. In the
following sections, unless otherwise indicated, corticothalamic refers to neurons originating in layer VI, particularly
in its upper part.
3.2. Electrophysiology of corticothalamic synapses
The largest group of excitatory synapses received by a
thalamocortical neuron are corticothalamic synapses originating from layer VI cells (Erisir et al., 1997b, 1998; Liu et
al., 1995a). However, these synapses occur at the distal
portions of thalamic cells and structurally are relatively
small, which usually corresponds to synapses that have a low
release probability and a single release site. Thus, it is
possible that despite the massiveness of the corticothalamic
pathway it may have little impact on thalamocortical cells
because the small excitatory responses they generate are
filtered by the dendritic cable and shunted by the
feedforward inhibition produced by nRt fibers.
Corticothalamic synapses activate both NMDA and nonNMDA receptors (Turner and Salt, 1998; Scharfman et al.,
1990; Kao and Coulter, 1997). In addition, glutamate
released by these synapses may activate metabotropic
glutamate receptors (Turner and Salt, 1999). At many
synapses, usually those with a low release probability, when
two action potentials depolarize a presynaptic terminal in
rapid succession the second action potential releases more
neurotransmitter than the first (Zucker, 1989). This shortterm enhancement of release that persists for tens to
hundreds of milliseconds following a conditioning pulse is
known as facilitation. Facilitation has long been believed to
reflect a transient increase in the probability of neurotransmitter release and several studies have provided
evidence that this is the case (Stevens and Wang, 1995;
Debanne et al., 1996). It is thought that residual presynaptic
Ca2+ contributes to the increased probability of release that
is responsible for the observed facilitation (Katz and Miledi,
1968; Zucker, 1989; Kamiya and Zucker, 1994). Several
studies have shown that corticothalamic pathways display
some form of facilitation in vivo (Lindstrom and Wrobel,
1990; Tsumoto et al., 1978; Hu, 1993; Scharfman et al.,
1990). Recently, it was realized that isolated corticothalamic
EPSPs display strong synaptic facilitation (von Krosigk et
al., 1999; Turner and Salt, 1998; Castro-Alamancos and
Calcagnotto, 1999) that contrasts with the synaptic
depression produced by primary sensory synapses (e.g.
lemniscal) onto the same thalamocortical neurons (Turner
and Salt, 1998; Castro-Alamancos, 2002b) (Fig. 10A).
Stimulation of corticothalamic fibers produces a small
amplitude and slow rising EPSP that can be graded in
amplitude with increases in stimulation current reflecting the
Fig. 10. Facilitation of corticothalamic EPSPs in vivo and in vitro. (A)
Corticothalamic EPSPs evoked by stimulating corticothalamic fibers in a
slice preparation show synaptic facilitation. For comparison, EPSPs evoked
by a pair of stimuli at 20 Hz in the corticothalamic pathway are overlaid
with the EPSPs evoked by a pair of stimuli in the lemniscal pathway. (B)
Extracellular field potential recordings in VPM evoked by thalamic radiation stimulation display strong facilitation, especially at frequencies above
5 Hz. Based on Castro-Alamancos and Calcagnotto (2001).
recruitment of fibers and release sites. The slow rise time of
the EPSPs is likely a consequence of the low pass filtering
exerted by the dendrites on corticothalamic EPSPs, and the
small amplitude of the events may be related to the
possibility that corticothalamic synapses have a low release
probability (Granseth and Lindstrom, 2003). Thus, despite
the large number of synapses formed on thalamocortical
cells by corticothalamic fibers, the amplitude of corticothalamic EPSPs is relatively small during low frequency
corticothalamic activity because corticothalamic synapses
have a low release probability and occur at distal portions of
the dendritic tree (Fig. 10). However, during high frequency
corticothalamic activity (>5 Hz) the probability of release at
these synapses sharply increases due to synaptic facilitation
producing large amplitude EPSPs that can be as powerful or
more than those produced by primary sensory afferents
(Turner and Salt, 1998; Castro-Alamancos, 2002b).
Interestingly, not all corticothalamic EPSPs are created
equal. Corticothalamic EPSPs produced on nRt cells differ
from those produced on thalamocortical cells (Golshani et
al., 2001; Gentet and Ulrich, 2004). Corticothalamic EPSPs
produced by fiber collaterals on nRt neurons are fast-rising
and activate both NMDA and AMPA receptors (Warren and
Jones, 1997). The amplitude of EPSPs evoked in nRt
neurons by stimulating single corticothalamic fibers are
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several times larger than those evoked in thalamocortical
neurons, and the number of GluR4-receptor subunits at these
synapses may provide a basis for the differential synaptic
strength. At a functional level, the strong corticothalamic input
to nRt neurons is believed to underlie the strong capacity for
corticothalamic activity to drive feedforward inhibition in the
thalamus (Zhang and Jones, 2004). In addition, corticothalamic EPSPs produced by layer V axons on thalamocortical
neurons of secondary thalamic nuclei differ from those
produced by layer VI axons. Recent work in the visual system
has shown that layer V corticothalamic EPSPs have properties
that differ from those of layer VI corticothalamic EPSPs; layer
V corticothalamic EPSPs resemble those produced by primary
sensory afferents (Li et al., 2003a).
Although the basal efficacy of corticothalamic synapses
is relatively weak, synapses have mechanisms to change
their efficacy for long periods of time by processes such as
long-term potentiation (LTP) and long-term depression
(LTD). Corticothalamic synapses display a robust form of
LTP when stimulated repetitively at relatively high
frequencies (10 Hz and above), while LTD is also induced
when repetitive stimulation occurs at low frequencies
(1 Hz), thereby providing mechanisms for bidirectional
changes in synaptic efficacy (Castro-Alamancos and
Calcagnotto, 1999). This resilience contrasts with the
rigidity of primary sensory synapses (e.g. lemniscal), which
do not seem to be amenable to activity-dependent long-term
changes in efficacy (unpublished observations). Corticothalamic LTP is input specific and seems to be induced and
expressed presynaptically via a protein kinase A second
messenger pathway (Castro-Alamancos and Calcagnotto,
1999). Thus, corticothalamic synapses possess mechanisms
to modify the effectiveness with which the neocortex can
influence the thalamus. Possibly, this could serve as a
mnemonic mechanism for regulating thalamic activity and
responsiveness as a function of experience.
3.3. Effects of neuromodulators on corticothalamic
synapses
In addition to activity-dependent changes, corticothalamic
synapses may be subject to neuromodulator-dependent
changes by the actions of several neuromodulatory systems.
In fact, neuromodulatory synapses from the brainstem and
corticothalamic synapses may provide the two most numerous
synaptic inputs to the thalamus (Erisir et al., 1997), and it is
possible that they modulate each other. Recent work has tested
the effects of two neuromodulators, acetylcholine and
norepinephrine, on corticothalamic responses. Results from
rodent slices in vitro showed that acetylcholine and
norepinephrine depress the efficacy of corticothalamic
synapses while enhancing their frequency-dependent facilitation (Castro-Alamancos and Calcagnotto, 2001). This
produces a stronger depression of low frequency responses
than of high frequency responses. The effects of acetylcholine
and norepinephrine are mimicked by muscarinic and a2-
adrenergic receptor agonists and blocked by muscarinic and aadrenergic antagonists, respectively. Thus, acetylcholine
acting on muscarinic receptors and norepinephrine acting
on a2-adrenergic receptors depress corticothalamic synapses.
This contrasts with the lack of effects of these same
neuromodulators at primary sensory afferents (lemniscal
synapses) (Castro-Alamancos, 2002b). It has also been shown
that group III metabotropic glutamate receptors depress
corticothalamic synapses (Turner and Salt, 1999). In addition,
glutamate released by corticothalamic fibers may activate
metabotropic glutamate receptors and lead to the depolarization of thalamocortical neurons via cellular mechanisms
similar to those activated by other neuromodulator systems
(McCormick and von Krosigk, 1992).
3.4. Corticothalamic responses during information
processing states
The firing properties of corticothalamic neurons have
been extensively studied in awake rabbits (Swadlow, 1989,
1990, 1991, 1994; Swadlow and Weyand, 1987). In general,
many of these neurons are described as virtually unresponsive to sensory stimuli and display very little spontaneous
activity. Moreover, corticothalamic cells may be sensitive to
changes in arousal (Livingstone and Hubel, 1981; Swadlow
and Weyand, 1987), and corticothalamic responses evoked
by sensory stimuli are clearly observed in the thalamus in
lightly anesthetized animals (Temereanca and Simons, 2004).
Changes in corticothalamic activity during information
processing states would affect thalamic processes that
corticothalamic connections mediate such as thalamic
neuromodulation exerted by corticothalamic fibers, and the
spatial and temporal properties of thalamic receptive fields.
Thus, understanding the firing properties of corticothalamic
cells during activated states is an essential step to comprehend
the functional role of corticothalamic pathways.
A few technical details about corticothalamic stimulation
are worth mentioning. First, electrical stimulation of the
cortex or thalamic radiation can stimulate intracortical
circuits that can feed their activity back to the thalamus. This
effect can be eliminated by inactivating the cortex with
muscimol or TTX and stimulating in the radiation. Second,
electrical stimulation of the thalamic radiation or of the
neocortex will inevitably lead to the antidromic discharge of
some thalamocortical cells. Generally, it is quite feasible to
record thalamocortical cells that are only orthodromically
driven by corticothalamic stimulation, and not antidromically. This does not mean that other thalamocortical cells are
not being antidromically stimulated, they surely are. One
main consequence of this effect is that those cells could
activate the nRt via their recurrent collaterals and produce
recurrent inhibition in the thalamus. However, this effect is
basically also produced by orthodromic stimulation of
corticothalamic synapses in nRt. Third, stimulation of cortex
and thalamic radiation leads to an additional potential
confound in vivo. This stimulation can discharge cortico-
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231
bulbar cells that would stimulate brainstem nuclei (e.g.
principal trigeminal nuclei) that feed back to the thalamus.
This problem can be eliminated by inactivating the
brainstem nucleus, and it is not a concern in corticothalamic
slices.
3.4.1. Temporal response properties
An interesting proposal is that corticothalamic activity is
merely a modulator of thalamocortical activity (Sherman
and Guillery, 1998). This would agree with the small
amplitude EPSPs produced by corticothalamic synapses,
and thus primary sensory inputs would be the main drivers of
thalamocortical activity. This seems to be the case during
low frequency corticothalamic activity, but not during
high frequency (>5 Hz) corticothalamic activity (see Fig.
11). Indeed, low frequency stimulation of corticothalamic
fibers rarely drives VPM cells in vivo (Fig. 11B) or in slices
(Fig. 11A). In contrast, during stimulation at frequencies
above 5 Hz corticothalamic activity is a very effective driver
of thalamocortical neurons. Thus, the corticothalamic
pathway is an activity dependent driver of thalamocortical
activity. When layer VI neurons fire at frequencies above
5 Hz they drive thalamocortical cells as effectively as
primary sensory (lemniscal) inputs. It is also noteworthy that
corticothalamic fibers on nRt neurons lead to strong
feedforward inhibition, and consequently corticothalamic
activity produces profound inhibitory effects on thalamocortical cells, especially during quiescent states.
Indeed, inhibition may be the predominant effect of
corticothalamic activity in the thalamus during low
frequency corticothalamic activity and during quiescent
(non-activated) states. However, during high frequency
corticothalamic activity, inhibition will tend to depress while
excitation will enhance due to facilitation and there will be a
net excitatory effect at thalamocortical neurons. Moreover,
as described in the previous section, during activated states
the large amplitude and long-lasting IPSPs characteristic of
quiescent states will be reduced.
During activation caused by BRF stimulation, corticothalamic responses are depressed, and this result is
consistent with the effects of neuromodulators on corticothalamic synapses in slices (Castro-Alamancos and
Calcagnotto, 2001). The suppression of corticothalamic
responses by neuromodulators or activation is strong for low
frequency corticothalamic activity, which does not produce
synaptic facilitation, but mostly absent for high frequency
corticothalamic activity, which triggers facilitation. The net
effect is the high-pass filtering of corticothalamic activity
during arousal. These effects of arousal seem to be mediated
by the activation of muscarinic and a-adrenergic receptors
because application of muscarinic and a-adrenergic
antagonists into the thalamus in vivo abolish the suppression
of corticothalamic responses induced by BRF stimulation
(Castro-Alamancos and Calcagnotto, 2001). Thus, cholinergic and noradrenergic activation during arousal serves to
high-pass filter corticothalamic activity. When these
Fig. 11. High-frequency corticothalamic activity effectively drives VPM
cells. (A) Effects of pairs of pulses delivered at different intervals in a slice
preparation in vitro. Note the discharge of the cell at intervals below 200 ms.
The membrane potential of the cell is in the bursting mode, but the same
behavior is observed in the tonic mode, only that a single action potential is
produced (not shown). (B) Single-unit recording of a VPM cell in a urethane
anesthetized rat during stimulation of the thalamic radiation at 1 Hz and
20 Hz. Notice that at 1 Hz the cell discharges unreliably, but very effectively
at 20 Hz.
neuromodulators are released in the thalamus the flow of
low-frequency activity from the neocortex is suppressed,
while high frequency activity is allowed. This suggests that
during activated states the corticothalamic pathway becomes
a more selective activity-dependent driver of thalamic
neurons; only activity at frequencies above 5 Hz will be
allowed to reach thalamic cells.
3.4.2. Functional relevance during behavior
The results discussed above indicate that during arousal
only high frequency inputs from the neocortex are allowed to
reach the thalamus. The thalamocortical network undergoes
dramatic functional changes between sleep and arousal
(Steriade et al., 1997). For example, during slow wave sleep
the neocortex and thalamus are engaged in low frequency
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oscillations, while during arousal they engage in highfrequency gamma oscillations (Steriade et al., 1993). Gamma
oscillations at 20–40 Hz coincide with the frequencies that are
effective in triggering short-term synaptic facilitation in
corticothalamic synapses. Interestingly, BRF stimulation
enhances both gamma oscillations (Steriade et al., 1991;
Steriade and Amzica, 1996) and corticothalamic facilitation
(Castro-Alamancos and Calcagnotto, 2001). Thus, an
important role for this corticothalamic high-pass filter during
arousal may be to permit the flow of gamma oscillations
between neocortex and thalamus, while impeding low
frequency oscillations. It would serve as a gate that allows
the flow of low frequency and gamma activity during sleep,
while allowing only gamma activity during arousal.
4. Thalamocortical pathway
There are several types of thalamocortical pathways,
which are differentially sensitive to activity and arousal
(for reviews of their morphology and physiology see
(Castro-Alamancos, 1997; Castro-Alamancos and Connors,
1997b). A particularly useful classification of the thalamic
nuclei relies on the type of information relayed to the
neocortex. This classification distinguishes between thalamocortical pathways that convey information of multiple
modalities or relatively non-specific information about
modulatory or state-dependent processes and thalamocortical pathways that convey specific information about a
particular modality. Nuclei that convey specific information
can be classified further as primary and secondary
depending on the information transmitted. Although both
might transmit information of a particular modality, the
activity from the primary nucleus would reflect more
precisely the stimulus presented at the peripheral receptors,
while the activity in the secondary nucleus would be the
result of more elaborate higher order processing. A good
example of a primary specific nucleus in the somatosensory
system is VPM, while the corresponding secondary or
higher order nucleus is POm. Both of these thalamocortical
pathways provide sensory information about the vibrissae,
but the quality of this information is quite different. For
instance, the activity of POm neurons is much more
processed and strongly dependent upon corticothalamic
influences (Diamond et al., 1992a), while the activity of
VPM neurons reflects more faithfully the sensory input. In
the following sections, the focus is on the properties of
primary thalamocortical pathways, and in particular the
pathway originating in VPM.
4.1. Electrophysiology of thalamocortical synapses
An important question relates to the response properties
of thalamocortical synapses formed by VPM neurons in
neocortex. Specifically, the question is: what is the
excitatory response produced by thalamocortical synapses,
in the absence of recurrent cortical excitation or inhibition
and thalamic feedback? It is important to recognize upfront
that such isolation is difficult to accomplish because of
several major caveats. The most notable problem is that it is
difficult to block recurrent cortical excitation without also
affecting thalamocortical excitation. A second major
problem is that complete block of inhibition in the neocortex
produces seizures making it complicated to interpret cortical
responses under those circumstances. A third problem in the
thalamocortical system that is mainly encountered when
using extracellular electrical stimulation to drive thalamocortical fibers is that such stimulation almost inevitably
leads to stimulation of corticothalamic fibers, which
produces two unwanted consequences: (1) corticothalamic
activity can synaptically drive thalamocortical cells (see Fig.
11), and consequently this activity will be fed back to the
cortex. Fortunately, this unwanted consequence of electrical
stimulation can be surmounted by inactivating the thalamus
and stimulating thalamocortical fibers in the thalamic
radiation (Castro-Alamancos and Oldford, 2002); (2) the
second unwanted consequence of electrical stimulation is
recurrent cortical excitation and inhibition mediated by the
intracortical axon collaterals of corticothalamic cells. There
are several potential ways to bypass this major problem such
as using intracellular stimulation of thalamocortical cells or
fibers, using sensory stimulation instead of electrical
stimulation to drive thalamocortical cells or using chemical
instead of electrical stimulation of thalamocortical cells.
Each of these alternatives presents their own challenges. It is
also noteworthy that because thalamocortical fibers leave
collaterals in the nRt as they ascend to the neocortex,
thalamocortical activity will lead to recurrent inhibition of
thalamocortical cells which may affect subsequent thalamocortical activity or produce rebound excitation of
thalamocortical cells. These intrathalamic recurrent effects
can be eliminated by inactivating the thalamus. With this in
mind we consider the data about the response properties of
thalamocortical synapses.
A major contributor to the study of thalamocortical
synapses has been the development of a thalamocortical
slice preparation (Agmon and Connors, 1991). Using this
preparation, it has been possible to record cortical responses
evoked by thalamic electrical stimulation. An interesting
property of these responses is that they show frequencydependent depression (Castro-Alamancos, 1997; Gil et al.,
1997) similar to what is observed in the previous and
subsequent synapses in this ascending axis; i.e., both
primary sensory (lemniscal) synapses of the thalamus
(Castro-Alamancos, 2002b) and layer IV-to-layer III
synapses in the cortex (Castro-Alamancos and Connors,
1997a) show frequency-dependent depression. A further
characterization of thalamocortical responses evoked by
minimal electrical stimulation has revealed that quantal
events from thalamocortical and intracortical fibers onto
layer IV cells were indistinguishable (Gil et al., 1999).
However, thalamocortical fibers have about three times more
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release sites than intracortical axons, and the mean release
probability at thalamocortical synapses was about 1.5 times
higher than that at intracortical synapses. These differences
in innervation ratio and release probability make the average
thalamocortical connection several times more effective
than the average intracortical connection, and may allow
small numbers of thalamocortical axons to dominate the
activity of cortical layer IV cells during sensory inflow. It has
also been found that thalamocortical synapses excite a
population of inhibitory interneurons called fast-spiking
cells, and the response evoked on these cells is also stronger
than that observed on excitatory cells of layer IV (Gibson et
al., 1999).
Consequently, in addition to exciting the neocortex and
depressing in response to activity, an important property of
thalamocortical synapses is that they recruit strong
feedforward inhibition mediated by fast-spiking interneurons, a property also observed in vivo (see Section 4.4).
In addition to short-term changes in efficacy caused by
activity, thalamocortical synapses may be able to undergo
long-term changes in efficacy, such as LTP and LTD. Indeed,
thalamocortical synapses can produce LTP in slices, but only
up to postnatal day 9 (Crair and Malenka, 1995). This time
seems to coincide with the critical period for development
alterations in the barrel cortex caused by sensory perturbations, and also with the time when silent synapses (i.e.,
synapses devoid of AMP A receptors, but containing
NMDA receptors (Liao et al., 1995; Isaac et al., 1995))
disappear from thalamocortical connections (Isaac et al.,
1997). However, high-frequency thalamocortical stimulation in adult rodents in vivo seemingly causes LTP of
thalamocortical evoked responses (Heynen and Bear, 2001)
(see also Fig. 12 in Castro-Alamancos and Connors, 1997b).
Further work is needed to reconcile these in vitro and in vivo
results.
4.2. Effects of neuromodulators on thalamocortical
synapses
It appears that the most likely consequence of acetylcholine release in neocortex during behavior is the selective
enhancement of the sensory thalamocortical pathway
through activation of nicotinic receptors. This is based on
the effects of cholinergic receptor agonists and antagonists
in slices and in vivo. Thus, application of neuromodulators
to thalamocortical slices has revealed that thalamocortical
responses are depressed by activating muscarinic receptors,
but not by activating GABAB receptors. In contrast,
intracortical responses evoked on the same neurons by
cortical stimulation are depressed by activating either
muscarinic or GABAB receptors. In addition, activation of
nicotinic receptors selectively enhances thalamocortical but
not intracortical responses (Gil et al., 1997; Hsieh et al.,
2000). Similarly, in vivo, application of cholinergic receptor
agonists in neocortex differentially affects sensory and
intracortical responses (Oldford and Castro-Alamancos,
233
2003). In fact, increasing endogenous acetylcholine by
cortical application of an acetylcholinesterase inhibitor
selectively enhances the sensory evoked response in
neocortex, while leaving the intracortical response
unchanged and this effect is mimicked by nicotine (Oldford
and Castro-Alamancos, 2003). These results suggest that the
main effect of acetylcholine in the neocortex during
behavior may be a selective enhancement of the sensory
thalamocortical pathway relative to intracortical pathways.
Neuromodulators can affect a neural network by both
presynaptic and postsynaptic actions, and dissociating these
actions is not a simple feat. The site of action of
acetylcholine on thalamocortical pathways has not yet been
established, but it is noteworthy that at least some of its
actions are input specific. That is, they selectively modify
one pathway but not a second pathway innervating a cell
population. This is the case for the cholinergic effects
mediated by nicotinic receptors (Oldford and CastroAlamancos, 2003; Gil et al., 1999; Gioanni et al., 1999),
which suggests a presynaptic action of acetylcholine at
nicotinic receptors localized on thalamocortical fibers (Bina
et al., 1995; Sahin et al., 1992; Lavine et al., 1997) or a
selective localization of nicotinic receptors at postsynaptic
cortical targets innervated by thalamocortical synapses
(Clarke et al., 1985). The preferential distribution of
nicotinic receptors in the vicinity of synapses relaying
sensory information (i.e. thalamocortical) would modulate
thalamic inputs in neocortex while not affecting others.
The importance of selectively modulating the thalamocortical pathway is noticeable when considering that the
majority of synapses in thalamocortical recipient layers of
the neocortex (e.g. layer IV) originate from cortical
neurons. In particular, only a minority of synapses on layer
IV thalamocortical-recipient cells are thalamic in origin
(i.e., approximately 5–10%), whereas the remaining
are intracortical in origin (Peters and Payne, 1993; Ahmed
et al., 1994; White, 1989). Note that other work has
suggested significantly higher numbers of thalamocortical
synapses (i.e., approximately 25%), but these are still
fewer than intracortical synapses (LeVay and Gilbert, 1976).
This suggests that under normal conditions, intracortical
pathways could dominate cortical processing because of
their larger numbers. Therefore, acetylcholine release
during various behaviors may serve to facilitate the
numerically inferior thalamocortical pathway in order to
maximize transfer of information from the periphery to the
cortex.
The effects of other neuromodulators on thalamocortical
pathways have also been investigated. For example, it has
been shown that norepinephrine can depress sensory evoked
responses in neocortex (Foote et al., 1975; Waterhouse et al.,
1980), but whether such an effect is specific for
thalamocortical pathways is unclear. Serotonin receptors
are expressed transiently at thalamocortical synapses, and
accordingly, thalamocortical neurotransmission is depressed
by serotonin during development (Rhoades et al., 1994).
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4.3. Thalamocortical responses during information
processing states
Stimulation of different thalamic nuclei leads to different
cortical responses. In rodents, low frequency (<0.3 Hz)
stimulation of VPM produces a large field potential response
in neocortex that is almost indistinguishable from the
response produced by a sensory stimulus (i.e. whisker
deflection) (Castro-Alamancos and Oldford, 2002; CastroAlamancos, 1997; Castro-Alamancos and Connors, 1997b).
This large amplitude response is also observed in other
species (e.g. cat), and was termed the primary response by
the pioneering studies of thalamocortical pathway excitability (Dempsey and Morison, 1942a). The pattern of
cortical activity produced by the primary response can be
best observed by performing current source density analysis
(CSD) in neocortex (Castro-Alamancos and Connors, 1996;
Castro-Alamancos and Oldford, 2002; Mitzdorf and Singer,
1978; Di et al., 1990). The primary response consists of short
latency inward current flow (current sinks) in the
thalamocortical recipient layers of neocortex, in layers IV
and upper layer VI. The initial short-latency current flow in
layer IV very effectively spreads into the upper layers
because layer IV cells are strongly synaptically coupled with
layer III cells (Silver et al., 2003). Thus, the primary
response consists of the current flow produced in neocortex
by thalamocortical synapses plus all the intracortical current
flow triggered by the thalamocortical input recipient cells.
As mentioned above (see Section 4.1) electrical
stimulation of the thalamus or thalamic radiation produces
several effects in addition to activation of thalamocortical
synapses, which make it difficult to interpret data obtained
after electrical stimulation of the thalamus or thalamic
radiation. The two most noticeable unwanted effects are the
stimulation of corticothalamic fibers and their intracortical
collaterals, and the stimulation of recurrent collaterals of
thalamocortical fibers in the nRt. Stimulation of thalamocortical recurrent collaterals in the nRt robustly excites nRt
neurons (Gentet and Ulrich, 2003) leading to recurrent
inhibition and possibly rebound excitation of thalamocortical cells, which would be relayed to the cortex. Note that
this effect would also occur during sensory stimulation.
More importantly, corticothalamic fibers are also stimulated
by electrodes placed within the thalamus or thalamic
radiation. This will lead to direct excitation of nRt and
thalamocortical cells by corticothalamic synapses, plus the
excitation of cells in neocortex that are targeted by the
intracortical collaterals of corticothalamic cells. Fortunately,
the effects produced by direct excitation of nRt and
thalamocortical cells caused by the electrical stimulation
of thalamocortical and corticothalamic fibers can be
eliminated by inactivating the thalamus. Fig. 12 shows
the effect of stimulating the thalamic radiation during
control conditions and during thalamic inactivation with
TTX (Castro-Alamancos and Oldford, 2002). When the
thalamus is intact a single stimulus at low frequency
Fig. 12. Properties of primary thalamocortical responses and incremental
responses in barrel cortex in vivo. The upper three traces correspond to
extracellular recording from layers IV–III of the barrel cortex, and show
the primary responses evoked by a single stimulus in the thalamic
radiation or by four stimuli delivered at 10 Hz, when VPM is intact
or when it was inactivated with TTX. Notice the spindle oscillation (*)
that is triggered by the first stimulus, and the facilitating (incremental)
response that appears in the neocortex during stimuli at 10 Hz when VPM is
intact (control). However, after application of TTX in VPM the primary
response is enhanced, but the facilitating response is abolished. The
incremental response is caused by corticothalamic activity evoked by the
thalamic radiation stimulation that triggers synaptic facilitation in VPM (see
Fig. 10B) and this activity is relayed to neocortex. The lower traces are
close-ups of the traces shown above. Based on Castro-Alamancos and
Oldford (2002).
produces a primary response that is followed by a rebound
oscillation at 10 Hz (asterisks in Fig. 12). This rebound
oscillation is completely abolished by thalamic inactivation
with TTX, and reflects the stimulation of nRt cells by the
axon collaterals of VPM cells, which triggers a thalamic
spindle oscillation. The other usual effect of thalamic
inactivation with TTX is the enhancement of the primary
thalamocortical response evoked by low frequency stimulation. This occurs because of the abolishment of spontaneous
thalamocortical activity which normally tends to depress
thalamocortical synapses. As discussed below (see Section
M.A. Castro-Alamancos / Progress in Neurobiology 74 (2004) 213–247
4.3.1), additional effects are observed during high frequency
thalamic radiation stimulation.
After the thalamus is inactivated with TTX, there is really
only one confound in the primary response evoked by
thalamic radiation stimulation: the intracortical fiber
collaterals of corticothalamic cells (for Discussion see
Castro-Alamancos and Oldford, 2002). Thus, an important
question relates to the relative contribution of these synapses
to the primary response, as compared to thalamocortical
synapses. There are several arguments that suggest that
during low frequency stimulation, the contribution of the
collaterals of corticothalamic cells is quite small (i.e., <5%
of total current flow). First, the neocortical primary response
produced by low frequency sensory stimulation and by
electrical stimulation of the thalamic radiation when the
thalamus is inactivated is almost indistinguishable. This
suggests that these two methods pretty much produce the
same effect in neocortex; namely, the stimulation of
thalamocortical synapses. Second, although intracortical
fiber collaterals of corticothalamic cells may be stimulated,
they will contribute minimally to the primary response
during low frequency stimulation because these collaterals,
like corticothalamic synapses, have a very low release
probability while displaying strong facilitation at high
frequencies (Stratford et al., 1996). Indeed, even when the
responses of these synaptic collaterals are maximized by
high frequency stimulation their contribution to the cortical
response is relatively small when compared to the primary
response (Castro-Alamancos and Oldford, 2002). This is
because both thalamocortical (Gil et al., 1999) and layer IVto-layer III synapses (Silver et al., 2003; Castro-Alamancos
and Connors, 1997a) have a very high release probability
which contributes to the large amplitude of the primary
response. For example, if the release probability of
thalamocortical synapses were 0.9 while the release
probability of the intracortical collaterals of corticothalamic
cells were 0.1, then an action potential arriving at these
synapses would produce (release) a postsynaptic EPSP at
90% of the thalamocortical synapses, but only at 10% of the
intracortical corticothalamic synapses. Without further
assumptions, this indicates that the cortical response evoked
by electrical stimulation will be at least 90% caused by
thalamocortical synapses. In conclusion, it is safe to say that
in sensory cortex the primary response produced by low
frequency electrical stimulation, when the thalamus is
inactivated, is mostly caused by thalamocortical synapses
and the intracortical network that these synapses engage.
Recent work has shown that the primary thalamocortical
response is strongly suppressed during natural arousal or
activation induced by BRF stimulation (Castro-Alamancos
and Oldford, 2002). BRF stimulation robustly suppresses
whisker-evoked responses in the neocortex, but not in the
thalamus. BRF stimulation also suppresses the cortical
response evoked by electrically stimulating thalamocortical
fibers. This same suppression of the thalamocortical
pathway is observed in freely behaving rats during natural
235
arousal. For instance, suppression occurs when animals
transition from slow-wave sleep to waking (CastroAlamancos and Oldford, 2002; Castro-Alamancos, 2004).
Current-source density analysis revealed that sensory
suppression in the neocortex caused by BRF stimulation
occurs at the thalamocortical recipient layers (layers IV and
VI); the earliest current sinks in those layers are suppressed.
Thus, sensory suppression during arousal occurs at the
thalamocortical connection.
But what causes the suppression of the thalamocortical
primary response during arousal? During natural arousal or
after BRF stimulation, thalamocortical neurons display
significantly enhanced spontaneous firing rates (see Fig. 2).
Synapses are sensitive to activity and, in particular,
thalamocortical synapses display robust depression when
stimulated at high rates (Castro-Alamancos, 1997; Gil et al.,
1997). These properties suggest that differences in the tonic
firing rates of thalamocortical neurons between quiescent
and aroused states could change the gain of thalamocortical
synapses and significantly impact the mode of sensory
transmission at the thalamocortical connection. The
prediction would be that during aroused states, the enhanced
activity of thalamocortical neurons results in the depression
of thalamocortical synapses. Thus, during aroused states,
sensory inputs traveling to the neocortex would encounter a
depressed thalamocortical synapse due to the activitydependent depression caused by enhanced activity of
thalamocortical neurons. This is supported by the fact that
blocking the thalamocortical activity by application of TTX
in VPM completely eliminates the suppression of the
thalamocortical pathway caused by BRF stimulation
(Castro-Alamancos and Oldford, 2002). Thus, thalamocortical sensory suppression is mainly a consequence of the
activity-dependent depression of thalamocortical synapses
caused by increased thalamocortical tonic firing during
arousal (Swadlow and Gusev, 2001; Castro-Alamancos and
Oldford, 2002). It is also noteworthy that increased
thalamocortical activity will lead to a strong recruitment
of intracortical inhibition due to the fact that thalamocortical
cells and some inhibitory interneurons (fast-spiking cells) in
neocortex are very effectively coupled (Bruno and Simons,
2002; Swadlow, 1995). Thus, enhanced tonic inhibition in
neocortex driven by enhanced thalamocortical activity may
also contribute substantially to sensory suppression of
primary responses during arousal.
4.3.1. Temporal response properties
Repetitive stimulation at high frequencies of different
thalamic nuclei leads to different effects in the cortex (for
reviews see (Castro-Alamancos and Connors, 1996, 1997b;
Castro-Alamancos, 1997). For example, stimulation of the
VL thalamus at 7–14 Hz produces augmenting responses in
the motor cortex. These augmenting responses evoked
primarily in motor cortex by VL stimulation are clearly
distinct from the responses evoked in sensory cortex by
stimulating VPM (Castro-Alamancos and Connors, 1996).
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As discussed above, low frequency stimulation of
thalamocortical fibers from VPM produces large amplitude
primary responses. When the thalamus is intact, the primary
response evoked by thalamic or thalamic radiation stimulation is usually followed by oscillatory activity at 10 Hz
(Fig. 12, asterisks). This oscillatory activity is a spindle
oscillation generated in the thalamus, and thus, is abolished
by inactivating the thalamus. Higher frequency stimulation
of thalamocortical fibers leads to different effects depending
on whether or not the thalamus is intact. When the thalamus
is inactivated with TTX, repetitive stimulation of the
thalamic radiation at frequencies above 0.3 Hz leads to the
activity-dependent depression of the primary thalamocortical response (see Fig. 12). When the thalamus is intact,
electrical stimulation of the thalamic radiation or thalamus
produces a primary response in neocortex which depresses at
frequencies above 0.3 Hz, but an additional slightly longer
latency response appears at stimulation frequencies above
2 Hz, which we call here incremental response (CastroAlamancos, 1997). As shown in Fig. 12, the cortical
incremental response is completely abolished by inactivating the thalamus with TTX (Castro-Alamancos and Oldford,
2002), and reflects the facilitation produced in thalamocortical cells by stimulating corticothalamic synapses at
frequencies above 2 Hz (Castro-Alamancos and Calcagnotto, 2001) (see also Section 3; Fig. 10). Thus, this
incremental response is generated in the thalamus by
corticothalamic facilitation and is fed back to the cortex via
thalamocortical fibers.
The primary response, but not the incremental response,
is evoked in neocortex by sensory (whisker) stimulation
(Chung et al., 2002; Castro-Alamancos, 2004; CastroAlamancos and Oldford, 2002). The activity-dependent
depression of the primary response leads to a well known
phenomenon in sensory physiology, called rapid sensory
adaptation, which basically means that sensory inputs
reaching the cortex are low-pass filtered. Sensory adaptation
has been described in virtually all sensory modalities
(Ohzawa et al., 1982; Nelson, 1991b; Wilson, 1998; Hellweg
et al., 1977). The functional role of sensory adaptation is
unclear, but it has been suggested to serve as a means to
enhance sensory coding and as a mechanism to affect
perception of subsequent stimuli (Adorjan et al., 1999;
Fairhall et al., 2001; Kohn and Whitsel, 2002). As discussed
above (see Section 2.4.1), during quiescent states, the
responses of thalamocortical cells to sensory inputs are also
low-pass filtered due to the activity dependent depression of
primary sensory (lemniscal) synapses (Castro-Alamancos,
2002a). Thus, during quiescent states the sensory adaptation
observed in the neocortex is a consequence of depression at
both lemniscal and thalamocortical pathways.
During activated states produced by BRF stimulation in
anesthetized animals or when animals are alert (i.e. actively
exploring the environment or actively expecting stimuli),
sensory evoked responses in the neocortex are suppressed
and rapid sensory adaptation is reduced (Fig. 13). In
Fig. 13. Reduction of sensory adaptation in anesthetized rats during
activation. (A) Field potential responses evoked by whisker deflections
and recorded in layers IV–III of urethane-anesthetized rats. Shown are the
first four responses in a whisker stimulus train evoked at 2 Hz and 5 Hz
during quiescent states (thin traces) and during activated states produced by
BRF stimulation (thick traces). (B) Spectrum analysis of whisker evoked
responses during control (open circles) and activated states (closed circles;
RF stimulation) in urethane anesthetized rats. The average response amplitude of the 10th response in a stimulus train (steady-state response) is
displayed as a percentage of the control response delivered at 0.1 Hz (n = 6
rats). The response was defined as the maximum amplitude of the whisker
evoked negative field potential response measured during a 10-ms time
window starting 6-ms after the whisker deflection (*p < 0.001). Based on
Castro-Alamancos (2004).
contrast, during quiescent states such as slow-wave sleep or
awake immobility, sensory evoked responses are strong in
neocortex and adaptation is present (Castro-Alamancos,
2004). Thus, during the processing of sensory inputs, the
thalamocortical pathway is already in an adapted state.
These properties change rapidly and dynamically to meet
information processing demands imposed by behavioral
contingencies. The potential functional role of these changes
is discussed below (see Section 4.3.3).
4.3.2. Spatial (receptive field) response properties
During anesthesia or quiescent states, sensory inputs
spread through large areas of neocortex giving rise to large
receptive fields and large sensory representations (Armstrong-James and Fox, 1987; Armstrong-James et al., 1991;
Chen-Bee and Frostig, 1996; Sheth et al., 1998; Moore and
Nelson, 1998; Brett-Green et al., 2001; Petersen and
Diamond, 2000; Ghazanfar et al., 2000). Hence, during
quiescent states, the neocortex favors the spread of activity.
In contrast, other studies find a great spatial contrast between
adjacent whiskers in the barrel cortex (Simons and Carvell,
1989; Goldreich et al., 1999) primarily mediated by locally
recurrent inhibition (Simons, 1995). The more restricted
M.A. Castro-Alamancos / Progress in Neurobiology 74 (2004) 213–247
receptive fields and barrel independence may be attributed to
different levels of brain activation (Armstrong-James and
George, 1988; Simons et al., 1992). Indeed, recent work has
shown that receptive fields and cortical representations
change size depending on the level of arousal (Fig. 14), so
Fig. 14. Focusing of sensory inputs in neocortex during arousal. (A)
Schematic representation of the location of the 16-channel silicon probe
placed at a 1358 angle in the barrel cortex to record field potential responses
through an extension of layer IV–III of the barrel neocortex. (B) Contourplot of the amplitude of the negative field potential recorded from 16-sites
(100-um intervals) along layer IV–III of the barrel cortex in response to
stimulation of a single whisker. Note the spread of activity under control
conditions and the suppression of spread and focusing of the representation
after BRF stimulation (RF stim). (C) Enhanced selectivity of a neuron in
layer IV–III of barrel cortex during activation. Effect of activation induced
by BRF stimulation on single-unit response to stimulation of the principal
whisker and of an adjacent whisker. Single-unit responses are displayed as
the probability of firing per 2-ms bins before (upper) and during (lower)
activation (RF stim). The whisker stimulus is delivered at time zero. Based
on Castro-Alamancos (2002c).
237
that they are more focused during aroused states (CastroAlamancos, 2002c). As shown in Fig. 14B, the area of
neocortex excited by a single whisker deflection is much
larger during quiescent states as compared to activated
states. This was determined by placing a 16-channel linear
array silicon probe in the horizontal plane within layer IV to
determine the extent of activity spread. Likewise, individual
cortical cells respond to more whiskers during quiescent
states than during activated states (Fig. 14C). The focusing
of thalamocortical receptive fields during arousal seems to
be a consequence of the factors that cause thalamocortical
sensory suppression. Namely, the activity-dependent depression of thalamocortical synapses and enhanced recurrent
inhibition during arousal. Locally recurrent inhibition has
been proposed as the means to achieve selectivity in the
neocortex (Simons, 1985; Miller et al., 2001; Pinto et al.,
2003). In fact, thalamocortical neurons produce a very
powerful connection with cortical inhibitory interneurons
(Swadlow, 1995), much more so than with excitatory
neurons of layer IV (Gibson et al., 1999). Although the
efficacy of thalamocortical connections with interneurons is
reduced during aroused states (Castro-Alamancos and
Oldford, 2002; Swadlow and Gusev, 2001), it should still
be effective in producing inhibitory potentials and reducing
the spread of activity. In fact, one of the main consequences
of BRF stimulation is a reduction of the spontaneous firing
rate of a large percentage of cortical neurons (CastroAlamancos and Oldford, 2002). This is consistent with the
hyperpolarization of cortical neurons via the activation of
GABAA receptors. One possibility is that the enhanced firing
rates of thalamocortical neurons during arousal increase the
firing of cortical inhibitory interneurons that are strongly
innervated by thalamocortical inputs (White and Rock,
1981). This would result in an enhanced tonic level of
recurrent inhibition in the neocortex during activated states.
Therefore, thalamocortical synaptic depression and
enhanced cortical inhibition during arousal, which are both
a direct consequence of enhanced thalamocortical firing,
result in the increased selectivity (focusing) of cortical
receptive fields and sensory representations. In conclusion,
increased thalamocortical tonic firing during activation
reduces the strength of the thalamocortical connection and
may increase tonic cortical inhibition. Under these conditions the response of cortical neurons to sensory inputs
becomes more selective for their principal input. Thus,
cortical representations and receptive fields become focused
during arousal.
4.3.3. Functional relevance during behavior
During arousal or activated states, neuromodulators are
released in the thalamus and they increase the discharge rate
of thalamocortical neurons as compared to quiescent states.
Enhanced thalamocortical activity leads to two consequences, the activity dependent depression of thalamocortical synapses and the recruitment of inhibition in neocortex.
As a result of these changes, thalamocortical sensory
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M.A. Castro-Alamancos / Progress in Neurobiology 74 (2004) 213–247
suppression occurs, which means that primary thalamocortical responses are strongly suppressed during arousal. As a
consequence of this suppression, rapid sensory adaptation is
no longer observed because the thalamocortical pathway is
already in an adapted (depressed) state, and thus cannot be
further depressed by activity. Thus, two major functional
consequences occur during arousal as a result of thalamocortical sensory suppression: the focusing of sensory inputs
in neocortex (Castro-Alamancos, 2002c) and the absence or
reduction of sensory adaptation to high frequency sensory
inputs (Castro-Alamancos, 2004).
Thalamocortical suppression may be functionally useful
as a gain regulator of activity reaching the neocortex
(Abbott et al., 1997; Tsodyks and Markram, 1997). Thus,
when a sensory input reaches the neocortex during
behaviorally activated states it encounters a depressed
thalamocortical synapse and likely enhanced tonic inhibition. This produces the suppression of primary thalamocortical responses during arousal. By reducing the impact
of thalamocortical inputs sensory representations may
become focused in neocortex. At a functional level this may
well serve as a mechanism to focus sensory inputs to their
appropriate representations (barrels) in neocortex, which
may be helpful for the spatial processing of sensory
information. This is important because in studies of sensory
representation mapping in anesthetized animals, the area of
neocortex that responds to a focal peripheral stimulus is
extremely large. For instance, several barrels respond in the
neocortex to deflection of a single whisker in anesthetized
rodents (Armstrong-James et al., 1992; Masino et al., 1993;
Ghazanfar and Nicolelis, 1999; Moore et al., 1999; Petersen
and Diamond, 2000). In fact, in anesthetized rodents
stimulation of whiskers with corresponding barrels located
in the border of the barrel cortex revealed that activity
spreads from these border barrels into adjacent non-sensory
cortex (Brett-Green et al., 2001). This suggests that the
strong spread of sensory-evoked activity through cortex
during anesthesia, and consequently the large representations and receptive fields attained during quiescent states,
are not the norm during information processing states.
However, because of thalamocortical sensory suppression
during arousal, sensory inputs (i.e. whiskers) may become
significantly focused in neocortex to their appropriate
representations (i.e. barrels). This could be particularly
helpful for spatial processing, such as stimulus location,
because the topographic arrangement at the morphological
level is maintained at the physiological level. Also,
focusing may be helpful for sensory processing because
the lack of selectivity observed during quiescent states
seems to hinder information processing. For example,
simple tasks performed by the somatosensory system (e.g.
two-point discrimination) are more difficult to conceive
with such overlapping and large cortical representations
and receptive fields. Obviously, these behavioral capacities
are possible only during brain-activated states typical of
alertness, attention and arousal, and not during quiescent
states typical of drowsiness, inattentiveness and sleep.
Cortical sensory suppression during arousal may serve to
focus sensory inputs in order to allow a more discrete and
segregate representation of sensory information in the
neocortex. Thus, activation typical of arousal provides
enhanced sensory selectivity via thalamocortical suppression (Castro-Alamancos and Oldford, 2002; CastroAlamancos, 2002c).
Sensory adaptation caused by repetitive sensory stimulation has been proposed as a way to focus sensory
representations in neocortex (Sheth et al., 1998; Moore et
al., 1999; Kohn and Whitsel, 2002). Thus, it is logical that
during alert and expectant states, typical of active
information processing and learning, sensory suppression
is prevalent and adaptation is mostly absent. In contrast, the
functional role of the large unadapted (non-suppressed)
responses that occur at low frequencies during quiescent
states is not obvious. They have been proposed to serve as a
mechanism of heightened sensitivity for detecting transient
stimuli (Moore et al., 1999; Fanselow and Nicolelis, 1999;
Chung et al., 2002; Sherman, 2001). Thus, these large
evoked responses could serve to alert quiescent animals of
the presence of a stimulus. For instance, when animals
perform a behavioral task in which they learn to use a
sensory stimulus (CS) to avoid an aversive stimulus,
dramatic changes occur in the size of the primary
thalamocortical response evoked by the CS. When the
animal is very alert the primary thalamocortical response is
strongly suppressed. Thus the thalamocortical pathway is in
the adapted state because thalamocortical activity is high
and consequently, thalamocortical synapses are depressed.
However, when the animal has learned the task and the level
of alertness and attentiveness is lessened, the primary
thalamocortical response becomes large as in sleeping or
quiescent animals, and thus the thalamocortical pathway is
in the unadapted state (Castro-Alamancos, 2004). There are
several potential interpretations of this observation. As
already mentioned, one possibility is that the animals may be
using the unadapted (large amplitude) responses as a wakeup call of the presence of the CS. When a stimulus reaches
the neocortex during an alert state it encounters a depressed
thalamocortical synapse, and probably also enhanced
inhibition, both leading to sensory suppression, which
places the thalamocortical pathway in the adapted state.
Although fewer cells in neocortex respond to the sensory
stimulus during activated states, current knowledge is
consistent with the idea that these fewer responding cells are
better synchronized (see Castro-Alamancos, 2004). These
effects may well serve to focus sensory inputs to their
appropriate cortical representations, as a means of enhancing selectivity while also allowing for enhanced synchronization between responding neurons, which seems to be a
hallmark of attention (Steinmetz et al., 2000; Fries et al.,
2001) and of activation (Munk et al., 1996). These two
effects, enhanced selectivity and synchronization, may serve
to produce salient responses in higher order cortical areas
M.A. Castro-Alamancos / Progress in Neurobiology 74 (2004) 213–247
239
Fig. 15. Changes in temporal response properties during arousal in the major pathways of the thalamocortical network. Upper plots show spectrum analyses of
the change in stimulus evoked response amplitude of thalamocortical, corticothalamic and lemniscal pathways as a function of frequency during quiescent states
(thin traces) and during activated states (thick traces). The response used as reference (100%) in each plot is the response at the lowest frequency (0.1 Hz) during
quiescent states. The table below describes the major changes shown in the upper plots.
leading to a behavioral outcome. In conclusion, during
alertness and attentive states the thalamocortical pathway is
in the adapted (i.e. suppressed) state, which leads to
enhanced selectivity by focusing sensory inputs and the
absence of rapid sensory adaptation to high frequency
inputs. In addition, the fewer and more selective responding
cells are much better synchronized leading to a stronger
output to the next stage of processing. This occurs
dynamically to meet information processing demands
dictated by behavioral contingencies. Thus, sensory
responses at even the earliest stage of cortical processing
are strongly regulated by behavioral state and attention.
5. Conclusions
The thalamocortical network consists of the pathways
interconnecting the thalamus and neocortex. Three major
pathways are involved: lemniscal, corticothalamic and
thalamocortical. The present review considered how these
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different pathways operate during aroused and quiescent
behavioral states. During arousal or activated states
electroencephalographic activity consists of low amplitude
fast activity, which is displayed when subjects are vigilant,
alert and attentive. During quiescent states electroencephalographic activity consists of large amplitude slow activity,
which is typical of drowsiness and sleep. The response
characteristics of the thalamocortical network to a sensory
input ascending via the lemniscal pathway will depend on
two main variables, the behavioral state and the recent
activity history of the network.
As depicted in Fig. 15, during quiescent states, the
lemniscal and thalamocortical pathways are low-pass
filtered due to synaptic depression and recurrent inhibition,
leading to sensory adaptation. Meanwhile, the corticothalamic pathway amplifies high frequency inputs due to
synaptic facilitation, but also allows low frequency
corticothalamic responses. In contrast, during activated
states the low-pass filtering is eliminated at both lemniscal
and thalamocortical pathways, but this occurs via two
distinct mechanisms. For the lemniscal pathway, neuromodulators depolarize VPM cells and suppress recurrent
inhibition so that cells that previously did not discharge
to high frequency lemniscal inputs during quiescent states
are able to do so during activated states. For the
thalamocortical pathway, neuromodulators depolarize
VPM cells enhancing their spontaneous firing rate. This
enhancement of thalamocortical activity depresses thalamocortical synapses so that both low and high frequency
sensory inputs reaching the neocortex during this state
generally encounter a depressed thalamocortical synapse.
Consequently, the thalamocortical pathway is already
suppressed and does not lead to sensory adaptation because
it is already adapted. For the corticothalamic pathway,
neuromodulators released in the thalamus depress corticothalamic synapses, and this leads to the suppression of low
frequency corticothalamic activity because facilitated
corticothalamic responses are less affected by this depression. The net effect is a high-pass filtering of corticothalamic
activity, so that during activated states corticothalamic
responses at low frequencies are suppressed while those at
high frequencies are not.
5.1. Dynamics of the thalamocortical network
during an ascending input
During quiescent states, when an action potential (caused
by a low frequency sensory stimulus) ascends toward the
thalamus via a lemniscal fiber there is a fairly good chance
(80%) that it will trigger an action potential in a VPM cell
contacted by the lemniscal fiber. The 20% failure occurs
because the VPM cell is somewhat hyperpolarized during
quiescent states (although still within the tonic firing mode),
and thus the large amplitude lemniscal EPSP on occasion
fails to reach the action potential generation threshold. Then
the VPM action potential is relayed to the neocortex via the
thalamocortical pathway resulting in the stimulation of at
least three major cell populations: nRt cells, layer VI
corticothalamic cells and layer IV cells. Thalamocortical
collaterals discharge nRt cells, leading to recurrent
inhibition that feeds back to VPM, and possibly causing
full blown spindle oscillations lasting up to 1 s in duration
that bombard VPM cells with IPSPs at 10 Hz. Thalamocortical collaterals discharge corticothalamic cells in upper
layer VI, leading to the stimulation of corticothalamic
synapses providing feedback recurrent excitation to VPM
and nRt cells. Finally, the action potential ascending via the
thalamocortical fiber depolarizes both excitatory and
inhibitory cells in layer IV (in particular, fast spiking
inhibitory cells) resulting in strong excitation that is
curtailed by strong feed forward inhibition. The action
potentials produced in layer IV excitatory cells depolarize
cells in layer III, and these pyramidal cells distribute the
activity to other layers in the same cortical column as well as
horizontally to adjacent cortical territory. Thus, during
quiescent states the thalamocortical network is in a condition
that favors the spread of low frequency activity through all of
its connections.
Also, during quiescent states, if an additional action
potential (caused by a high frequency sensory stimulus)
travels shortly after the previous one (e.g. 100 ms later)
toward VPM via the same lemniscal fiber it will have a very
low chance of triggering an action potential in the contacted
VPM neuron, and thus the sensory input is low-pass filtered;
i.e., effectively blocked. This blockage is caused by
lemniscal synaptic depression and also by the recurrent
feedback inhibition from the nRt that was recruited by the
first sensory stimulus. The few VPM cells that do respond to
the lemniscal action potential relay this activity to neocortex
where they encounter synapses that are depressed by the
previous action potential. The ascending thalamocortical
action potential encounters depressed synapses at its major
targets, producing smaller amplitude EPSPs than it did in
response to the previous (low frequency) action potential.
Many of the targeted cells that reached firing threshold in
response to the previous action potential will not be able to
reach threshold to this action potential. The net effect will be
the suppression or adaptation of the responses to high
frequency sensory inputs in neocortex during quiescent
states (i.e., rapid sensory adaptation).
During activated states typical of information processing,
when an action potential (caused by a low frequency sensory
stimulus) ascends toward the thalamus via a lemniscal fiber
there is an excellent chance (100%) that it will trigger an
action potential in a VPM cell contacted by the lemniscal
fiber. This effectiveness occurs because the VPM cell is
more depolarized during activated states than during
quiescent states allowing the large amplitude lemniscal
EPSP to reach threshold with great certainty. The fact that
the VPM cell is more depolarized implies that its
spontaneous firing rate is greater than during quiescent
states, and the enhanced activity inevitably leads to the
M.A. Castro-Alamancos / Progress in Neurobiology 74 (2004) 213–247
activity-dependent depression of the synapses formed by
thalamocortical fibers in the nRt, upper layer VI and layer
IV. It may well also lead to enhanced tonic inhibition in
neocortex because thalamocortical cells and cortical fastspiking interneurons are very effectively coupled. The
ascending thalamocortical action potential encounters
depressed synapses at its major targets, producing smaller
amplitude EPSPs than it did during quiescent states. Thus,
many of the targeted cells that reached firing threshold
during quiescent states will not during activated states. As
during quiescent states, thalamocortical collaterals depolarize nRt cells leading to recurrent inhibition in VPM, but
these IPSPs are smaller in size and duration because they are
suppressed during activation. Thalamocortical collaterals
depolarize corticothalamic cells in upper layer VI that
produce feedback recurrent excitation of VPM and nRt cells.
However, corticothalamic synapses are depressed by
neuromodulators released in the thalamus during activation
resulting in the suppression of the excitatory corticothalamic
feedback. Finally, the action potential ascending via the
thalamocortical fiber produces smaller EPSPs in both
excitatory and inhibitory cells in layer IV. The suppressed
excitation leads to fewer layer IV cells producing action
potentials and fewer cells in layer III that are stimulated.
Overall, the result is the focusing of the cell population that
is stimulated by the ascending input as compared to
quiescent states. Interestingly, despite the fact that the
number of cells firing in the neocortex may be reduced
during activated states, this cortical activity is nevertheless
more tightly synchronized, surely to allow an effective
discharge at the target cell populations.
Also, during activated states, if an additional action
potential travels shortly after the previous one (e.g. 100 ms
later) toward VPM via the same lemniscal fiber it will have
an excellent chance of producing an action potential in the
contacted VPM neuron, and thus it will be effectively
relayed to the neocortex. This effectiveness occurs despite
the fact that lemniscal synapses were depressed by the
previous action potential, and thus the lemniscal EPSP that
follows is quite small. But during activated states the VPM
cell is depolarized and much closer to firing threshold than
during quiescent states, and even depressed lemniscal EPSPs
can reach firing threshold. Moreover, recurrent inhibition
from the nRt is strongly suppressed, which also further
favors the effectiveness of high frequency (i.e. depressed)
lemniscal EPSPs to produce an action potential in the VPM
cell. The response properties of the VPM action potential at
the targets of thalamocortical fibers will be similar to that of
the previous (low frequency) action potential with one
notable exception at corticothalamic synapses. Since
corticothalamic synapses display frequency-dependent
facilitation they will produce a much larger EPSP to an
action potential that occurred shortly after (<200 ms) a
previous one. Thus, during activated states recurrent
corticothalamic feedback will be enhanced but only for
high frequency inputs. It is possible that corticothalamic
241
activity caused by high frequency sensory inputs during
activated states has a strong impact on VPM cells. Regarding
the responses produced in cells targeted by thalamocortical
fibers in layers VI and IV, their properties should be quite
similar to those produced by the previous action potential
occurring at low frequency. Thus, during activated states
thalamocortical responses do not depress or adapt as during
quiescent states because the thalamocortical network is
already in an adapted state.
5.2. In conclusion
Sensory inputs from the whiskers reach the thalamus via
the medial lemniscus tract, which originates in the brainstem
trigeminal nucleus. The lemniscal synapses are quite
specialized producing fast-rising, large amplitude all-ornone events that are very secure (i.e., high release
probability) when stimulated at low frequencies (<2 Hz),
but that significantly depress upon stimulation at high
frequencies (>2 Hz). Thus, during quiescent states, sensory
stimuli delivered at frequencies above 2 Hz are not relayed
to the neocortex despite the fact that thalamocortical cells
are firing in the tonic mode. However, during activated states
the low pass filtering of sensory inputs is eliminated, and TC
cells are able to relay sensory inputs to the neocortex at high
frequencies. The low-pass filter is eliminated during
activated states because of the postsynaptic depolarization
exerted by neuromodulators on thalamocortical neurons,
which places the depressed lemniscal EPSPs closer to firing
threshold allowing them to trigger action potentials. While
this happens at the lemniscal pathway significant changes
are also occurring at the other major thalamic synapses;
corticothalamic synapses. During activated states, corticothalamic activity is high-pass filtered; i.e., low frequency
cortical inputs to the thalamus are depressed while highfrequency inputs, which trigger presynaptic facilitation in
corticothalamic synapses, are unaffected. The high-pass
filtering during activated states is due to the synaptic effects
of neuromodulators acting on muscarinic and a2-adrenergic
receptors, which depress corticothalamic synapses and
enhance their facilitation. Thus, during activated states,
sensory inputs are allowed through the thalamus at low and
high frequencies with enhanced effectiveness, but activity
from the cortex is high-pass filtered so that only high
frequency cortical activity is allowed to reach the thalamus.
Most interesting is that the neocortex is simultaneously
undergoing dramatic changes. A notable change is that
during activated states, occurring naturally in behaving
animals or induced by BRF stimulation, the thalamocortical
pathway is depressed, so that sensory inputs reaching the
cortex are suppressed. The suppression is primarily caused
by the activity-dependent depression of thalamocortical
synapses. During activated states, thalamocortical neurons
increase their spontaneous firing rates and consequently
their thalamocortical synapses become depressed. Therefore, when a sensory input reaches the neocortex during
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M.A. Castro-Alamancos / Progress in Neurobiology 74 (2004) 213–247
behaviourally activated states it encounters a depressed
thalamocortical synapse. The functional implications of this
sensory suppression are intriguing. It eliminates rapid
sensory adaptation because thalamocortical responses are
already adapted, and serves to focus sensory inputs to their
appropriate cortical representation while also allowing for
enhanced synchronization between responding neurons,
which seems to be a hallmark of attentive states. As a
consequence of the suppression, the size of cortical
representations and receptive fields are reduced during
activated states providing enhanced selectivity, which may
be advantageous for sensory processing, such as for example
two-point discrimination in the somatosensory system.
Acknowledgments
Supported by grants from the National Institutes of
Health, EJLB Foundation and PA Department of Health. I
thank members of my lab for helpful discussions. More
information can be found at http://neurobio.drexel.edu/
castroweb/castro.html.
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