Download Intrinsic firing patterns of diverse neocortical neurons

Intrinsic firing patterns of diverse neocortical neurons
B a r r y W . C o n n o r s a n d M i c h a e l J. G u t n i c k
Neurons of the neocortex differ dramatically in the
patterns of action potentials they generate in response to
current steps. Regular-spiking cells adapt strongly
during maintained stimuli, whereas fast-spiking cells
can sustain very high firing frequencies with little or no
adaptation. Instrinsically bursting cells generate clusters of spikes (bursts), either singly or repetitively. These
physiological distinctions have morphological correlates.
RS and IB cells can be either pyramidal neurons or
spiny stellate cells, and thus constitute the excitatory
cells of the cortex. FS cells are smooth or sparsely spiny
non-pyramidal cells, and are likely to be GABAergic
inhibitory interneurons. The different firing properties
of neurons in neocortex contribute significantly to its
network behavior.
temporal patterns of repetitive firing, and thus determine to a large extent the way individual neurons
transform synaptic input into spike output. These
intrinsic physiological properties constitute a reasonable basis for neuronal classification, since studies
from a large number of brain areas show that the
electrical fingerprint can be extremely uniform from
cell to cell within a particular neuronal class (e.g.
among cerebellar Purkinje cells, thalarnic relay cells,
or dopaminergic cells of the substantia nigra; for a
recent comprehensive review, see Ref. 4).
Neurons of the neocortex are not physiologically
homogeneous ~-14. Three basic types of intrinsic
physiology have been recognized, and our terms for
them are: regular-spiking (RS), fast-spiking (FS) and
intrinsically bursting (IB). For each type, classification is based on three general variables - the
characteristics of individual action potentialafterpotential complexes, the response to a justthreshold intracellular current pulse, and the repetitive response to prolonged, intracellularly applied
stimuli. While these neuron classes are based entirely
on physiological differences, intracellular staining
experiments suggest that there are also some distinct
morphological correlates.
The general characteristics of the three classes of
neurons, derived mostly from studies of rodent
neocortex in vivo, of slices in vitro, and from tissue
culture (both explants and dissociated cells), are
summarized in Table I and discussed below. It is not
our intention here to describe the specific ionic
mechanisms underlying these neuronal behaviors,
since only RS neurons have been examined in any
detail. We also emphasize that these categories are
not necessarily comprehensive, exclusive or definitive. On the one hand, it is very likely that subcategories exist, or that a continuum of variation
better describes some cell populations; on the other,
Barry W. Connorsis
at the Section of
Neurobiology,
Division of Biology
and Medicine, Box 6,
Brown University,
Providence, R102912,
USAand MichaeIJ.
Gutnick is at the
Department of
Physiology, Faculty of
Health Sciences,BenGurion University of
the Negev,
Beersheva, Israel.
It is axiomatic in neuroscience that the informational
output of most neurons is completely defined by their
temporal patterns of action potentials. This notion is
implicit in all contemporary models of the functions of
neocortex, making it essential to understand how
each neuron transforms its input into output. Studies
show that the intrinsic membrane properties of
neurons in the neocortex are not homogeneous, but
instead produce several categories of transform
characteristics.
The fine structure of the neocortex varies from
region to region and from species to species;
however, unifying principles underlie the assembly of
individual neocorfical neurons into functional circuits 1.
A fundamental unit of neocortex appears to be a group
of diverse, radially organized neurons, each with its
own morphological and physiological characteristics
and its own pattern of synaptic connections. One
classic investigational approach to this complex local
circuitry is taxonomic classification. Neocortical
neurons have been categorized according to various
criteria such as location, morphology (i.e. size, soma
shape and dendrite patterns),
synaptic relationships locally and TABLE I. General classification scheme for neocortical neurons
with distant cortical and subcortical
Physiological class
regions, and biochemical properties (especially neurotransmitters Characteristics
Regular-spiking
Intrinsically bursting
Fast-spiking
and their associated enzymes) 1'2.
(RS)
(IS)
(FS)
Nevertheless, in order to under- Single-spike:
stand a particular neuron's funcrate of rise
++
++
4-+
tional role within a circuit, it is not
++
rate of fall
+
+
enough to know only these charac- Single-spike afterpotential
Complex, AHPs
Complex, AHPs and
Simple, AHP
teristics. Its electrical fingerprint,
and ADP
ADP
alone
++
Variable
as determined by its intrinsic Frequency adaptation
membrane properties, is also Spike bursts during
injected current
++
important.
Laminar
location
of
soma
II
to
VI
IV
or V
II to VI
It has long been known that
Pyramidal or spiny
Pyramidal or spiny
Aspiny or
neuronal membranes do not all Presumed morphology
stellate
stellate
sparsely spiny
behave similarly3. Neurons differ
non-pyramidal
in the types and distributions of Presumed synaptic function
Excitatory
Excitatory (glutamate
Inhibitory (GABA)
specific ion channels on their
(glutamate or
or aspartate)
somata and dendrites. These inaspartate)
trinsic membrane differences are
manifest as differences in the Symbols: +, the presence and relative strength of a characteristic; -, the absence of a characteristic.
Abbreviations: AHP, afterhyperpolarization; ADP, afterdepolarization. Table adapted from Ref. 15, and
shapes of individual action poten- compiled from data in the following Refs: 7-12, 16, 18, Gutnick, M. J. and White, E. L., unpublished
tials. They also lead to distinctive observations, and Agmon, A., PhD Thesis, Stanford University, CA, 1988.
TINS, VoL 13, No. 3, 1990
© 199o.ElsevierSciencePublishersLtd.(UK) 0166-2236/90/$02.00
99
A
Regular-spiking
C
Stimulus current
I
Fast-spiking
4OO
50 mV
3 nA
50 m s
Fast-spiking
B
• ooo
• :o
e° .o • • • ooo °°°e
eooo
o. • °° oo • ooooe
° • oo • oo
t~
~
300
~200
Regular-spiking
_J
--"-I__
,°° t
50 mV
3nA
0
0
i
I
i
i
i
i
i
I
i
i
I
50
100
Time during stimulus (ms)
25 m s
Fig. 1. Differences in intrinsic firing patterns between regularspiking (RS) and fast-spiking (FS) neurons. (A) When stimulated
with a suprathreshold step of depolarizing current, RS cells respond
with an initial high-frequency spike output that rapidly declines to
much lower sustained frequencies. In this and subsequent figures,
intracellular voltages are displayed in the top trace, injected current
steps in the bottom trace. (B) Under similar conditions F5 cells
generate high frequencies that are sustained for the duration of the
stimulus. ((:) Temporal patterns of typical RS and t=5 firing displayed
graphically. The firing frequencies were calculated from the reciprocal of the interspike interval, and plotted as a function of time
during a strong step pulse of intracellular current, as in (,4) and (B).
Although each cell initially generated similar spike frequencies
(about 320 Hz), the RS cell (solid line) declined within 50 ms to
<100 Hz, while the F5 cell (dotted line) actually accelerated slightly
to >350 Hz. [(A) taken, with permission, from Ref. 9; (B) and (C)
modified from Ref. 10.]
it is possible that rare cell types have not yet been
described. There is also a dearth of comparative data
across both species and cortical areas.
Regular-spiking (RS) neurons
As their name implies, the neurons most commonly
encountered in electrophysiological studies generate
what Mountcastle and his colleagues TM were the first
to call 'regular' action potentials. Most published
intracellular recordings from neocortex in vivo have
been from RS neurons (e.g. Refs 5, 6). Individual
regular spikes of RS cells are relatively long-lasting,
mainly because of a slow rate of repolarization. Each
spike is usually followed by a complex set of
intrinsically generated afterhyperpolarizations (AHPs)
and afterdepolarizations (ADPs). When stimulated at
threshold, an RS neuron generates only a single spike
and, in contrast to IB behavior, as the stimulus
amplitude increases, the first interspike interval
decreases as a strong function of current intensity.
When presented with prolonged stimuli of constant
amplitude, RS neurons exhibit pronounced adaptation
of the spike frequency (Fig. 1A, C).
spikes with an extracelular electrode. Since the
development of in vitro preparations, it has been
possible to study the FS neurons using intracellular
methods 1°-1z'15 (Agrnon, A., PhD Thesis, Stanford
University, CA, 1988). However, recordings continue
to be infl'equent and technically challenging.
Individual fast spikes usually last less than 0.5 ms.
Although spikes of all three neocortical cell types have
similar depolarization rates, those of FS cells are
faster because of a more rapid rate of repolarization,
and each spike is cut short by a deep, relatively brief
AHP (Fig. 2B, C). The more prolonged hyperpolarizing (and depolarizing) afterpotentials that characterize
RS and IB neurons are not prominent in FS cells.
FS neurons are most impressively defined by their
repetitive firing pattern; they undergo little or no
adaptation during prolonged intracellular current
pulses (Fig. 1B, C). Indeed, when strongly stimulated,
they can sustain spike fl-equencies of at least 500-600 Hz for hundreds of milliseconds. FS cells are thus
able to perform a relatively faithful conversion of input
to output over a wide dynamic range; in strong
contrast to RS and IB cells, the output of these
neurons is likely to retain the precise temporal
features of their input (Fig. 1C; cf. FS and RS firing
patterns).
Fast-spiking (FS) neurons
Mountcastle et al. 13 also described rarely encountered neurons with relatively 'thin' (i.e. brief duration)
extracellular spikes in monkey cortex. Nine years Intrinsically bursting (IB) neurons
later, Simons TM made similar observations in rat
IB neurons are distinguished by the tendency for
neocortex and called these 'fast' spikes. Both groups their spikes to appear in a stereotyped, clustered
remarked on how difficult it was to record thin/fast pattern, the burst 8-u. Bursts are often the minimal
100
TINS, Vo/. 13, No. 3, 1990
response to a just-threshold intracellular stimulus
(Fig. 3A). The individual spikes of IB cells are quite
similar to those of RS cells, although they are often
followed by more prominent ADPs which can summate to form a slow, low-amplitude depolarizing wave
during a burst. Within a burst, each successive spike
usually declines in amplitude, presumably because the
sustained depolarization inactivates sodium conductances (Fig. 3A-C).
When presented with a simple, prolonged intracellular stimulus, IB neurons can respond with a
complex, often periodic pattern of bursts and single
spikes (Fig. 3B-D). Non-IB cells under the same
conditions respond with monotonic frequency patterns (cf. Fig. 1). Specific patterns of intrinsic
bursting may vary widely from one IB neuron to
another. The IB neurons first described 8'1° were
found either in layer IV or upper layer V of parietal
and cingulate neocortex of guinea-pigs. These cells
generally responded to a prolonged current pulse with
one burst followed by repetitive single spikes. More
recent studies in primary somatosensory cortex of
mice9 and rats 16 have revealed robust IB cells
restricted to layer Vb. Many of these can generate
rhythmic bursts in the range of 5-15 Hz9'16 (Fig.
3C, D).
The term 'burst' is commonly used in the neurophysiological literature to describe a neuron's firing
behavior. However, when classifying cells, the designation 'bursting cell' is ambiguous unless modified to
indicate whether the firing pattern reflects an inherent
property of the cell, or a direct response to its
synaptic drive. As used in this review, intrinsic
bursting refers to a cell's tendency to generate
dusters of high-frequency spikes solely as a manifestation of its intrinsic membrane properties, and
independent of its synaptic input. Almost any neuron
might produce dusters of spikes in response to phasic
synaptic input. However, this response pattern does
not, of itself, justify dassifcafion as an IB neuron. The
distinction between intrinsic bursts and synaptically
driven bursts, which is essential for understanding a
neuron's role within a circuit, cannot be made without
methods that isolate the activity of a cell from its
extrinsic connections. This may account, in part, for
the fact that IB neurons were only recently recognized in neocortex 8,m. Moreover, IB neurons are
relatively rare and are usually encountered only in
certain laminae.
C o r r e l a t i o n s b e t w e e n i n t r i n s i c p h y s i o l o g y and
morphology
By impaling neocortical neurons with micropipettes
that contain an intracellular dye (such as Lucifer
yellow, horseradish peroxidase or biocytin) it has
been possible to correlate intrinsic physiological
properties, as described above, with the traditional
classifications of the Golgi anatomists, as determined
by light microscopy. There is now a relatively
consistent and accepted scheme for the morphological
categorization of cortical neurons 1,2. Virtually all
neocortical neurons can be placed into one of two
groups: pyramidal cells, which have a high density of
dendritic spines, prominent apical dendrites, excitatory synaptic function, and an axon that projects out
of the cortex as well as locally; and non-pyramidal
cells, most of which have smooth or sparsely spined
TINS, VoL 13, No. 3, 1990
40 mV
A
8 mV
s
Cell1
CeB2
3mM DGG
B
L
20 mV
s
Cell3
Cell4
20 p~ Bicuculline
C
20 mV
•
ms
i"
!
Fig. 2. Neurons that elicit EPSPs have more prolonged
action potentials than neurons that elicit IPSPs. Pairs of
neurons were recorded intracellularly in microcultures of
rat neocortical neurons. One cell was stimulated with
intracellular current to generate an action potential, while
the resulting synaptic response was monitored in the
second cell. (,6,) In this pair, a spike in cell I yielded a
monosynaptic EPSP in cell 2. Application of the excitatory
amino acid antagonist 7-o-glutamylglycine (DGG)
blocked the EPSP. (B) In a different pair of neurons from
those shown in (A), a spike in cell 3 yielded a monosynaptic IPSP in cell 4. Application of bicuculline, a GABAA
receptor antagonist, blocked the IPSP. (C) Action potentials of seven excitatory (E) and seven inhibitory (I)
presynaptic neurons superimposed to show the differences in spike duration. (Figure modified from Ref. 12.)
dendrites of various configurations, inhibitory
(GABA-mediated) synaptic function, and axons that
arborize only locally within the cortex. One major
subtype, found in layer IV of many primary sensory
areas, is a class of small neurons usually called spiny
stellate cells 17. With their high spine densities and
presumed excitatory synaptic function, spiny stellate
cells are very similar to pyramidal cells. However,
their axons usually do not leave the cortex.
Pyramidal cells constitute the majority of neurons in
the neocortex (60-70%). Their sizes range from
some of the smallest to the very largest cortical cells,
and their somata can be found in layers II through VI.
101
A
D
40 mV
1 nA
J
25 m s
B
20 mV
L_
2 nA
20-
J
50 m s
L
v
¢J
=~
1o
~3
C
I.
t,
I
_J
I
I
I
I
I
I
200
400
600
Time during stimulus (ms)
L_
50 m s
Fig. 3. Diverse firing patterns of intrinsically bursting (IB) neurons.
(A) Single intrinsic bursts evoked by threshold pulses of intracellular
current in a neuron from guinea-pig sensorimotor cortex. Slightly
larger currents generated a very similar burst at much shorter
latency. Figure shows three superimposed traces. Voltage and
current calibrations in (A) apply also to (B) and (C). (B) Response of
an IB cell in mouse SI cortex to prolonged current stimulus.
Sequence of bursts and single spikes terminating with a train of
single spikes. Arrowhead points to a prominent ADP following a
single spike. (C) Repetitive intrinsic bursting in response to prolonged stimulus. Mean interburst frequency was about 9 Hz.
Recording site was near the border of layers V and Vl in mouse SI
cortex. (D) Transition from rhythmic bursting to single-spiking in a
deep layer V neuron from rat 51 cortex (top). Each burst consisted of
three spikes firing at about 250 Hz. The graph plots the response:
the neuron generated four bursts at 10-I 1 Hz (interburst frequencies plotted by broken line), then abruptly changed to single-spike
firing at 15-20 Hz (plotted by solid line). Each triplet of vertical lines
represents an interburst interval Each single vertical line is an
interspike interval [(A) taken, with permission, from Ref. 10; (B)
and (C) taken, with permission, from Ref. 9; (D) provided by Y.
Chagnac-Amitai, L. R. Silva and B. W. Connors, see Ref. 17.]
It is therefore not surprising that this is the cell type
most frequently encountered by dye-containing microelectrodes. In recordings from neocortex both in
vitro and in vivo, almost all RS cells that have been
morphologically identified have been pyramidal cells
(e.g. Refs 10, 18, 19). Most IB cells have also been
identified as pyramidal cells; however, their somata
are restricted to layers IV and V 1°' 16. A preliminary
study of layer IV spiny stellate cells indicates that they
show the same spectrum of physiological properties
as layer IV pyramidal cells; some are RS cells while
others burst intrinsically (Gutnick, M. J. and White,
E. L., unpublished observations).
That neurons of different morphological classes can
show similar intrinsic physiological characteristics,
and vice versa, implies that these parameters are not
causally related. Nonetheless, there is recent evidence that they can be consistently correlated.
Chagnac-Amital et al.20 have found that although RS
102
and IB cells in rat layer Vb are all pyramidal neurons,
the IB cells have larger somata, more dendritic
branches, and markedly different patterns of mtracortical axons. This latter difference may be an important
clue to the function of these IB cells within the cortical
circuit; while the RS cells all had axon collaterals that
ascended and branched profusely within supragranular
layers, the axons of IB cells tended to stay within
infragranular layers, and often extended far in the
horizontal dimension.
Two primary lines of evidence imply that the
elusive FS cells are GABAergic non-pyramidal cells.
First, all neurons with the physiological properties of
FS cells that have also been intracellularly stained
have had the somatic size and shape, and the smooth
or sparsely spiny dendritic morphologies that are
peculiar to cells containing GABA or its associated
enzyme systems 1°. Second, paired recordings in
cultures of dissociated neocortical neurons have
TINS, Vol. 13, No. 3, 1990
I
Iv}jL
II
Ill
V
1.~
IB
t__
RS
l
J
_1
1~
FS
VI
WM
Fig. 4. Schematic summary of correlations between intrinsic physiology and anatomy of rodent neocortical neurons. RS
neurons (open symbols) are spiny cells, either pyramidal or stellate, distributed through layers II through Vl. F5 neurons
(filled symbols) are aspiny or sparsely spiny non-pyramidal cells, with presumed GABAergic inhibitory function, also
distributed through layers II through Vl. IB neurons (shaded symbols) are restricted to layers IV and V, and are also spiny
cells of pyramidal or stellate morphology. Neurons of layer I have not been studied physiologically. Braces on the right
summarize the laminar distributions of the three neuron types, and illustrate a typical firing pattern of each. WlV1, white
matter.
shown that cells generating monosynaptic, GABAmediated IPSPs onto follower neurons have significantly faster spikes than those cells generating
monosynaptic EPSPs 12 (Fig. 2). It is still quite
possible that there exist types of neocortical
GABAergic neurons that are not FS cells, as suggested for the hippocampus 21. However, the data
strongly suggest that every FS neuron encountered in
the neocortex is a GABAergic inhibitory cell.
The data are too scant to ascertain whether
classification into three types of neurons on the basis
of intrinsic physiological properties is generally
applicable to all cortical areas and all species. Analogous neuronal classes have been described for the
dorsal cerebral cortex of turtles, where pyramidalshaped cells generate RS-like or IB-like activity and
non-pyramidal interneurons generate FS-like activity22. Thus it is likely that this separation arose
early in forebrain evolution, and may now be widespread. All three classes have been repeatedly
observed in rodent neocortex (i.e. mice, rats and
guinea-pigs), as described above. Mountcastle's original description of FS and RS neurons applied to
monkey neocortex, and human neocortex also has
both FS and RS cells (Ref. 23; McCormick, D. A.,
unpublished observations). The prevalence of IB cells
across species is less well described. They have not
been observed in extensive investigations of layer V
neurons in cat sensorimotor cortex in vitro18;
however, these studies targeted only the largest
(presumed Betz) cells by using microelectrodes with
large tip diameters. An earlier study of cat pyramidal
tract cells in vivo described some features of the
rhythmic IB cells seen in rodents (see Fig. 6C in Ref.
6). There are at least two preliminary reports of IB
TINS, VoL 13, No. 3, 1990
neurons in human neocortex 23'24. Figure 4 schematically depicts the general distribution of neuron
classes in neocortex, based largely upon studies in
rodents.
There are several morphological classes of neocortical neurons whose intrinsic physiological properties
have not yet been examined 2. These include the small
population of non-GABAergic, non-pyramidal neurons
(notably peptidergic bipolar cells) and the assorted
enigmatic neurons of layer I, many of which are
GABAergic. Also, neurons of layer VI have been only
sparsely studied. Finally, it would be of great interest
to know whether the diversity of anatomy and
biochemistry among GABAergic neurons 2 is paralleled by a diversity of intrinsic firing patterns 21.
Significance of diverse intrinsic firing patterns
in neocortex
The intrinsic physiological properties of a neuron's
membrane play a central role in determining (1) how it
transforms the information it receives into an output
pattern, (2) how these transformations are modulated
by humoral or environmental factors, and (3) whether
(and with what pattern) the neuron generates spontaneous activity. Since these properties can vary
widely from neuron to neuron, knowledge of the
quirks of each cell type is an essential step in
unraveling the functions of a neural circuit 25. In the
neocortex, it is evident that RS cells will attenuate
prolonged excitatory stimuli while favoring the transmission of phasic ones; by contrast, FS cells offer a
wide-band responsiveness and, if necessary, sustained high-frequency output. The complexities of IB
cell behavior suggest more varied possibilities. Near
threshold for firing they have very high gains,
103
Acknowledgements
We thank our
colleaguesAric
Agmon, Yael
Chagnac-Amitai,
Alon Friedman, David
McCormick, David
Prince, LaurieSilva
and Ed White for their
invaluable
contributions to the
work describedhere.
We also thank Larry
Cauller for comments
on the manuscript,
and J. E. Huettner and
R. W. Baughman for
permission to
reproduce their data
in Fig. 2. Theauthors'
studies were
supported by grants
from the NIH and the
Klingenstein Fund
(BWC) and the DFG
(MJ6).
7 Stafstrom, C. E., Schwindt, P. C. and Crill, W. E. (1984)
generating either a very large output or none at all in
J. Neurophysiol. 52, 264-277
response to small increments of input amplitude.
8 Connors, B. W., Gutnick, M. J. and Prince, D. A. (1982)
When coupled to each other synaptically IB cells may
J. Neurophysiol. 48, 1302-1320
serve as initiators of synchronized cortical activities 15.
9 Agmon, A. and Connors, B. W. (1989) Neurosci. Lett. 99,
Those IB cells with a tendency to oscillate may play a
137-141
pivotal role in cortical rhythmogenesis. During dif- 10 McCormick, D. A., Connors, B. W., Lighthall, J. W. and
Prince, D. A. (1985) J. Neurophysiol. 54, 782-806
ferent behavioral states, various neurotransmitters
11 Wolfson, B., Gutnick, M. J. and Baldino, F. (1989) Exp. Brain
would be expected to modulate the intrinsic firing
Res. 76, 122-130
patterns of RS, and presumably IB and FS, neurons 12 Huettner, J. E. and Baughman, R. W. (1988) J. Neurosci. 8,
160-175
by altering their intrinsic membrane properties 26'27.
Many important questions remain. We are just 13 Mountcastle, V. B., Talbot, W. H., Sakata, H. and Hyvarinen,
(1969) J. NeurophysioL 32,452-484
beginning to understand the varied functional prop- 14 J.Simons,
D. J. (1978) J. Neurophysiol. 41,798
erties of neocortical neurons and how they correlate 15 Chagnac-Amitai, Y. and Connors, B. W. (1989) J. Neurowith other cellular features. The ionic mechanisms of
physiol. 62, 1149-1162
intrinsic firing patterns 7'8'18 and their sensitivity to 16 Silva, L. R., Chagnac-Amitai, Y. and Connors, B. W. (1989)
Soc. Neurosci. Abstr. 15, 660
neuromodulators 26'27 have only been extensively
17 Lund, J. S. (1984) in Cerebral Cortex, Vol. I, Cellular
examined in RS neurons, and there is an urgent need
Components of the Cerebral Cortex (Peters, A. and Jones,
to extend these analyses to IB and FS cells. We also
E. G., eds), pp. 255-308, Plenum Press
need more extensive comparative data, across both 18 Stafstrom, C. E., Schwindt, P. C., Flatman, J. A. and Crill,
W. E. (1984) J. Neurophysiol. 52,244-263
species and neocortical areas, to establish the generLandry, P., Wilson, C. J. and Kitai, S. J. (1984) Exp. Brain Res.
ality of the principles outlined here. As computational 19 57,
177-190
approaches to the functions of neocortex advance 28, 20 Chagnac-Amitai, Y., Luhmann, H. and Prince, D. A. J. Comp.
many realistic models will need to incorporate not only
Neurol. (in press)
the morphological and biochemical aspects of cortical 21 Lacaille, J-C. and Schwartzkroin, P. A. (1988) J. NeuroscL 8,
1400-1410
connectivity, but also the specific biophysical charac22 Connors, B. W. and Kriegstein, A. R. (1986) J. Neurosci. 6,
teristics of each class of neuron.
Selected references
1 White, E. L. (1989) Cortical Circuits: 5ynaptic Organization of
the Cerebral Cortex - Structure, Function and Theory
Birkh~user
2 Peters, A. and Jones, E. G. (1984) Cerebral Cortex, Vol. 1,
Cellular Components of the Cerebral Cortex Plenum Press
3 Hodgkin, A. (1948) J. Physiol. (London) 107, 165-181
4 Llin~s, R. (1988) Science 242, 1654-1664
5 Takahashi, K. (1965) J. Neurophysiol. 28, 908-924
6 Calvin, W. H. and Sypert, G. W. (1976) J. Neurophysiol. 39,
420-434
164-177
23 Masukawa, L. M., Strowbridge, B. W., Kim, J., Spencer, D. D.
and Shepherd, G. M. (1987) Biophys. J. 51, 67a
24 Frederick, D., Wilson, C. J., Wyler, A. J. and Foehring, R. C.
(1989) Soc. Neurosci. Abstr. 15, 1309
25 Getting, P. (1989) Annu. Rev. NeuroscL 12, 185-204
26 McCormick, D. A. (1989) Trends NeuroscL 12,215-221
27 Foehring, R. C., Schwindt, P. C. and Crill, W. E. (1989)
J. NeurophysioL 61,245--256
28 Koch, C. and Segev, I. (1989) Methods in Neuronal Modeling. From Synapses to Networks The MIT Press
Hormonalcontrola neuropeptidegene expressionin
sexuallydimorphicolfactorypathways
R i c h a r d B. S i m e r l y
RichardB. Simedyis
with the Howard
HughesMedical
Institute at TheSalk
Institute for Biological
Studies, LaJolla, CA
92037, USA.
An abundance of experimental literature has established that gonadal steroid hormones are responsiblefor
the sexual differentiation of neural circuitry, mediating
a rarity of reproductive behaviors and physiological
mechanisms. These same hormones regulate the
expression of reproduetivefunction in the adult and may
influence the responsiveness of the brain to specific
olfactory cues. The recent demonstration that the
expression of the neuropeptide cholecystokinin is activationally regulated by estrogen at the mRNA level,
within a sexually dimorphic p@ulation of neurons in
the medial amygdala, suggests a possible cellular
mechanism for the hormonal modulation of olfactory
information relayed along the vomeronasal pathway to
the h39othalamus.
Gonadal steroid hormones influence manlmalian reproductive function in two fundamental ways. First,
during the perinatal period these hormones can
permanently alter the pattern of copulatory behavior
and gonadotropin secretion expressed during adulthood, and second, the expression of these sexually
104
dimorphic functions in the adult is dependent on
adequate levels of circulating gonadal hormones. In
the rat, perinatal exposure to differential levels of
gonadal steroids determines, at least in part, whether
the mounting behavior that is typical of male rats, or
the lordosis response typical of females, will be
displayed by adult animals 1. In a similar way, perinatal
steroids determine whether the adult pattern of
gonadotropin secretion will be cyclic (with the periodic
surges of luteinizing hormone that lead to ovulation in
female rats), or relatively constant as it is in male
animals 2. Furthermore, gonadectomy reduces copulatory behavior in both mature male and female
animals, and subsequent hormone treatment restores, or 'activates' these behaviors in response to
appropriate sensory cues. The discovery that the
morphological organization of certain brain regions
thought to mediate reproductive function is sexually
dimorphic led to the now widely accepted idea that
functional sexual differentiation has an anatomical
basis 3'4. Thus, gonadal steroids permanently alter the
morphology and connections of certain groups of
© 1990,ElsevierSciencePublishersLtd,(UK) 0166-2236/90/$02.00
TINS, Vol. 13, No. 3, 1990