Download Initiation of the arousal response

II.
Brain Systems mediating the reponses to biologically relevant
events and objects: stress, arousal, and motivation
 2003-2011 Edward Loewenton All rights reserved.
THIS IS A DRAFT COPY AND MAY NOT BE DISTRIBUTED OR COPIED BY ANY MEANS
A central theme of this paper is the primacy of the environment and
experience in the etiology of emotional, cognitive, and behavioral pathology. The
arguments employed to that end are considerably strengthened by the
demonstration that stressful events and circumstances can affect brain physiology
and even gross morphology, in ways that can be linked to observed symptoms of
psychopathology. The changes may be transitory, persistent, or apparently
irreversible. These linkages to symptoms are supported by evidence that ranges
from well-understood, to strongly suggestive, to speculative. However, there is a
commonality to the brain effect-symptomatology linkages across disorders that are,
according to conventional wisdom, independent nosologically [REFERENCE??
Teicher? Loewenton 2002?]. This commonality would seem to offer additional
evidence supporting the central theses of this paper.
For these reasons, a concise primer of the functions of these brain structures
may be useful to the non-technical reader. The reader may wish to skim this
section, and use it as a reference when questions arise during the reading of the rest
of the paper.
This brief exposition of the structure and function of the mammalian arousal
and motive-emotional system is simplified for brevity and to maintain the focus of
the paper overall. The systems discussed here seem almost infinitely complex, with
most neural circuit responses balanced by some sort of anti-response, in networks
where loops of mutual interaction are the rule, so that it is rarely possible to say
which processes are definitely upstream or downstream from another. Paradoxical
effects are common. The following analysis is neither exhaustive nor altogether
precise, since arcane technical details that would add discriminatory levels of
information have been omitted.
The brain systems or axes most discussed in this context are those regulating
arousal, memory, emotion, motivation, and attention and higher processes,
especially working memory and inhibitory functions. Respectively (not exhaustively)
these are Hypothalamic-Pituitary-Adrenocortical Axis (HPA) along with the
Hippocampus and the Locus Coeruleus-Sympathetic-AdrenomedullaryNorepinephrine (also referred to as Noradrenergic) axis (commonly abbreviated to
SAM for Sympathetic-Adrenomedullary), with associated connections to somaticvegetative circuits; Hippocampus (HC) and Prefrontal Cortex (PFC); Amygdala and
Hippocampus; Dopaminergic (DA) circuits involving midbrain nuclei and Nucleus
Accumbens Septi (commonly shortened to Nucleus Accumbens, or NAc), along with
Orbitofrontal Cortex and Amygdala; midbrain DA and NA circuits and HC, and
their connections to PFC structures.
Neurotransmitters and neurohormones utilized in these circuits include
Corticosteroids (Cortisol in humans and primates, corticosterone in rodents) in
arousal and motivation; Norepinephrine in attention, arousal, and cognitive
functions; Glutamate and GABA (the principal excitatory and inhibitory signaling or
information-carrying neurotransmitters in the brain); Dopamine in motivational
functions, as well as attention, arousal, and cognitive functions; and Serotonin,
which affects a wide variety of functions, including emotion, motivation, and
metabolism.
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PREFRONTAL CORTEX: COGNITIVE-INHIBITORY PROCESSES
ATTENTION, WORKING MEMORY, SENSORI-MOTOR GATING, ETC.
PRIMARY & ASSOCIATIONAL
SENSORY CORTEX
DIRECT SENSORY INPUT
(ESPECIALLY AUDITORY)
CORTISOL
HPA AXIS
HYPOTHALAMUS
PVN
LSAN AXIS
THALAMUS:
SENSORY RELAYS
GABA
C
R
H
NOREPINEPHRINE
HIPPOCAMPUS
GLUTAMATE
PITUITARY
AMYGDALA
A
C
T
H
CORTISOL
CORTISOL
CRH
NE
ADRENAL
CORTEX
LOCUS
COERULEUS
CORTISOL
NOREPINEPHRINE
BRAINSTEM
NUCLEI
SOMATIC & VISCERAL EFFECTS:
HEART RATE, BLOOD PRESSURE,
DIGESTION, METABOLISM, AUTONOMIC
NERVOUS SYSTEM, ETC
ADRENALINE
(EPINEPHRINE)
SOMATIC INPUT: PAIN
RECEPTORS, VISCERAL,
HOMEOSTATIC, ETC.
ADRENAL
MEDULLA
Figure II-1: Arousal System structures in the Brain, showing some of the significant functional
relationships. Illustration is not to scale and does not suggest actual relative positions of the structures
within the nervous system. GABA (Gamma-Amino Butyric Acid) is an inhibitory neurotransmitter;
Glutamate is excitatory.
EXCITATORY CONNECTION
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INHIBITORY CONNECTION
The Hypothalamic-Pituitary-Adrenal system (HPA)
Corticosteroids are the principal neurohormones active in the stress and
arousal system.The primary stress neurohormone in humans and primates is
cortisol; in rodents, the laboratory subject used in much of this research, it is
corticosterone.
Information presented below is adapted from Bremner et al (2003), De Kloet
(2003), De Kloet et al (1998), Sapolsky (2003), Carlson (2001), and others.
Initiation of the arousal response
A principal starting point for the cascade of neurohormones involved in
stress, arousal, and adaptive motivated behavior resides in the paraventricular
nucleus of the hypothalamus (PVN). The PVN receives stimulative input from a
number of brain structures.
The amygdala transmits information about the aversive or rewarding value
of stimuli, and is a principal pathway for turning such information into levels of
arousal sufficient to result in adaptive behavior. The amygdala is generally thought
of as principally involved in direct detection of threat, defensive and escape
behavior, and fear learning, but it is important to note that it is also part of a circuit
with the prefrontal orbital cortex that allows the organism to sense the value of
positive reward (Baxter and Murray, 2002; Baxter, Parker et al., 2000).
This
commonality of influence of both rewarding and aversive events is emphasized by Piazza
and Le Moal (1997). The amygdala receives auditory and somatic-visceral
information directly from sensory input, and information in all modalities from
primary and association sensory cortices; in this way, it responds both to current
environmental events and stored representations of events and objects. Since the
amygdala responds only to information regarding the biological relevance of stimuli,
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i.e., reward or threat, it is an important gateway in determining the response or
non-response of the organism depending on stimulus meaning.
The Amygdala also receives direct stimulatory input from the Locus
Coeruleus (LC), which contributes to attention, arousal, and metabolic acceleration
by means of its noradrenergic neurotransmitter signal. The role of the LC in arousal
is further discussed below.
Input from the amygdala stimulates the PVN to secrete corticotropin
releasing hormone (CRH). Other structures also secrete CRH, notably the amygdala.
CRH then stimulates an adjoining structure, the pituitary, to release
adrenocorticotropic hormone (ACTH), which circulates through the blood to the
adrenal cortices located on the kidneys, which in turn secrete cortisol into the
bloodstream. Cortisol has a variety of effects both in the brain and in the rest of the
body, including mobilization of energy resources, immunosuppression, and the
general direction of efforts toward coping and away from normal homeostatic
activities. The principal concern here is with cortisol's role in the brain in
facilitating adaptive behavior to reduce the originating environmental stimulus, and
limiting or terminating the stress response after such behavior is successful.
Other inputs which stimulate the PVN include the locus coeruleus (LC), a
brain stem structure that secretes norepinephrine (NE), alternately referred to as
noradrenaline (NA), a neurotransmitter involved in vigilance, attention and arousal,
and other processes noted below. CRH from the PVN or other sources in turn
directly stimulates the LC, thus creating a positive feedback loop. The LC can
receive direct information from internal and external sources by means of somatic,
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visceral, and pain receptors, and so participates directly in the perception of
biologically relevant events.
The PVN is also stimulated to secrete CRH by serotonin
(5-hydroxytriptamine, often referred to as 5HT0). This relationship may be central
to understanding exactly how the organism's perception of control is effective in
limiting stress levels of arousal. The relationship of perceived control of stressful
events to psychopathology is important in understanding the origins of
psychopathology; a detailed discussion of this is provided in Chapter III.
Two kinds of Cortisol receptors
There are two kinds of cortisol receptors: the Mineralocorticod
Receptor (MR), which is excitatory to the neurons on which it occurs, and the
Glucocorticoid Receptor (GR), which is inhibitory and has a tenfold lower sensitivity
to cortisol. For this reason, GRs are only stimulated under conditions of high
arousal, i.e., high concentrations of cortisol.
Control and termination of the arousal response
The PVN, the most significant initiator of the hormonal cascade, is well
supplied with Glucocorticoid receptors (GR’s), which act in an inhibitory fashion, and
so reduce the output of CRH, thus limiting the arousal response through a negative
feedback loop. The PVN does not express MR,, but is the primary locus of GR, which
functions on this structure to inhibit the secretion of cortisol releasing factor (CRH),
and so tends to return the system to a homeostatic basal level of arousal if the
initiating environmental signal is also reduced (De Kloet, 2003; De Kloet et al,
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1998). In this manner, stress levels of circulating cortisol act to limit both the
intensity and duration of the stress response.
The PVN is also controlled by inhibitory input from the Hippocampus (HC).
The HC receives information from the amygdala (and many other inputs) and helps
construct spatial or narrative long term memories regarding threatening or
rewarding stimuli, among other things. The HC is well supplied with
Glucocorticoid receptors, which allow it to detect and respond to arousal. HC sends
an inhibitory signal to the CRH-producing neurons in the PVN, thus helping restore
arousal to basal levels.
GR and MR are co-localized in the HC, so the action of high levels of cortisol
in the HC are also inhibitory. Thus, high stress levels actually serve indirectly to
disinhibit secretion of CRH, resulting in continued or increased stress response.
Neither De Kloet nor Sapolsky suggest an adaptive purpose for this apparently
paradoxical and potentially autodestructive function (personal communications).
Hippocampal MR, on the other hand, is excitatory, and serves to maintain
the HC's function as a homeostatic regulator of basal or non-stress levels of arousal.
MR enhances HC-dependent or contextual (explicit) memory, whereas GR, when
maximally or chronically occupied, tends to degrade this kind of memory
performance. The effects of high stress-levels of corticosteroids with resultant high
GR stimulation are seen more in deficits of recall than in the original learning of
contextual or contingent information, although the latter may be impaired, too. Cuedependent learning that is HC-independent is not affected. This kind of implicit
memory is exemplified by cued fear memory, such as may occur during trauma, and
may be mediated by the amygdala (Richter-Levin, 2002 [89]; Sapolsky, 2003 [23];
Van der Kolk, 1997 [357]). In this manner, anxiety in trauma survivors may be cued
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by stimuli and experienced without association to an originating context. Under high
arousal, narrative memories may be unavailable, or they may have been stored in a
degraded form without narrative (Van der Kolk, 1997 [357]).
HC functions that mediate learning and memory are most effective in states
of moderate to high levels of Cortisol-involved arousal, such that excitatory MR’s are
fully occupied, and GR’s are only partly occupied. Since GR and MR are also colocalized in the PFC, very high or very low levels of cortisol are correlated with less
effective inhibitory functions such as attention and working memory. (It will be seen
later in this section that other neurotransmitters, production of which is tightly
linked to corticosteroid-dependent arousal, must also be active at intermediate levels
for adaptive function in PFC and other structures.)
Actually, encoding of contextual information into long term memory requires
some degree of GR activity, and thus a fairly high level of arousal (Sapolsky, 2003
[23]). It is interesting that cognitive tasks cause increased amygdalar activity (which
is why such activities, e.g., writing a paper like this, can be stressful). This may help
ensure that a sufficient level of arousal is present to facilitate the task.
Alternatively, the brain may rely on coffee input.
Cortisol and Cerebellar Function in Psychopathology
Another locus of cortisol receptors with relevance to this discussion is the
cerebellar vermis; it has an especially high density of GR in infancy, thus responding
strongly to states of high arousal. This structure sends inhibitory signals to the HC
and amygdala, moderating excitability in these structures. Vermal damage has
been implicated in limbic excitability and temporal lobe epilepsy, symptoms of which
are seen in survivors of early childhood trauma, neglect, and abuse who otherwise
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have no indiciae of epilepsy (Teicher et al, [99], [177]). Preliminary findings suggest
functional and morphological (e.g., size) differences in the cerebellum in Borderline
patients, a diagnosis reliably correlated with abuse history, and, interestingly, in
ADHD patients as well. This finding has importance to the later discussion of early
effects of traumatic stress. It is interesting to speculate that the response of the
cerebellum to stress in infancy may be a factor in the findings that the adequacy of
maternal-infant contact is correlated with the development of effective arousal
regulation later in life. This relationship may explain the value of rhythmic
soothing, such as rocking. [Author’s note: Teicher’s “Limbic System 33” Checklist
asks subjects about experiences in childhood and youth that have been reliably
associated with temporal lobe epilepsy. Teicher et al [xxx] found a high score to be
predictive of a history of childhood sexual abuse or neglect. I have used this
instrument with several patients in psychotherapy, and have found an unfailing
relationship between score and reports of adverse early experience, as well as my
more subjective or anecdotal assessment of the patients’ emotional and behavioral
difficulties, or degree of pathology. In non-patient subjects, the relationship between
score and reports incidence of early childhood adverse family experience or trauma
and/or current emotional and experiential problems was also strong. ]
Effects of chronic stress on the brain
Brain structures involved in stress, arousal and motivation in which these
two kinds of cortisol receptors occur side-by-side on the same neurons include the
amygdala, the medial prefrontal cortex (mPFC), and most importantly and most
abundantly, the hippocampus (HC). GR appears to achieve its inhibitory effect by
keeping calcium channels in a chronically open state, which hyperpolarizes the
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neuron. In other words, the neuron is left running at high power, which prevents
neuronal signaling and normal participation in synaptic function. Cortisol only
produces this effect, however, in active, that is, signaling neurons (De Kloet, 2003).
Since a consequence of the chronic open state of the calcium channel may be
cell death, the fact that chronic high stress levels of cortisol result in dendritic
retraction and thus a loss of synaptic connections may be seen as a protective
measure (Sapolsky, 2003). This dendritic atrophy during prolonged chronic stress
has been most thoroughly studied in the hippocampus, but is also known to occur in
prefrontal cortex ([207], [237], [90]). This effect is reversible upon the cessation of
prolonged or chronic stress and return of cortisol to basal levels (Sapolsky, [23]).
Interestingly, prolonged stress has the opposite effect in the amygdala, parts of
which may show increased dendritic growth during chronic stress ([xxxxxxxx]).
These properties of the central arousal system would appear to be directly related to
symptoms of psychopathology, especially cognitive and memory impairments, and
impairments of control of affect.
There is also evidence that prolonged stress can result in Hippocampal cell
death. Reduced HC size, whether through cell death or reversible processes, has
been associated with a history of acute or chronic trauma, as in survivors of combat
or assault, or in patients with long-term chronic depression [(Sapolsky], [xxxxxxx],
others, discussed further in Chapters III and IV).
Relationship between arousal and adaptive behavior
The inverted U-shaped curves describing the relationship between arousal and
working memory and long term consolidation of memory, as well as between arousal and
perormance, seen in the brain as a relation ship between corticosteroid levels and
hippocampal function (Diamond, Bennett, et. al., 1992) and cortical (Arnsten & Golman-
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Rakic, 1998), are understandable at the common-sense, functional face-value level,
which is to say they make sense from a behaviorally adaptive and evolutionary point of
view. At very low levels of arousal, measured behaviorally, chemically, or
electrophysiologically, tasks, skills, and contextual information are less effectively
learned and retained than at higher levels; at upper extremes of stress-induced arousal,
there is a progressive breakdown in the establishment of long-term memory. Retrieval of
memory, or performance, requires a lower level of arousal, with only moderate activation
of GR.
At the neural level, this relationship is seen in the hippocampal processes which
mediate long term memory storage, which are maximally enhanced at intermediate
corticosteroid levels, and break down at either very high or low values. Since cortisol
responses are determined in large part by the biological saliency of events, i.e., their
reward value, either negative or positive, this relationship would serve to limit what is
learned and remembered to those events most important to the organism. Events that
do not cause an increase in arousal are not likely to be remembered, or to result in
adaptive behavior. Conversely, failure to remember events that cause traumatic levels of
arousal might be seen as having a protective value; similarly, reduction of inhibitory
cognitive functions under high arousal may facilitate reflexive performance of older,
over-learned or genetically programmed survival responses.
The adaptive importance of moderate stress-level activation of Corticosteroids is
treated at length by Piazza and LeMoal (1967 [165]). These authors demonstrate that
Cortisol administration can actually serve as a reinforcer in humans, and may even cause
feelings of euphoria. The adaptive role of arousal system activation is further discussed
in a following section in this book.
In sum, the Hypothalamic-Pituitary-Adrenicortical (HPA) and Locus
Coeruleus-sympathetic-adrenaline-norepinephrine (SAM) circuits, which are
mutually interactive and potentiating, serve to focus the organism's attention on
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biologically relevant events, and to mobilize arousal, cognitive and motor processes
to respond adaptively to these events. Upon termination of the salient or motivating
circumstance, these systems are returned through negative feedback to homeostatic
levels. De Kloet (1998) expresses it well:
"While the action of corticosteroid in hippocampus is thus involved in HPA
regulation, further fine-tuning of the HPA response to stress occurs by its
behavioral effect. The hormone does not necessarily cause a behavioral
change, but rather influences information processing and thereby affects
the likelihood that a particular stimulus elicits an appropriate behavioral
response. Moreover, through coordinated MR- and GR-mediated actions
in...neocortical regions,... hippocampus,... and amygdala, (cortisol) affects
learning and memory processes. Accordingly, when (this) facilitates
behavioral adaptation to stress, the associated HPA response is more
readily extinguished..." (De Kloet et al., 1998. p. 292)
Interestingly, as a stressor becomes familiar and learned behavior routinely
terminates the motivating event, response to it ceases to cause rises in cortisol level,
and the rise in Dopaminergic activity associated with HPA arousal is likewise of
lower amplitude; although Sympathetic-Noradrenergic responses remain largely
undiminished ([271]).
When the organism's responses are ineffective, high chronic levels of
glucocorticoids appear to be an initiating factor in the withdrawal of effort and
motivation. Evidence for this is seen in the research into the relationship of
uncontrollable stress and dopaminergic activity. This phenomenon is discussed in
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Chapter III. What nature's purpose may have been for building in positive feedback,
which becomes chronic and deleterious when stressful input continues, is not so
clear.
Monoamine Neuromodulators: Dopamine, Norepinephrine, and Serotonin
A class of neurotransmitters referred to as neuromodulators has become
important, even part of the popular jargon, with the ascendancy of drugs as the
common medical treatment for behavioral and emotional problems. As the term
neuromodulators suggests, the relatively few midbrain neurons that secrete
Dopamine (DA), Norepinephrine (NE) or Noradrenaline (NA), and Serotonin
(usually abreviated as 5HT, for 5-Hydroxytriptamine ) adjust the likelihood of
activation of the great majority of neurons which are involved in signaling and the
transmission of information. In so doing, they influence processes and circuits that
control motivation, cognition, arousal, motivation, and the ability to focus and
maintain attention. Because of this influence, these are the neurotransmitters
referred to when the claim is made that this or that disorder is caused by a
“neurotransmitter imbalance”, and they are the targets of most
psychopharmacology.
These neuromodulators function by means of a complex network of inhibitory
and excitatory connections throughout the brain. The nature of the connection is
determined by the subtype of the receptor on the target neuron.
The neuromodulators do not by themselves cause target neurons to fire.
They cause the neurons which express receptors for the neuromodulators to be
either more or less likely to participate in a defined behavioral circuit when those
neurons also receive signaling (e.g., GABA or Glutamate) input from neurons in that
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behavioral circuit. The Neuromodulators increase or decrease the sensitivity of
behavioral circuits, making more or less likely the occurrence of the behavior.
Despite the fact that DA, NE, and 5HT are each associated with distinctive types of
behavioral processes, they do not mediate the behavior, but rather project to neural
systems that mediate that behavior, enhancing or moderating their activity (Le
Moal, 2000).
For example, a monoamine transmitter receptor inhibitory subtype will,
when occupied by a monoamine transmitter, make the neuron on which it occurs
less likely to fire, the circuit of which it is a part silent or less active, and the
behavior mediated by the circuit less vigorous or less likely to occur. An excitatory
receptor subtype will produce the opposite results. Each of the neuromodulators
makes more or less likely a variety of behaviors and processes dependent on a
variety of circuits.
Neuromodulator activity is self-limiting, due to inhibitory presynaptic
receptors and re-uptake transporters. Blockage of transporters by drugs such as
methamphetamine, cocaine, and antidepressants results in greatly increased
transmitter in the synapse, activity at a greater distance from the synapse
influencing neurons not part of the synapse (and not properly a part of the active
behavioral circuit), prolonged and more intense synaptic activity followed by
depletion of transmitter in the originating neuron and a reduction in normal
signaling. One theory of the efficacy of reuptake blockers (e.g., Ritalin, Prozac) as
drugs is that the increased extracellular transmitter preferentially stimulates
inhibitory presynaptic receptors, thus reducing signaling and the downstream
activity of the transmitter. The evidence for this is strongly suggestive but
contradictory and paradoxical (Seeman & Madras, 2000).
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Dopamine
Dopamine (DA) appears to be involved primarily in response initiation and
reward (Jacobs & Fornal, 2000), and can be loosely characterized as the brain's
universal "on" or "go" switch. It facilitates previously learned motor responses
(Graybiel, 1994) and response switching based on outcome and reward value (Cabib
& Puglisi-Allegra, 2002; Ikemoto & Panksepp, 1999). Dopaminergic activity in the
Nucleus Accumbens (NAc), a subcortical forebrain structure, increases during
response to appetitive as well as aversive stimuli, and is required for motivated
incentive-based behavior and the translation of motivation to active effort (Cabib
and Puglisi-Allegra, 2002; Ikemoto & Panksepp, 1999).
DA activity originates in one of two small clusters of neurons (nuclei) in the
brainstem. The Ventral Tegmental Area (VTA) projects to structures which mediate
motivated behavior, such as the NAc, and the calculation of the value and
probability of reward (NAc, Amygdala, Orbitofrontal Cortex). VTA circuits including
the NAc and PFC may be referred to as meso (midbrain)- cortico-limbic. The more
dorsal Substantia Nigra (SN) projects to the Basal Ganglia, which controls learned,
successful motor patterns no longer dependent on focused awareness. DA input to
the Basal Ganglia is important in smoothing and initiating learned motor responses.
SN deterioration is causal in Parkinson’s disease. Neuroleptics, which generally
attempt to control psychotic states by reducing DA-dependent PFC arousal, may
produce side effects of loss of energy and motivation and a variety of motor
disturbances by downregulating NAc and basal ganglia DA activity. Lithium, used
to treat manic states, most likely works by downregulating NAc DA activity.
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The NAc might be considered the neural structure that embodies the saying:
"It's not how good you are, it's how bad you want it" (seen on a sweatshirt). It is also
involved in the withdrawal of effort and motivation from ineffective behaviors and
inaccessible goals. Downregulation of DA activity appears to be involved in
conditioned helplessness and anhedonia (Cabib and Puglisi-Allegra, 2002; [112];
[197]; [241]; see also chapter III).
Circuits expressing DA, cortisol, and their respective receptors are mutually
interactive. VTA DA neurons contain excitatory cortisol receptors, and components
of the HPA and/or associated circuits express DA receptors, so that increase in DA
activity is associated with increased in HPA arousal and associated circuits (and
vice-versa) in a state-dependent manner, i.e., only in the presence of threat or
reward or in other contexts where these arousing circumstances are expected
(Piazza & Le Moal, 1997). Since GR are found only on DA neurons projecting to
cortex or NAc, this relationship affects motivation and cognitive processes, not motor
circuits. This relationship is important to the organism’s ability to respond
adaptively to important events and objects in its environment, and to the deleterious
consequences when efforts at adaptive behavior fails.
The temporal qualities of the rise and fall in NAc DA activity are correlated
in well-understood ways with anticipation of and motivated response to reward, and
the phenomenon of addiction. In fact, Piazza & Le Moal (1997) have demonstrated
that a high acute level of cortisol can itself act as a reward, most likely due to the
interaction of the two systems.
DA's role in the cortex appears to involve regulation of inhibitory functions
and working memory, and conscious preparation for execution of appetitive or drivebased activity, including temporal structuring of information and searching for an
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adequate strategy, as well as switching attentional and behavioral focus. Similar to
the dynamics of cortisol, either too little or too much cortical dopamine degrades
working memory and cognitive performance (Murphy, Arnsten. et al., 1996; Arnsten
& Golman-Rakic, 1998). Further, uncontrollable stress results in high levels of PFC
dopamine, and high levels in PFC that persist for a sufficiently long time or that are
high enough appear to be correlated with a profound reduction of DA activity in the
NAc. The mechanism by which this inverse relationship works was not discovered in
the literature for this paper. This inverse relationship is likely part of the process by
which chronic stress can adversely impact cognitive processes as well as reward
value and effort, the latter impairment seen as helplessness or anhedonia due to
profound downregulation of NAc DA activity (Cabib & Puglisi-Allegra, 2002).
Norepinephrine
Norepinephrine (NE) is believed to be concerned primarily with vigilance,
focused attention, working memory, and cognitive processes or "executive" functions
mediated by the Prefrontal Cortex (PFC), in addition to a role in autonomic
functions (Arnsten et al., 1996; Carlson, 2001; Jacobs & Fornal, 2000). As with
Dopamine, too much or too little activity in the PFC impairs adaptive function.
Dopamine is a precursor of NE; that fact, and the interactivity of ciruits mediated by
both neurotransmitters and Cortisol account for correlation between their levels of
activity in such processes as working memory, attention, arousal, and motivation.
NE and DA systems may become de-linked when the organism has learned a
successful coping response to a recurring stressor or motivating situation. In these
cirumstances, the HPA stress response, and the associated rise and fall of NAc DA
with anticipation and successful behavioral response, are attenuated compared to
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the same neurochemical responses to the original novel event; but NE arousal
remains strong, serving to mobilize energy, motor response, and focused attention
sufficient to complete the learned coping response. There is some evidence that the
ratio of DA to NE activity in response to a stressor may be characteristic of
externalizing vs. internalizing psychopathologies (James Henry, [329]).
Serotonin
"Serotonin is implicated in virtually everything but responsible for nothing"
(Jacobs & Fornal, 2000, no page number [web document]). Axon terminals
containing 5-HT are found in even the remotest reaches of the central nervous
system (CNS); the release of 5-HT may not be subject to classical synaptic
physiology; and 5-HT acts at a bewildering diversity of pre- and postsynaptic
receptor subtypes. 5HT influences cardiovascular and respiratory activity, blood
clotting, sleep, aggression and sexual behavior, nutrient intake, anxiety, mood,
motor output, neuroendocrine secretion, and nociception and analgesia (67).
The primary function of 5-HT neurons is to facilitate gross motor output in
both the tonic and repetitive modes. Concurrently, the system acts to inhibit sensory
information processing and to coordinate autonomic and neuroendocrine function
with the demands of ongoing motor output. Under certain conditions, when the 5-HT
system is inactivated, these relationships are reversed: Tonic motor output is
reduced and sensory information processing is disinhibited.
Loud noise, physical restraint, a natural enemy (dog), a variety of mildly
painful stimuli, a heated environment or systemic administration of a pyrogen,
drug-induced increases or decreases in blood pressure, or insulin-induced
glucoprivation do not increase 5HT activity in cats above active waking baseline in
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spite of the fact that these evoke strong behavioral, LC noradrenergic and
sympathetic activation. (Jacobs & Fornal, 2000). These findings are somewhat
discrepant with the well-established connections among stress and depression, and
especially with the finding that uncontrollable stress, a significant initiator of
pathological consequences, increases 5HT activity, while perception of controllability
(Maier & colleagues, various references, discussed in Chapter III) serves to suppress
this effect.
5-HT is associated in ways not currently well understood with depression and
obsessive-compulsive disorders (OCD). 5-HT activity increases with tonic motor
output and even more during repetitive motor acts. If 5HT is involved in depression,
then the mood-altering effects in patients and non-depressed individuals of simple
repetitive motor tasks, notably those involved in exercise such as bicycling or
jogging, might be explained by this increased 5HT activity. Thus, if there is a deficit
in 5-HT neurotransmission in at least some forms of depression, it might be
beneficial for such patients to increase their tonic motor activity or to engage in
some form of simple repetitive motor task, such as riding a bicycle or jogging.
Indeed, it has been shown than hippocampal neurogenesis, an important factor in
hippocampal functioning and a principal casualty of elevated cortisol during chronic
high or traumatic states of arousal, is protected, enhanced, or restored by exercise
and a resulting increase in hippocampal 5HT activity, as well as administration of
serotenergic drugs; thus offering two pathways for the similar effects of
antidepressants and exercise (explained further below). Repetitive or compulsive
motor acts increase 5-HT neuronal activity. According to Jacobs & Fornal (2000, no
page number [web-page]): “Patients with OCD may be engaging in such behaviors as
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a means of self-treatment by activating their brain 5-HT system in a physiological
manner in order to derive some (as yet unknown) benefit or rewarding effect.”
Interestingly, repetitive non-goal oriented behavior, i.e., sterotypy, has been
associated in animals with resistance to some of the neurochemical consequences of
uncontrollable stress (Berridge et al, 1999). This may involve the same 5HT
enhancement referred to by Jacobs and Fornal. Anecdotally, drumming fingers,
biting nails, and a wide range of repetitive activities observed in stressful situations
may be comparable to the chewing rats observed by Berridge.
[201110 Author’s comment: Or so-called OCD behavior.]
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PREFRONTAL CORTEX: INHIBITORY PROCESSES
ATTENTION, WORKING MEMORY, SENSORI-MOTOR GATING, ETC.
CORTISOL
BASAL
GANGLIA
H
P
A
VARIOUS
PROCESSES
A
X
I
S
NUCLEUS
ACCUMBENS
CORTISOL
HC
V
T
A
(DA)
SN
(DA)
RAPHE’
NUCLEI
(5HT)
DORSAL
RAPHE
NUCLEUS
AMYGDALA
LOCUS
COERULEUS
(NE)
MONOAMINERGIC
NUCLEI
BRAINSTEM
NUCLEI
AUTONOMIC, SOMATIC &
VISCERAL PROCESSES
ADRENALINE
(EPINEPHRINE)
ADRENAL MEDULLA
Figure II-2: Monoamine Neuromodulator circuits and some interconnections with other structures.
Illustration is not to scale and does not suggest actual relative positions of the structures within the nervous
system. Abbreviations: HC: Hippocampus; 5HT: Serotonin; NE: Norepinephrine; LC: Locus Coeruleus;
NAc: Nucleus Accumbens; DRN: Dorsal Raphe’ Nucleus; mPFC: medial PreFrontal Cortex; VTA: Ventral
Tegmental Area; SN: Substantia Nigra.
INHIBITORY CONNECTION
EXCITATORY CONNECTION
21
MUTUAL PROJECTIONS: EXC. OR INHIB.
Chapter Summary
Effective and flexible response to motivating events requires an intermediate
to moderately high level of activation in brain systems that contribute to arousal
and motivation: the HPA axis, and limbic, dopaminergic and noradrenergic ciruits.
Levels of corticosteroids in the brain are directly related to this arousal level. At low
levels of activity in these systems, incoming stimuli are not stored, effective
behaviors are not learned, and learned behaviors are not expressed in effective
action. At very high levels of activity, performance of learned behaviors is degraded
and events may not be stored in memory in a useful way.
New or stored environmental input regarding biologically relevant events,
filtered through the Amygdala and other structures, begins the neurohormonal
cascade resulting in motivated arousal. Neural feedback systems, mediated by
inhibitory corticosteroid receptors, notably in the Hippocampus, return the system to
baseline level if the behavior energized during the aroused state succeeds in
resolving the motivating event. If behavioral resolution fails, motivated or stress
levels of Corticosteroids continue, with deleterious consequences for behavior, and
ultimately, the brain structures involved. Reduction of synapses in the Prefrontal
Cortex and Hippocampus may reduce attentional focus and cognitive abilities;
Hippocampal feedback is reduced, further prolonging the aroused state; and
Dopaminergic activity in the Nucleus Accumbens may be profoundly reduced, a state
associated with apparent anhedonia and an inability to expend effort to gain reward
or reduce threat.
Edits 20060701: Add material from [41].
sapolsky_depression_biology\20050202_GC&HC&MEMORY&STRESS.rtf
Also add Oxytocin, Vasopressin to PVN; GC feedback to pituitary, PFC; PVN, Pit receptors possibly not
changed by hypercort, these are more mechanical – Psych influenced receptors in HC & PFC are reduced
in density by high chronic cort. Also: CRH as neurotransmitter, from Amygdala, PVN, other sites, target is
Amygdala, especially DRN.
22