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The	integration	of	stress	by	the
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H.B.M. Uylings, C.G. Van Eden, J.P.C. De Bruin, M.G.E Feenstra and C.M.A. Pennartz
ProgressinBrainResearch,Vol 126
© 2000 Elsevier Science BV. All rights reserved.
CHAPTER 9
The integration of stress by the hypothalamus, amygdala
and prefrontal cortex: balance between the autonomic
nervous system and the neuroendocrine system
Ruud M. Buijs* and Corbert G. Van Eden
Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands
Introduction
The hypothalamus is the center in the central
nervous system (CNS) that is mainly responsible
for the organization of homeostasis. This statement
can be made, since numerous studies have provided
evidence that hypothalamic nuclei not only control
basic functions such as food and water intake, but
are also essential for the organization of reproduction,
body temperature regulation and hormone
secretion by the pituitary (see review Swanson,
1987). Carrying out these tasks not only requires
that the appropriate behavior is regulated, but also
that the adequate hormonal balance and the integration
of the correct moment of the day in relation to
the sleep wake cycle are taken care of. These three
aspects work together with respect to whether the
setting of one condition will influence the setting of
another. The sensation of an empty stomach, for
example, will influence hormonal balance in a way
that is completely different from the way it will
affect behavior, depending on the moment of the
sleep/wake cycle at which this sensation is transmitted
to the central nervous system (Iraki et al.,
1997).
In this context stress can be seen as a potentially
life-threatening situation where external and/or
*Corresponding author: Tel.: +31 20 5665500; Fax:
+ 31 20 6961006
internal influences may seriously disrupt the homeostasis
of the body. The hypothalamus thus plays a
major role in the registration and integration of
stressful information and in orchestrating an adequate
response of the organism in order to cope
with the stress. In this respect we would like to
make a distinction between two types of stress, i.e.
homeostatic stress, a situation that has already
disturbed or will disturb the internal balance of the
organism, like severe thirst, hunger, pain, etc.
(Aguilera et al., 1993), or emotional stress, the
perception of a threatening situation that may cause
a disturbance in the homeostatic balance (for which
memory systems that recognize the stress as such,
such as fear, for instance, are essential) (La Bar et
al., 1998; Le Doux, 1998). As we will see, the
hypothalamus plays a crucial role in the organization
of the final response of the animal to both types
of stressors. Brain regions other than the hypothalamus,
such as the prefrontal cortex and the
amygdala, play a major role in mobilizing the
emotional stress response (Diorio et al., 1993; Le
Doux, 1998), while ascending information from the
periphery to the hypothalamus plays a role in
homeostatic stress response (Renaud et al., 1988).
In the present review the major brain regions
implicated in these two stress systems will be
discussed, but special attention will be paid to the
role of the hypothalamus in integrating emotional
stress information from 'higher' brain structures
118
such as the amygdala, hippocampus, septum and
prefrontal cortex. Because the stress response can
be measured for a large part as a hormonal response
orchestrated by the hypothalamus, recent experimental
data will be discussed that shed new light on
how hypothalamic nuclei play an essential role in
sensitizing organs of the body to the hormones of
the pituitary as well.
Sensing the environment
Homeostasis can only be maintained if the organism
can adequately register its internal as well as its
external environment; in the course of evolution
various sensory organs have developed that transmit
information about the body and information
about the environment to the central nervous
system. To us humans the surrounding world is
limited to what our sensory organs tell us exists,
and we often tend to forget that much more
happens in and around us than we consciously
realize. Our recently discovered (and still disputed,
possibly due to its recent discovery) sixth sense, the
vomeronasal organ (Keverne, 1999; Monti-Bloch et
al., 1998), only emphasizes that we should not
preclude the existence of a seventh sensory organ.
For example, the recently discovered sensory
structure in the trout brain (Walker et al., 1997) that
enables the trout to orient itself using the earth's
magnetic field does not necessarily indicate that
humans, too, might have such organ, but to exclude
such a seventh sense, or any other sense, for that
matter, would be preposterous. In fact, most
sensory information that reaches our brains does so
without reaching our consciousness, a situation that
is hardly surprising given the fact that most of this
information deals with the homeostatic balance of
our organs. More surprisingly, recent evidence
shows that a great deal of the visual and acoustic
information can affect our homeostatic balance. If
we have been taught that a certain visual or acoustic
stimulus signals danger, we will subconsciously
react to it with an autonomic response (Damasio,
1998; Le Doux, 1998).
It will be clear that even the most primitive
organisms use sensory organs - essential not only
for pain perception but also for registering the
internal environment - and it is therefore not
surprising that a large part of the initial integration
of sensory information takes place in brain regions
that are evolutionary older, such as the spinal cord,
brainstem and mid-brain structures that are connected
with the hypothalamus as the center where
sensory information of body and environment
converges. In principle this sensory information
(about pain or the internal state of the body) may
lead to homeostatic stress if a severe disbalance is
noted. This imbalance will be detected in all
regions to which this information is sent, leading,
initially, at the level of the spinal cord and brain
stem, to a reflex response that adjusts, for example,
blood pressure, by vasoconstriction or vasodilatation
(Tjenalooi et al., 1997). Higher up, in
hypothalamus or cortex, similar responses are
initiated and will result in proper behavioral and
hormonal measures (Hatton et al., 1997). Furthermore,
other (visual or acoustic) peripheral
information reaches cortical and subcortical structures
(e.g. amygdala) and is coupled with memory
and other associative processes that come from
amygdala and prefrontal cortex (PFC). In coordination
with these two regions, the hypothalamus
decides what the autonomic output of the organism
will be; we call this type of stress emotional stress.
The hypothalamus
The brains of fish, amphibians and reptiles are
organized in such a way that relatively few
structures besides the spinal cord, brainstem and
hypothalamus are needed to drive essential behavior
such as, for instance, food intake, reproduction
and body homeostasis. However, food intake and
especially behavior associated with reproduction
can become quite complex and in mammals the
functioning of the cerebral cortex is therefore also
required. The increasing complexity of these
behaviors and the increasing demands on the
memory systems later in evolution, forced structures
such as the amygdala and the PFC to evolve
more extensively. As we have seen earlier, these
brain regions allow the animal to take into account
its (recent) past and warn it if its sensory systems
activate its memory systems for earlier encountered
harmful environments, and initiate a stress
response. For this reason amygdala, hippocampus,
119
septum and PFC have massive connections to the
hypothalamus (Swanson, 1987; Moga et al., 1990;
Diorio, 1993; Dayas et al., 1999; Van Eden and
Buijs, Chapter 4, this volume). One of the interesting
aspects of the regulation of the behavioral
and hormonal stress response by the 'higher'
centers (amygdala; hippocampus; septum and prefrontal
cortex) is that recent evidence suggests that
these regions may both play either an activating or
an inhibiting role in the stress response (Van de Kar
et al., 1991; Herman et al., 1995; Lee and Davis,
1997; Van de Kar and Blair, 1999). A stressful
learning situation results in sympathetic activation;
there is compelling evidence that the PFC and the
amygdala are essential for the induction and
integration of this autonomic response. Damage of
the PFC in humans results in a severe impairment
of aversive or reward-reinforced learning (see
Chapter 27 by Damasio; Andersen et al., 1999;
Bechara et al., 1999). Apparently the PFC in
particular detects potentially harmful situations and
warns human beings when they encounter such a
situation. In this chapter we will pay particular
attention to the way in which the PFc and
amygdala are involved in the induction of the stress
response. Ia this connection we will discuss our
own recent data as well as the data of others, all
providing detailed information on the interaction of
PFC and amygdala with hypothalamus and autonomic
nervous system in relation to, especially,
hormonal control. Here we will pay particular
attention to the control of adrenal cortex hormones,
since this can be considered a reliable means of
measuring the stress level of an animal. As we will
see, stress-induced corticosterone levels are influenced
by many different factors, most of which are
associated with one of the above-mentioned brain
regions. Furthermore, new insights will be presented
that show that the same neuronal structures
that organize hormonal secretion also prepare the
organs of the body for these oncoming hormones
and in this way safeguard an efficient communication
with the periphery.
Inevitable for the scope of this review is that
considerable attention is paid to the paraventricular
nucleus of the hypothalamus (PVN). Within its
anatomical boundaries the PVN combines neuro
endocrine neurons containing, e.g. corticotropinreleasing
hormone (CRH) with 'autonomic'
neurons connected to autonomic parasympathetic
and sympathetic centers in brainstem and spinal
cord (Swanson, 1987). The PVN is of fundamental
importance for the control of ACTH secretion and
hence for the adrenal cortex and corticosterone
secretion (Dallman et al., 1992). How the PVN
receives its information from the periphery and the
brain and how it organizes an adequate response
will be discussed; furthermore, the similarities in
organization of the PVN, amygdala and prefrontal
cortex with respect to their neuroendocrine and
autonomic control will be discussed and related to
their function in the response to stress.
Theparaventricular nucleus of the hypothalamus
The PVN is centrally situated in the midline of the
hypothalamus; the hypothalamus is surrounded by
other brain regions that co-organize the stress
response (septum, hippocampus, amygdala and
suprachiasmatic nucleus (SCN)). The PVN consists
of three main parts: (1) A magnocellular part
(PVNm) containing vasopressin and oxytocin neurosecretory
neurons. (2) A parvocellular part
(PVNp) containing mainly anterior pituitary hormone-releasing
hormones such as CRH and
thyrotrophin-releasing hormone (TRH) and (3) A
magnocellular part with neurons projecting to
autonomic centers in the brain stem and spinal cord
(PVNa) (Swanson, 1987; Renaud et al., 1988). This
part extends into the zona incerta, which also
contains many autonomic projecting neurons. Anatomical
analysis of direct neuron-neuron contacts
within the PVN indicates the possibility of a great
deal of interaction between these different types of
neurons by means of somatic or dendro-dendritic
interaction (Van den Pol, 1982; Theodosis and
McVicar, 1996) and hence a putative exchange of
information between the respective neurons. However,
whether this means interactions between
different groups of neurons is not clear; in contrast,
a differential control of these subdivisions is
suggested, since they receive input from quite
different sources. This even goes for the two types
of magnocellular neurons in the PVNm that contain
either vasopressin or oxytocin, since there is
physiological evidence that stimuli that activate one
120
set of magnocellular neurons do not necessarily
influence the other set. This has been documented
quite extensively, for example by a selective
activation of oxytocin neurons by stomach distention
or by the activation of vasopressin neurons by
a fall in blood pressure; both stimuli failed to elicit
a response in the heterologous neurons (see, e.g.
Renaud et. al., 1988; Renaud and Bourque, 1991).
There are no similar electrophysiological data for
the specific classes of parvocellular neurons,
although the different daily secretion patterns of
TSH, ACTH and GH suggest that the corresponding
neurons in the PVN that produce the releasing
factors are selectively activated. Tanimura and
Watts (1998) demonstrated that PVN neurons have
a different sensitivity for the feedback of corticosterone;
no data are available for the 'autonomic'
PVN neurons that suggest selective activation or
inhibition. In order to evaluate which input is
essential for the various outputs of the PVN, over
the past decades numerous laboratories have
invested tremendous efforts in unraveling the
anatomical organization of the PVN afferents.
Initially little attention was paid to deciphering this
input in relation with the functional subdivisions of
the PVN, but as the work progressed the need for
this knowledge became self-evident. The anatomical
data suggest that the majority of the direct input
to PVN cell bodies arises from noradrenergic A1
and A 2 cell groups in the lower brainstem and
from adrenergic neurons in the C1 area and
serotonergic neurons in the dorsal raphe nucleus
(for a detailed review on these direct afferents see
Sawchenko and Swanson, 1981; Swanson, 1987).
All these ascending systems have a direct
functional activating synaptic access to the cell
body and therefore play a major role in the acute
activation of the neurons in the PVN (Day and
Renaud, 1984).
Most activational stimuli are very powerful
stimulators of the secretion of one or more
hormones of the PVN. In general these stimuli
(nausea, dehydration, hypotension, pain, etc.) can
be considered homeostatic stressors since they pose
an acute threat to the homeostatic balance of the
animal. Interestingly, it seems that the majority of
the inputs from other (higher) brain regions, such as
hippocampus, septum, amygdala and PFC, in the
PVN that may represent the anatomical substrate
for emotional stress seem to be organized around
the PVN rather than aimed directly at the cell
bodies of the PVN. As we will see, such an
orientation of the (sub)cortical inputs allows more
differentiation in the control of the PVN neurons.
Organization of theforebrain input to the
paraventricular nucleus
Direct input to the neuroendocrine PVN
In this chapter we will pay attention not so much to
the above-described ascending (activating) input to
the PVN, which is mainly derived from brainstem
and spinal cord centers receiving direct autonomic
information, but rather to the (modulatory)
descending input from other brain regions. Tracing
and functional studies have indicated that, in
addition to the ascending direct input, structures in
the immediate vicinity of the PVN, too, have a
direct input to this central hypothalamic nucleus
(Roland and Sawchenko, 1993; Herman et al.,
1994; Boudaba et al., 1995, 1996). We will mainly
pay attention to the input in the parvocellular and
autonomic neurons because this is the most relevant
for the control of the emotional stress response.
Since the direct monosynaptic input to PVN
neurons, and especially to the cell body, is
physiologically the most relevant, we would first
like to discuss the brain regions that, in addition to
giving such input to brain stem autonomic disorders,
also provide input to the PVN. The
dorsomedial nucleus of the hypothalamus (DMH)
was shown to have a massive input in the PVN,
whereby especially the PVNp receives the strongest
innervation (Levin et al., 1987; Roland and Sawchenko,
1993). Both GABA and galanin are
neurotransmitters used in this pathway. Furthermore
the bed nucleus of the stria terminalis (BNST)
also projects to the parvocellular PVN, mainly
utilizing GABA as inhibitory neurotransmitter
(Herman et al., 1994). The medial preoptic nucleus;
the anterior periventricular region; the ventromedial
hypothalamus, the lateral hypothalamus and
the arcuate nucleus all project to the medial
parvocellular PVN and thus in principle to the CRH
neurons. Many hypothalamic regions in the
immediate vicinity of the PVN contain GABA as a
121
neurotransmitter (Boudaba et al., 1996), often in
addition to a certain peptide. The circumventricular
organs, such as the subfornical organ, project to the
parvocellular and magnocellular PVN and have a
special role in the control of circulation and directly
innervate and activate (!) the hypothalamic CRH
neurons involved in the control of the hypothalamo-pituitary-axis
(HPA), although autonomic
projecting PVN neurons are also activated (Bains
and Ferguson, 1995). However, the main function
of circumventricular organs is generally also
thought to mobilize the PVNm in homeostatic,
mainly circulation-related stress responses (Li and
Ferguson, 1993). In short, the PVN is literally
surrounded by nuclei that project directly into the
PVN.
Interestingly, none of the forebrain regions
endowed with a high concentration of glucocorticoid
receptors (hippocampus, septum,
prefrontal cortex) and known to be implicated in
the inhibition of the HPA axis has direct extensive
projections to the medial parvocellular part of the
PVN, the location of the CRH neurons. Instead,
ventral hippocampus, septum and prefrontal cortex
seem to concentrate their projections to the hypothalamic
brain regions in the immediate vicinity of
the PVN, such as the DMH and the BNST, that
contain such a high density of GABA-ergic interneurons.
The high density of GABA-ergic
inhibitory input into the PVN stems from the BNST
and DMH and the presumed activation of BNST
and DMH neurons by glucocorticoid receptorcontaining
neurons forms the firm anatomical basis
for the inhibitory action of hippocampus, septum
and PFC on the neuroendocrine PVN (Boudaba et
al., 1996; Herman and Cullinan, 1997).
Interestingly, the pattern of projections from
ventral hippocampus, amygdala, septum and PFC
around the PVN closely resembles the pattern of
projections of the suprachiasmatic nucleus (SCN),
known to be responsible for the daily rhythm in
ACTH and corticosterone secretion (Fig. 1). Since
antrograde tracing has demonstrated that projections
of this nucleus also largely avoid the body of
the PVN, it was investigated on what basis our
biological clock could influence the HPA axis; the
observed interaction of the SCN with the PVN may
illustrate how forebrain regions influence the HPA
axis. Therefore we will pay particular attention to
the anatomical, physiological and electrophysiological
experiments that revealed the basis of the
control of the HPA axis by the SCN; furthermore
we will illustrate that this interaction may also hold
for the way the ventral hippocampus, septum,
amygdala and PFC may influence the HPA axis.
Forebrain control of the hypothalamo-pituitary
axis
Light microscopical evidence shows SCN terminals
in many midline regions of the hypothalamus, with
the exception of the PVN, which seems to be
largely avoided by SCN projections. Only close to
the ventricle in the periventricular zone of the PVN
and in the dorsal cap, the autonomic part of the
PVN can SCN fibers be visualized, whereas in the
so-called sub-PVN, an area just ventral from the
PVN, dense termination is seen (Watts et al., 1987;
Buijs et al., 1994). Other SCN terminations around
the PVN are observed in the medial preoptic area
(MPO), just rostral of the PVN, while just caudal of
the PVN another dense termination zone is seen in
the DMH (Buijs et al., 1993; 1994). As we have
seen above, the SCN seems to share these three
areas of termination with other forebrain regions
that also influence the HPA axis, such as the ventral
hippocampus (subiculum), the amygdala (the
medial (Ame) and central part (Ace)), the lateral
septum and the PFC (Figs. 1 and 2). The only
exception is that all these other brain regions also
have the BNST as important zone of termination,
whereas the SCN only gives sparse input and only
to the medial part of the BNST.
As discussed above, the regions directly surrounding
the PVN provide a substantial
(GABA-ergic) input to the neuroendocrine PVN;
consequently the hypothalamic projections of the
SCN, PFC and amygdala may influence hormone
secretion without a major direct innervation of the
neuroendocrine neurons.
Like the PFC and amygdala, the SCN plays a
major modulatory role in the process of corticosterone
secretion; in the case of the SCN, the factor
time-of-day is the variable, and in the case of the
PFC or amygdala the variable is the motivation or
the emotional condition.
122
Initially projections of the SCN were revealed in
combination with CRH staining, demonstrating
that SCN projections largely failed to contact CRH
cell bodies (Fig. 1).
In order to further identify where SCN projections
may interact in their zone of termination
with neurons involved in the regulation of the
stress response, we subjected rats to stress and
subsequently identified, by means of immunocytochemical
staining, c-fos as marker for neuronal
activation simultaneously with SCN projections. It
was demonstrated that SCN terminals synaptically
impinged on neurons showing c-fos in the DMH
and MPO (Buijs et al., 1993). In view of the direct
GABA-ergic inhibitory input to the parvocellular
PVN from DMH and MPO, this observation
illustrates the possible indirect pathways to the
PVN via which the SCN affects the stress response.
Apart from these neurons around the PVN, logically
also the parvocellular neurons in the CRH
containing part of the PVN show c-fos as an
indication of activation; this observation indicates
that almost simultaneous with the activation of the
CRH neurons, the inhibitory inputs of DMH are
activated as well.
Lesioning the SCN resulted in an enhanced
secretion of corticosterone during the day and after
stress, suggesting an inhibitory role for the SCN on
the HPA axis (Fig. 3) (Buijs et al., 1997). In order
to further investigate this SCN action on corticosterone
secretion, a series of physiological
experiments was undertaken whereby probes were
B
Fig. 1. A, B illustrates a transversal section of the hypothalamus in the region of the paraventricular nucleus (PVN). Bar= 100 Ixm.
(A) illustrates fibers arising from the suprachiasmatic nucleus (SCN) that penetrate (arrows) the boundaries of the PVN in which cell
bodies stained for corticotrophin-releasing factor are stained (dark brown). Branching and putative termination of SCN fibers are
visible just ventral of the PVN close to the ventricle and in the periventricular and dorsal part of the PVN (two arrows at the top). (B)
illustrates fibers arising from the ventral hippocampus that show very fine but dense termination in the area just ventral of the PVN
(arrows). Inset is a higher magnification of the area indicated by the upper arrow. PVN is stained for oxytocin (dark brown) to show
the outline of the PVN (rostral part).
123
placed in the vicinity of the DMH in SCN-intact
and SCN-lesioned animals, through which SCN
transmitters or antagonists were infused. The
results showed that vasopressin as a transmitter of
the SCN was able to inhibit ACTH and corticosterone
secretion strongly when infused in the DMH.
Furthermore, a vasopressin antagonist increased
blood ACTH and corticosterone levels quite
strongly, especially during periods of high endogenous
VP secretion, which occurs during the light
period (Kalsbeek et al., 1996a, b). Since plasma
corticosterone levels are quite low during the early
Fig. 2. illustrates a transversal section of the hypothalamus in the region of the paraventricular nucleus (PVN). Fibers arising from the
prefrontal cortex show terminations in the area just ventral of the PVN where in Fig. 1 termination of suprachiasmatic nucleus and
ventral hippocampus is present.
124
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125
moments of the day period this is taken as evidence
that the task of vasopressin secreted from SCN
terminals in the DMH area is to inhibit the HPA
axis. It is interesting to note that the very same
peptide, but this time secreted as a hormone from
PVN terminals in the median eminence, functions
as a corticotrophin liberating factor; apparently a
new role for this peptide has developed somewhere
during evolution and the neurotransmitter role for
the biological clock might be another adaptation.
This observation fits the fact that vasopressin is
generally excitatory to postsynaptic neurons and to
the GABA-ergic inhibitory projections from DMH
to PVN. These observations provide physiological
evidence for the idea that the DMH is an important
relay station for central information to the neuroendocrine
PVN. It is clear that by means of this
projection to the DMH the SCN but also the PFC
and amygdala are put in a position to modulate
the inhibitory input to the neuroendocrine PVN
(Fig. 4).
Next, electrophysiological studies were undertaken
to understand more precisely the possible
circuits involved; the SCN was stimulated and
electrical activity recorded in the PVN. Intracellular
and patch clamp recording revealed that
stimulation of SCN neurons induced both monosynaptic
and bi- or multisynaptic activation and
inhibition of PVN neurons (Hermes et al., 1996). It
was demonstrated by using specific antagonists that
both GABA and glutamate serve as aminoacid
transmitters of the SCN whereby PVN neurons are
monosynaptically inhibited or activated; apparently
this monosynaptic connection between SCN and
PVN neurons could not be revealed by neuroanatomical
techniques. Most probably therefore
the site of contact is on the dendrites of the PVN
neurons that extend into the periventricular or
subPVN (Fig. 1).
Insight in the multisynaptic inhibitory connection
was revealed when application of vasopressin
to hypothalamic brain slices resulted in an inhibi-
PFC
:.(: " ::: i/ : i: .:; : : .:..: ::.: :
".-i PFC neuroendocrine projections "-"." " : '"- ..... '". ..... '"' .... "i, .'.'.".i::::':, :",',".i:::;-:, .',',".?::::-:. .'.'.?::::':,
• (~3 .......... SCN neuroendocrine projections
Fig. 4. Sagittal scheme of the hypothalamus illustrating the projections of the suprachiasmatic nucleus (SCN) and the prefrontal cortex
(PFC) to neuroendocrine centers in the medial hypothalamus. The SCN reaches the medial preoptic nucleus (MPO), the subPVN
(sPVN) and the dorsomedial nucleus of the hypothalamus (DMH). These three regions give rise to input to the neuroendocrine
parvocellular (p) and magnocellular parts of the paraventricular nucleus (PVN). The PVNp gives rise to the corticotrophin-releasing
hormone (CRH) output of the PVN to the median eminence. It is not clear whether the dorsal cap of the PVN (PVNd) or zona incerta
(ZI), where the autonomic projecting neurons are located, also receives an input from the MPO, sPVN and DMH.
126
tion of a selected population of parvocellular PVN
neurons and oxytocin PVN neurons that could be
blocked by the GABA antagonist bicuculline. Since
vasopressin also activates neurons in the sub-PVN
area, which could be blocked by vasopressin
antagonists, we take this as evidence that vasopressin
inhibits PVN neurons via an indirect route
by activating GABA-ergic interneurons in the
immediate vicinity of the PVN (Hermes et al.,
2000). Consequently a dual mode of controlling the
functioning of the neuroendocrine PVN seems to
be in effect: a direct as well as an indirect input to
the PVN neuron (Figs. 4 and 5). Moreover, both the
direct and the indirect input may exercise an
inhibitory as well as a stimulatory influence. The
paucity or absence of contacts on the cell body in
the PVN seems to indicate that the direct inputs of
the SCN have a merely modulatory character that
can be overruled by information that reaches the
neuron more closely to the cell body. As is clear
from the results of the anterograde tracing from the
amygdala and PFC, both brain regions have
extensive projections to the DMH and subPVN,
suggesting a similar arrangement as has just been
described for the SCN (see chapter Van Eden and
Buijs; Coolen and Wood, 1998; Prewitt and Herman,
1998) (Figs. 1, 2, 4 and 5). The consequence
of this interaction seems clear; it gives each brain
region limited but direct access to the neuroendocrine
motor neurons of the PVN; at the same time,
by means of access to the neurons around the PVN,
the activity of main inhibitory centers that feed into
the PVN is changed. The duration and magnitude
of the change, however, will depend on the
information from the other brain regions; consequently,
emotional state, day/night conditions, and
other circumstances are integrated in the areas
around and within the PVN. Interestingly, lesioning
the PFC results in a similar response as lesioning
the SCN as far as corticosterone secretion is
concerned, i.e. enhanced secretion after a stressful
stimulus (see, e.g. Van Eden and Buijs, this
PFC
• ......................................
Fig. 5. Sagittal scheme of the hypothalamus illustrating the projections of the suprachiasmatic nucleus (SCN) and prefrontal cortex
(PFC) to the autonomic centers in the hypothalamus. Direct SCN and PFC projections are established to neurons in the dorsal cap of
the PVN (PVNd), zona incerta (ZI) and lateral hypothalamus (LH). These three regions have direct projections to sympathetic
preganglionic neurons in the spinal cord.
127
volume). This observation supports our view that
the PFC, too, by an excitatory input to GABA-ergic
neurons in the DMH, reduces the corticosterone
stress response (Figs. 4 and 5). Consequently, we
would like to propose that emotional/stress information
about the environment, for which PFC,
septum, amygdala and hippocampus are essential,
converges with circadian information in the same
areas and possibly the same neurons around the
PVN. In this way the anatomical basis is created
that enables the coupling of the time-of-the-day
message to emotional stress arising from other
brain areas. Support for this hypothesis is provided
by studies that showed animals responding to a new
environment with a time-of-day-dependentincrease
in ACTH and corticosterone secretion (Buijs et al.,
1997). Consequently, the response of the HPA axis
to stress (in this case: a new environment) is highly
dependent on the signal of the SCN; without the
SCN a very enhanced signal in both ACTH and
corticosterone is recorded, indicating that the SCN
has an overall inhibitory influence on the HPA-
axis.
Forebrain interaction with the autonomic nervous
system
Recent anatomical observations concurred with the
results from electrophysiology that indicated
monosynaptic contacts between SCN terminals and
PVN neurons. These anatomical data showed close
appositions between fibers arising from the SCN
and neurons in the PVN retrogradely filled from the
spinal cord (Teclemariam-Mesbah et al., 1997;
1999; Buijs et al., 1999). This proved to be the first
anatomical demonstration of the site where the
SCN may transmit its daily information to the
autonomic nervous system.
Since melatonin secretion from the pineal gland
is strongly under the influence of the SCN and
shows a very pronounced day/night rhythm, we
determined; by means of transneuronal virus tracing,
the pathway between the SCN and the pineal.
These anatomical studies showed that, seen from
the site of the biological clock, the PVN is indeed
the first relay station, after which the neurons in the
intermedio-lateral column (IML) in the spinal cord
transmit SCN information onwards, to the superior
cervical ganglion, and then to the pineal (Larsen et
al., 1998; Teclemariam-Mesbah et al., 1999). These
and other anatomical studies demonstrated the
monosynaptic interaction between the SCN and the
autonomic parts of the PVN and thus provided the
anatomical basis for the interaction of the biological
clock with the autonomic nervous system.
An as yet not very well understood phenomenon is
that, depending on the conditions, the adrenal
responds to the same amount of ACTH with a
liberation of different quantities of corticosterone
(Dallman et al., 1987). For example, the adrenal
has a circadian variation in its sensitivity to ACTH;
just before the onset of the activity period, the
adrenal cortex is the most sensitive to ACTH.
Consequently, we suspected that the SCN might
influence the adrenal gland also via the autonomic
nervous system.
In order to demonstrate such a putative connection
between the SCN and the adrenal cortex we
investigated, by means of transneuronal tracing, the
CNS neurons in command of the adrenal (Buijs et
al., 1999); first order neurons were found in the
IML. These neurons were shown to receive a
synaptic input from PVN neurons; next, second
order neurons were shown in the autonomic part of
the PVN. Interestingly, these neurons were shown
to receive an input from the SCN. Especially the
PVN dendrites received a strong SCN input, which
corroborated our earlier observations with pineal
and spinal cord retrograde tracing (TeclemariamMesbah
et al., 1997; 1999); furthermore, the third
order neurons found in the SCN were, among other
things, vasopressin- and VIP-containing neurons.
Interestingly, in addition to autonomic PVN neurons,
prefrontal cortex neurons are labeled after
tracer injection in the adrenal as well; the time of
appearance of these neurons is in between the
moments of appearance in the hypothalamus of the
2nd and 3rd order neurons (Fig. 6). Because the
distance to the spinal cord is further from the PFC
than from the hypothalamus, it is likely that these
neurons are also 2nd order (see chapter by Van
Eden and Buijs, this volume). This puts the PFC in
the same position as the PVN and some brain stem
nuclei, namely that it is able to affect the sympathetic
neurons controlling the adrenal directly.
Third order neurons in control of the adrenal
appear in the MPO, BNST, central amygdala and
128
subfornical organ, which is an interesting observation
because these areas are known to be involved
in the control of the HPA axis as well. The virus
tracing data consequently indicate that these structures
also have the capacity to influence not only
the neuroendocrine neurons of the PVN, but also
the sympathetic autonomic neurons of the PVN or
brain, and consequently also affect the neural
control of the adrenal. Interestingly, in spite of its
dense input to the PVN, the DMH contains just a
few 3rd order neurons, suggesting that the DMH
might largely interact with the neuroendocrine
PVN and that its interaction with the autonomic
PVN will thus be quite limited.
The hypothalamic projections from the medial
amygdala and ventromedial PFC are aimed especially
at the DMH and subPVN, and may
consequently serve to control, indirectly, the neuroendocrine
part of the PVN (Fig. 4). Interestingly,
with respect to their projections, large parts of the
dorsomedial PFC show a close resemblance to the
projections of the autonomic part of the PVN and
give input to (para)sympathetic in and output
regions of the brain stem such as the NTS and
nucleus ambiguus. Furthermore, similar to the
PVN, the dorsomedial part of the PFC also
provides input to the sympathetic motor neurons in
the spinal cord, located in the IML (Fig. 6).
CNS control of the adrenal
Fig. 6. Sagittal scheme of the rat brain illustrating the presence of first, second and third order neurons in control of the adrenal. After
pseudorabies virus injection in the adrenal, first order neurons appear in the intermediolateral column of the spinal cord (IML) where
the sympathetic preganglionic neurons are labelled. The next day second order neurons are labelled in the brain stem: the A5/
rostroventrolateral medulla (A5/RVLM) and locus coeruleus (LC). In the hypothalamus: the lateral hypothalamus (LH), the
retrochiasmatic area (RCA), the autonomic paraventricular nucleus (dorsal and ventral part) (PVNd) and the zona incerta (ZI). Only
in the prefrontal cortex are second order neurons detected. The next day third order neurons are detected in the brain stem and nucleus
tractus solitarius (NTS), hypothalamus, suprachiasmatic nucleus (SCN), arcuate nucleus (ARC), ventro- and dorsomedial
hypothalamus (VMH), medial preoptic area (MPO), subforuical organ (SFO), bed nucleus of the stria terminalis (BNST) and central
nucleus of the amygdala (Ace).
129
Moreover, the dorsomedial PFC not only projects
to the 1st order sympathetic or parasympathetic
motor neurons, but also to the zona incerta (ZI),
where a large group of 2nd order autonomic
neurons is located. This pattern of spatial separation
of autonomic and neuroendocrine projections
that can be discerned in the PFC, can also be
observed in a similar way in the amygdala; the
medial part of the amygdala contains the majority
of the neuroendocrine projections and the central
part the autonomic projections (unpubl. observations).
This spatial separation of projections within
the same anatomical structure does not necessarily
mean that these functions are also functionally
separated; intranuclear or intraregional interaction
has already been documented extensively for the
PFC and the amygdala. Of all the cortical and
neocortical areas, the autonomic projections seem
to be a specific property of the PFC and central
amygdala; even third order neurons are not
observed in other cortical or neocortical areas. The
close anatomical correlation with SCN projections
in and around the PVN warrants a comparison with
the SCN with respect to the way the SCN affects
physiology or homeostatic mechanisms.
As discussed above with respect to the role of the
SCN in adrenal control, several physiological
studies have demonstrated a daily variation in the
sensitivity of the adrenal to ACTH. Since light
selectively stimulates SCN neurons to become
activated, and SCN neurons in general have a low
electrical activity during the dark period, we
investigated blood corticosterone levels after subjecting
animals to nocturnal light exposure. Light
immediately decreased blood corticosterone levels
without affecting ACTH levels, but it did so only at
the beginning of the dark period (see Fig. 3). As we
could not see this effect in SCN-lesioned animals,
we took this as evidence for a multisynaptic
pathway between the SCN and the adrenal cortex
(Buijs et al., 1997, 1999); furthermore we did not
observe significant changes in blood adrenalin and
noradrenalin, indicating that the physiological
effect is indeed due to the neuronal effect on the
adrenal cortex. Interestingly, in humans, who,
contrary to rats, are day-active individuals, we
observed the opposite effect of light: an increase in
cortisol after light exposure only in the early
morning (Scheer et al., 1999a). Consequently, the
combined data show that the SCN is not only
capable of orchestrating the secretion of ACTH in a
timely manner, but also of setting the sensitivity of
the adrenal for the oncoming ACTH via its direct
and indirect projections to the PVN the SCN!
Since we also observed immediate effects of
light on the heart rate of healthy human subjects
and opposite changes on heart rate in rats (Scheer et
al., 1999b), we hypothesize that this SCN/ PVN
pathway transmits the circadian activity/rest setting
to all organs of the body. Since virus tracing from
many different organs produces, at least via the
sympathetic branch, more or less the same pattern
in the hypothalamus, PFC and amygdala, we are
confident that the PVN, SCN, PFC and amygdala
influence not only the adrenal cortex but also many
other organs in the body.
We would like to propose that the interaction of
the SCN with the autonomic nervous system and
the neuroendocrine system that we demonstrated,
not only goes for the SCN, but also for the PFC and
the amygdala. These two brain regions also seem to
have access both to the neuroendocrine and to the
autonomic system and it is suggested that they also
take care of setting the sensitivity of the peripheral
organs to different stimuli. There is a wealth of
literature that demonstrates that in depression or
other psychiatric disorders where dysfunction of
PFC or amygdala is known to be present, there are
pronounced disturbances of hormonal as well as
autonomic responses, especially after emotional
stimuli.
The changed sensitivity of the adrenal to ACTH
and the insensitivity to cortisol feedback as found
during depression and schizophrenia may support
this idea (Lammens et al., 1995); the PFC and/or
amygdala may influence the secretion of cortisol
from the adrenal directly, without using the HPA
axis. Lesion studies indicating an enhanced secretion
of corticosterone after ablating the PFC
indicate that the PFC plays an inhibitory role in
corticosterone secretion; data indicating enhanced
cortisol secretion in depression without simultaneous
elevation of ACTH support this idea. The
observation that the PFC is less active in depression
and certainly less active in schizophrenic patients
might be the basis for the observed endocrine and
130
autonomic changes in these patients. Furthermore,
observations of a correlated decrease in melatonin
secretion in depressive or schizophrenic patients
(Monteleone et al., 1997; Nathan et al., 1999) only
emphasize that a change in autonomic regulation
might be the basis of enhanced cortisol secretion in
depressive illness. The fact that this enhanced
cortisol secretion is insensitive to dexamethasone
feedback would suggest that these autonomic
projecting neurons have no sensitivity or a changed
sensitivity to glucocorticoids in depression.
Conclusion
The forebrain control of the neuroendocrine and
autonomic PVN shows many similarities between
the participating structures. The SCN, ventral
hippocampus, amygdala, septum and prefrontal
cortex all have access to the neuroendocrine PVN
via, mainly, indirect pathways.
The SCN has direct access to the autonomic
PVN and thus sets the sensitivity of the organs to
the hormones by a neuronal pathway. Consequently
the biological clock, the SCN, sets the endocrine/
autonomic balance, depending on the day/night,
sleep/wake rhythm.
The PFC and central amygdala have direct
access to sympathetic and/or parasympathetic
motor nuclei in brainstem and spinal cord. In this
way the amygdala and PFC resemble the PVN
functionally; within their anatomical boundaries
they control (via the PVN) the adenohypophysis,
or, directly, the autonomic nervous system.
The amygdala and PFC will set the endocrine/
autonomic balance, depending on the emotional
status. The information about the different set
points, time-of-day, emotion and food balance,
converges in the medial part of the hypothalamus
where the major players for regulating the homeostatic
balance are concentrated. We would like to
propose that this interaction forms part of the
explanation why emotional disturbances have such
profound effects on the homeostatic balance of the
individual and vice versa.
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