HYPOTHALAMUS and NEUROENDOCRINE SYSTEMS
FOUNDATIONS (ZABORSZKY,
2. Major Fiber Systems of the Hypothalamus
4. Hypothalamic Nuclei
5. Magno- and Parvocellular Neurosecretory System
6. Reflex Control of Vasopressin and Oxytocin Secretion
9. Behavioral State Control
12. Drinking
13. Temperature Regulation
1. Boundaries and Subdivisions
The hypothalamus forms the ventral part of the
diencephalon. The hypothalamus can be
divided longitudinally into periventricular, medial and lateral cell
groups. The medial and periventricular
hypothalamus contains most of the neurons concerned with regulation of the
pituitary, but also important efferent sources for projections to brainstem and
spinal autonomic areas. The medial
hypothalamus has, in addition, extensive reciprocal connections with the
medial division of the 'extended amygdala’.
The hippocampus, either directly or via the septum, also sends afferents
to medial hypothalamus. The lateral
preoptic-hypothalamic (LPO-LH) continuum
contain numerous cells which are interspersed among fibers of the medial
forebrain bundle (MFB). The LPO-LH area shares a wide variety of reciprocal
connections with the forebrain, caudal brainstem, and spinal cord. The physiology of this area is complicated by
the fact that many axons traverse this area which may or may not synapse
locally. Fig. 1 and Table 1 and 2
summarizes some of the functions of the hypothalamus.
2. Major Fiber Systems of the Hypothalamus
Some of the heavily myelinated hypothalamic fiber
tracts, e.g. fornix, mamillothalamic tract, stria medullaris, stria terminalis,
medial forebrain bundle can be identified by blunt dissections or using myelin
staining, however, the direction of fibers within these tracts can be
identified only by experimental tract-tracing methods.
Fornix. The fornix connects the hippocampal formation with the
septal area, anterior thalamus and hypothalamus.
Mammillothalamic Tract and Mammillary Peduncle.
The mammillary body in the caudal part of the hypothalamus is surrounded
by a capsule of heavily myelinated fibers.
Its function is not well known. Most of its efferent fibers leave the
mammillary body in a dorsal direction as the mammillothalamic tract, which
proceeds towards the anterior thalamic nuclei.
Collaterals of the mammillothalamic fibers form the mammillotegmental
tract, which projects to tegmental cell groups in mesencephalon. These cell groups in turn give rise to the
mammillary peduncle, which terminates primarily in the lateral mammillary
nucleus.
Stria Medullaris. The stria
medullaris, which can be easily recognized on the mediodorsal side of the
thalamus, connects the lateral preoptic-hypothalamic region with the habenular
complex. However, like most other
hypothalamic pathways, the stria medullaris is a complicated bundle that
contains many different
fiber components with various origins and terminations.
Stria Terminalis. The stria
terminalis reciprocally connects the amygdaloid body and the medial
hypothalamus. Similar to the fornix, the
stria terminalis makes a dorsally convex detour behind and above the
thalamus. It can be identified in the
floor of the lateral ventricle, where it accompanies the thalamostriate vein in
the groove that separates the thalamus from the caudate nucleus. In the region of the anterior commissure, the
stria terminalis divides into different components, which distribute their
fibers to the bed nucleus of the stria terminalis, medial hypothalamus and
other areas in the basal parts of the forebrain. The stria terminalis is an important pathway
for amygdaloid modulation of hypothalamic functions. The amygdaloid body is also related to the
lateral hypothalamus through a diffuse ventral pathway that spreads out
underneath the lentiform nucleus.
Dorsal Longitudinal Fasciculus The DLF is a component of an
extensive periventricular system of descending and ascending fibers, that
connects the hypothalamus with the midbrain gray and other regions in the pons
and medulla oblongata including preganglionic autonomic nuclei.
Medial Forebrain Bundle. The MFB
is an assemblage of loosely arranged, mostly thin fibres, which extends from
the septal area to the tegmentum of the midbrain. It traverses the lateral
preoptico-hypothalamic (LPO-LH) area, the scattered neurons of which are
collectively designated as the bed nucleus of the mfb. THe bundle is highly complex, comprising a
variety of short and long ascending and descending links.
3. Connections of the Hypothalamus
Most of the connections of the
hypothalamus consist of fine, unmyelinated fiber systems that cannot be traced
accurately in normal myelin- or fiber-stained preparations. As a result, much of what is now known about
the connections of the hypothalamus has been learned in the last decade or so,
since the introduction of the axonal tracer methods. These connections are summarized below.
Afferents
Cortical Inputs. Cortical inputs
to the hypothalamus in the rat arise primarily from insular, lateral frontal,
infralimbic, and prelimbic areas. These
afferents principally supply the lateral hypothalamic area.
Visceral inputs. The nucleus of
the solitary tract (NTS) projects directly to the hypothalamus in the rat. In the monkey and human, presumably the
visceral afferent influence from the NTS is relayed to the hypothalamus via the
projection of the NTS to the parabrachial nucleus.
Olfactory inputs. In rodents,
olfactory input arrives via relays in the olfactory tubercle, anterior
olfactory nucleus, corticomedial amygdala and olfactory cortex. From these regions, secondary olfactory
afferents terminate throughout the lateral hypothalamus.
Visual inputs may reach the hypothalamus via a direct retinal
projection. In all mammalian species,
including humans, some retinal fibers leave the optic chiasm and pass dorsally
into the hypothalamus, where they innervate the suprachiasmatic nuclei.
Somatosensory information may also reach the hypothalamus via a direct
route: a projection to the lateral hypothalamic area from wide-dynamic-range
mechanoreceptive neurons in the spinal dorsal horn.
Auditory input. Despite extensive study, no
direct projection to the hypothalamus from the auditory system has been
identified. Recently, however, it has
been shown that acoustic stimulation induce LH release in birds (MeiFang et
al., 1998). Many hypothalamic neurons respond best to complex sensory stimuli,
suggesting that the sensory information that drives them is highly
processed. It is likely, therefore, that
much of the sensory information that reaches the hypothalamus travels by
polysynaptic routes involving convergence of cortical sensory pathways in the
amygdala, hippocampus and cerebral cortex.
Monoamine cell groups. Each of
the classes of monoamine cell groups in the rat brainstem provides innervation
to the hypothalamus.
Projections from limbic regions. Hippocampal efferents via the
precommissural fornix-lateral septum innervates all three longitudinally
organized columns of the hypothalamus. Several cell groups of the amygdala
project via the stria terminalis or the ventral amygdalofugal pathway to the
hypothalamus. The ventral subiculum project via the medial corticohypothalamic
tract to the medial hypothalamic cell groups.
The Circumventricular Organs (CVOs). Chemosensory information
from plasma or CSF reach the hypothalamus via input from projections of CVOs.
CVOs has specialized fenestrated capillaries, permitting relatively large
molecules to leave the vascular bed and enter the extracellular milieu. Two of
these regions, the subfornical organ (SFO) and area postrema (AP) have
extensive connections with hypothalamic nuclei involved in neuroendocrine and
homeostatic regulation. Two other CVOs, the organon vasculosum laminae
terminalis (OVLT) and the median eminence (ME), are located within the
hypothalamus.
Efferents
The main outflow of hypothalamic nuclei are
directed 1) median eminence (parvocellular neurons), 2) posterior
pituitary (magnocellular) to influence neuroendocrine responses; 3) sympathetic
and parasympathetic pregangionic cell groups in the brainstem and spinal
cord to influence autonomic functions (primarily the dorsal, medial and
lateral parvocellular division of the PVN); 4) several cell groups in the
hypothalamus project to the amygdala, bed nucleus of the stria
terminalis, to the basal nucleus of Meynert, periaqueductal gray
(PAG), visceral sensory areas of the thalamus (ventroposterior
parvocellular nucleus) cerebral cortex (anterior insular cortex,
anterior tip of the cingulate cortex), and brainstem (nucleus of the solitary
tract= NTS, parabrachial
nucleus) to influence various behavioral responses.
4. Hypothalamic Nuclei (Fig. 2)
The suprachiasmatic nucleus
(SCN) has been identified as an endogeneous timekeeper. This nucleus receive afferents directly and
indirectly from the retina in order to synchronize otherwise free-running
circadian rhythms with the day-night cycle.
At least some of its actions, particularly on hormonal rhythms, appear
to be mediated via projections to the medial hypothalamus.
The paraventricular nucleus (PVN), in addition to
the magnocellular neurons, contain several subgroups of small (parvicellular)
neurons containing a variety of putative
neurotransmitters. Some of the
parvicellular neurons (e.g. CRF=corticotropin releasing factor) project to the
median eminence where they participate in the regulation of the anterior
pituitary. Other neurons in
the PVN project to sympathetic and parasympathetic autonomic
areas in the
medulla and the intermediolateral cell columns of the
spinal cord. The PVN has been implicated
in a variety of behaviors including feeding, thirst, cardiovascular mechanisms
as well as organization of autonomic and endocrine responses to stress.
The arcuate nucleus among
others contain dopamine which acts as a prolactin inhibiting factor at the
median eminence. In additions, its
neurons are eostrogen sensitive and project to the preoptic LHRH neurons. This circuit is involved in the regulation of
gonadotropin secretion and sexual behavior during female reproductive cycle.
The ventromedial nucleus
(VMH) in addition to its output to the median eminence, with their other
projections is thought to participate in the organization of reproductive
behavior, as well as in metabolic regulatory functions.
The dorsomedial hypothalamic
nucleus (DMH) among others is involved in mediating leptin actions to the PVN.
Fibers from the SCN via the DMH towards the locus coerules are suggested to
participate in circadian regulation of sleep and walking.
The mammillary body is at
the caudal border of the hypothalamus.
The lateral and medial mammillary nuclei are the recipient of a massive
input from the hippocampus that arrives via the fornix. These nuclei project via the
mammillo-thalamic tract to the anterior nuclei of the thalamus. These nuclei are frequently damaged in
Korsakoff's patients.
5. Magno- and Parvocellular Neurosecretory System (Fig. 3-6)
The magnocellular neurons of the supraoptic (SON) and paraventricular (PVN) nuclei along with scattered clusters of
large cells between these two nuclei comprise the hypothalamo-hypophyseal system. These cells send oxytocin and vasopressin
containing fibers to the posterior pituitary.
The latter is the well known antidiuretic hormone (ADH) and is released
in response to changes in the osmotic pressure of circulating blood or
extracellular space. ADH controls the water-balance. In plarticular, it is responsible for the
retention of water, which is regulated by the effect of vasopressin on the
distal tubules of the kidneys.
Oxytocin, through its effect on the uterine smooth
muscle and the myoepithelial cells of the mammary glands, promotes uterine
contraction during birth and milk ejection after birth. Potent stimulatory input for uterine
contraction reaches the brain via afferents from the vagina or cervix and the
nipples.
Hypothalmic (parvocellular) neurons originating in the preoptic, arcuate, ventromedial, periventricular, paraventricular nuclei transport a variety of releasing and inhibiting hormones to the portal vessels of the median eminence. These are then transported to the capillary beds of the anterior pituitary where they regulate the secretion of the pituitary troph hormones: TRH (Thyrotropin-Releasing Hormone) → TSH (Thyrotropin), CRH or CRF (Corticotropin-Relasing Hormone) → ACTH (Adrenocorticotropin Hormone), GnRH (Gonadotropin-Releasing Hormone) → FSH (Follicle-Stimulating Hormone) and LH (Luteinizing Hormone), GHRH (Growth Hormone-Releasing Hormone) and GHRIH (somatostatin) → GH (Growth Hormone), PRF (Prolactin-Releasing Factor) and PIF (Prolactin Release-Inhibiting Factor) → Prolactin, MRF (Melanocyte-stimulating hormone Releasing Factor) and MIF (Melanocyte-stimulating hormone release Inhibiting Factor) → MSH (Melanocyte-Stimulating Hormone). Figures 3 summarizes the design of the parvo- and magnocellular neurosecretrory system.
The magno- and parvocellular cell groups producing
the hypothalamic hormones receive a variety of stimuli from different parts of
the brain, primarily within the hypothalamus, but also from extrahypothalamic
areas including the amygdaloid body, hippocampus and various brainstem
areas. Furthermore, it is well known
that monoamines and several neuropeptides serve as modulators of the
neuroendocrine system, and both manoaminergic and peptidergic fibers, besides
those carrying the specific hypothalamic hormones, can be traced to the
periventricular zone and even into the median eminence, where they would have
an opportunity to interact with the parvicellular neurosecretory system or even
discharge neuroactive substances directly into the portal system. Figures 4-6
summarize the input-output relations of the PVN.
The
subject of neuroendocrine control mechanism is complicated further by the fact
that many neurons in the nervous system, including the hypothalamic
magnocellular and parvocellular neurosecretory neurons, contain two or even
several neuroactive substances. A well
known example is provided by the parvocellular CRF neurons in the PVN. They also contain vasopressin and the two
substances are released together into the portal vessels, through which they
are likely to cooperate in the control of ACTH-release from the adenohypophysis.
Hypothalamic neurons, including the neurosecretory neurons, are also subject to
hormonal feedback control. Such feedback
mechanisms are often quite complicated in the sense that they involve not only
the neurosecretory hypothalamic neurons but also hormone sensitive cells in
other brain regions, which in turn are in a position to modulate
hypothalamo-hypophysial function. Peripheral hormones (e.g. estrogen, etc)
exert their feedback actions also at the level of the median eminence and the anterior pituitary.
6. Reflex Control of Vasopressin and Oxytocin Secretion (Figs. 7-10)
The nonapeptides, oxytocin (OT) and vasopressin
(VP), two major biologically active hormones, are synthesized in separate cell
populations in the supraoptic and paraventricular nuclei of the
hypothalamus. These peptides are carried
by axoplasmic transport to various areas within the CNS and to the posterior
pituitary. OT and VP are released from
nerve endings in the neural lobe of the pituitary to reach the sytemic circulation
and influence primarily fluid balance (VP) and milk ejection/uterus contraction
(OT). In addition, by their axonal
projections in the CNS, VP and OT also play a role in neurotransmission.
Periphreal VP functions largely to maintain arteriolar
perfusion pressure and intravascular volume. One of the most potent effective stimuli
for VP secretion is a rise in extracellular osmolality. Although less potent, other indicators of
extracellular fluid depletion also stimulate VP release, including decreased
plasma volume (hypovolemia, hemorrhage), decreased blood pressure
(hypotension), and peripheral hypoxia or hyperkapnia or both. In
contrast, drinking fluids, even when they are hypertonic, results in an abrupt
fall in systemic VP levels, presumably via stimulation of osmoreceptors in the
oropharynx. In addition, various
stressors, fever, pain and nausea and emetic agents such apomorphine causes VP (and OT) release.
Circulating VP maintains extracellular fluid
balance by acting a) at the kidney, where it stimulates increased
retention of water and enhanced Na and Cl excretion, b) at arterioles,
where it is one of the most potent vasoconstrictors, c) it also modulate sympathetic
transmission and d) affect the baroreceptor reflex by a central
effect mediated by the area postrema. Peripheral VP has also been found to have
effects on hepatic glycogenolysis, platelet aggregation and blood coagulation.
Under emergency conditions, the peptide causes
vasoconstriction in skin, gastrointestinal tract and kidney. It serves to shunt blood from these tissues
to the brain, heart and lung.
Peripheral
Receptors and Pathways. Vasopressin is under tonic inhibitory influence
both from atrial receptors of the heart (low pressure receptors) and
from baroceptors (high pressure) in the aortic arch (X) and carotid
sinus (IX). Reduction in the discharge
of these receptors by a decrease in blood volume or blood pressure results in
the release of vasopressin. An
additional excitatory influence on vasopressin release is provided by carotid
body chemoreceptors and peripheral osmoreceptors. The signal from arterial baroreceptors,
cardiopulmonary receptors and peripheral osmoreceptors from the mesenteric and
hepatic vasculature is carried through the IX and X. nerves to the NTS. From the NTS information though GABAergic
neurons or directly may reach Al noradrenergic neurons which project to SON and
PVN VP neurons to stimulate VP release.
Bilateral carotid occlusion releases vasopressin and leads to activation
of carotid body chemoreceptors. It is
not clear, however, how the excitatory input from the chemoreceptors reach the
SON or PVN. A possibility is that
excitatory input to the VP neurons may arise from cholinergic neurons that lie
dorsal to SON. Indeed, ACh injected into
the SON results in nicotine mediated vasopressin release.
Central
Receptors and Pathways. Lesion studies established that both the
subfornical organ (SFO) and the AV3V (MPO, PPO, Mdn, OVLT) are involved in the
neural regulation of salt and water balance.
Both the SFO and the AV3V region are the major target for the dipsogenic
action of blood born ANG II. When blood
pressure falls, the kidneys release renin into the bloodstream. Renin triggers
a biochemical cascade that produces AII (angiotensin). ANG II is released from the periphery as a
chemical signal of hypovolemia and hypotension.
Additional evidence suggests that the SFO and OVLT and the magnocellular
neurons themselves may be sensitive to changes in extracellular osmolality and
sodium concentration. Afferents from the
SFO and AV3V reach both PVN and SON neurons. The projection from SFO to PVN and
SON use ANG II as transmitters.
In
addition, NTS afferents reach the AV3V region through the parabrachial
area. Afferents from the BST to PVN, SON
serve to integrate central cardiovascular and "limbic"
information.
Clinicopathology. The
lack of VP results in a condition known as diabetes insipidus (DI), which is
characterized by an increased production of urine (polyuria). The loss of fluid, in turn results in an
excessive thirst (polydipsia). Often DI
is caused by lesions of the base of the brain (e.g. tumors or skull fructures)
involving the SON, PVN or the hypothalamohypophyseal tract.
In contrast, circulating OT is best known in
female reproduction, where it is involved in the maintenance of parturition and
the initiation of lactation. Thus, OT
acts on the smooth muscle of the endometrium during labor and delivery to
increase the frequency and intensity of uterine contractions, and on the
myoepithelial cells surrounding mammillary alveolar glands to cause milk
let-down in response to suckling. An
increase in circulating OT also accompanies ejaculation in males. OT also stimulate the release of both insulin
and glucagon from the pancreas, and act on adipocytes, indicating that it plays
a role also in metabolic regulation related to feeding. Vaginal and uterine distension receptors,
somatic sensory receptors from the nipple and breast and nociceptive
information from much of the body are all relayed initially to the dorsal horn
of the spinal cord, from where axons project to the Al cell group and the
caudal NTS. From here, ENK, SS and
inhibin B pathways may mediate specific stimuli to OX neurons in the
hypothalamus.
7. Brain-Pituitary Gonadal Axis
(Figs. 11-17)
The hypothalamus plays a major integrative role in
the control of maternal and reproductive behavior, including sexual
development, and differentiation, as well as sexual behavior. Important stimuli for the various aspects of
reproductive functions come 'from a variety of exteroceptive and interoceptive
sources including circulating gonadal steroids.
Differences between male and female are not
limited to sexual organs and secondary sex characteristics; they are also
evident within the CNS. For example,
there is a sexually dimorphic nucleus of the preoptic area, which is
considerably larger in males and the same is true for a cell group in the
sacral spinal cord known as the nucleus bulbocavernosus.
The sex hormones, i.e. androgens and
estrogens, play important roles both in the development and differentiation of
the male and female sex organs and sexual behavior. GnRH producing neurons, responding to sensory
input and to circulating gonadal steroids, control the secretion of LH and FSH
from the anterior pituitary. GnRH
secreting neurons with projections to the portal system in the median eminence
are located in preoptic-anterior periventricular area. LH and FSH are released from the pituitary
into the systemic circulation in response to GnRH, and they travel to the
gonads, where they direct gamete production, as well as gonadal (testosterone
in male and estrogen and progesterone in female) hormone production.
Sexual behavior involves a number of general (e.g. respiratory and cardiovascular)
and specific (e.g. erection, ejacaulation, etc) responses mediated in large
part by the autonomic nervous system.
Although several of these specific responses represent involuntary or reflex
phenomena, descending pathways from the hypothalamus or basal forebrain regions
play a significant modulatory role. A
critical brain area in male copulatory behavior seems to be the medial preoptic
area, whereas feminine sexual behavior appears to be more dependent on regions
in and around the ventromedial nucleus.
GnRH
neurons are born outside the brain in the olfactory placod and migrate
caudally to their final positions in the septal, preoptic and anterior
hypothalamic areas. GnRH release into the portal bloodstream occurs in a
coordinated fashion, with distinct pulses of GnRH secretion. The pulsatile
stimulation of the anterior pituitary by GnRH leads, in turn, to pulsatile
release of LH and FSH from the pituitary gonadotropes into the peripheral
bloodstream. Multiple-unit recording electrodes placed in the medial basal
hypothalamus of rhesus monkeys have measured spikes of electrical activity that
correspond in time to pulses of LH release. These bursts of electrical activity
may come from GnRH neurons themselves or from neurons that impinge upon the
GnRH neural system and thereby govern its firing pattern. The question of how
GnRH neurons, distributed diffusely throughout the hypothalamus, coordinate the
release of discrete pulses of GnRH into portal bloodstream remains unanswered.
GnRH neurons might actually form an interconnected network. Anatomical studies
showing synapses between GnRH neurons, and perhaps cytoplasmic bridges between
adjacent GnRH neurons.
Synaptic
input from a variety of neuronal types has been reported, including other GnRH
neurons; dopaminergic, noradrenergic, serotoninergic; neurons containing GAD,
CRF, SP, NT, B-END, etc.
GnRH
release is affected by the negative feedback of steroid hormones at
the level of the hypothalamus. Steroid hormone (estrogen, progesterone)
negative feedback decreases the frequency of pulsatile GnRH stimulation of the
pituitary and thus results in decreased frequency of pulsatile LH release (e.g.
luteal phase). At the level of the hypothalamus, steroid hormones likely
modulate the firing of neurons that project to LHRH neurons, since the LHRH
neurons themselves lack estrogen receptors.
Pulsatile stimulation of the pituitary
by GnRH is necessary to maintain normal function of pituitary gonadotropes.
There is a fairly narrow window of acceptable frequency for stimulation of the
pituitary by GnRH to achieve normal gonadotropin secretion. Pulse frequency
faster or lower than once per hour usually leads to an inhibition of
gonadotropin secretion. The gonadal steroid hormones estradiol and
testosterone can negatively feedback at the levels of the hypothalamus and
pituitary to decrease the frequency of pulsatile gonadotropin secretion
and decrease the amplitude of LH pulses. In women, pulsatile LH secretion in
the early follicular phase of the menstrual cycle, when circulating
concentrations of ovarian steroid hormones are quite low, occurs at a frequency
of approximately one pulse per hour. As the follicular phase progresses, and
the developing ovarian follicles begin to secrete increasing amounts of
estradiol, slows to one pulse every 90 min. In the luteal phase of the
menstrual cycle, when the ovary is secreting large quantities of progesterone,
as well as estradiol, LH pulses occur at a frequency of once every 6-12 h. In
contrast, in man, LH pulse frequency remains rather stable throughout
adulthood, at approximately one pulse every 2-3 hr. However, testosterone
levels play a large part in determining this frequency, as seen by the effects
of castration.
Estrogen and cognition. It is well established
that estrogens affect the brain throughout the life span. Moreover, the effects
are not limited to the areas primarily involved in reproduction but also
include areas relevant to memory, such as the basal forebrain and hippocampus.
For example, there is extensive evidence that estrogen levels are correlated
positively with dendritic spine densities within CA1 of the hippocampus and
that estrogen administration ameliorates learning deficits and cholinergic
abnormalities in ovariectomized rats (McEwen). Also, there are sex differences
in the rate of development and the magnitude of age related impairments in
spatial reference memory (Markowska, 1999) that is paralleled with altered
estrogen levels. Figures 11-17 summarizes various aspects of the reproductive
cycle, including LHRH, LH, FSH, estradiol and progestreon regulation.
The
brain-pituitary-adrenal axis is a key player in an animal’s response to
stressful stimuli. Other participants are the adrenal medulla, which produces
NE and A and the autonomic nervous system, which modulates physiologic
functions through neurotransmitters.
Corticotropin-releasing
hormone (CRH) is a 41 amino-acid peptide expressed in the hypothalamus. The
region with highest expression is the medial parvicellular part of the PVN. CRH
neurons in the mpPVN project to the external ME, where peptides are secreted
into the portal bloodstream, through which they are transported to the anterior
pituitary. In addition to CRH, the same neurons in the PVN also express and
release vasopressin, although most of the VP is expressed in neighboring
magnocellular elements of the PVN that project to the posterior pituitary.
Corticotropes in the anterior pituitary express receptors for CRH and VP. In response to stimulation, corticoctropes
synthesize and release adrenocorticotropic hormone (ACTH). ACTH through the
systemic circulation binds and activate its receptors on the surface of cells
of the adrenal cortex. In response to receptor activation, adrenocortical cells
synthesize glucocorticoids.
Concentration of circulating glucocorticoids and ACTH show a daily rhythm. In humans, glucocorticoid levels peak around 7 AM and decline steadily throughout the day. The nadir is reached in the late evening at 7PM to midnight after which glucocorticoid levels begin to rise. The phase of the daily ACTH rhythm precedes that of the glucocorticoids by about 1-2 hrs. CRH expression of the PVN has also a daily rhythm, consistent with a negative feedback of glucocorticoids. Food intake, or the anticipation of eating is a major factor in controlling the CRH cycle, in addition to SCN.
Basal
activity of the brain-pituitary-adrenal axis oscillates, but the system is
activated under emergency conditions through neural input. In the hypothalamus,
the PVN appears to sum and integrate input from numerous loci. Input to PVN is
divided into several broad classes, like brainstem (catecholaminergic fibres
via the NTS convey viscerosensory information); hypothalamic or limbic inputs
(amygdala, septum, hippocampus, prefrontal cortex reach PVN primarily via the
bed nucleus of the stria terminalis). Blood-borne signals through neural
projection from SFO and OVLT apparently also reach stress-related PVN
parvicellular neurons.
Removal
of the adrenal, and hence of glucocorticoids, removes the negative feedback
effects of these steroids. In this situation, concentrations of CRH and VP mRNA
in the mp PVN increase.
Glucocorticoid
receptors are members of a superfamily of receptors that act as
ligand-regulated transacting receptors. In each case, the receptor protein
resides in the cytoplasm in a complex containing heat-shock proteins, which
fold the receptor into the appropriate configuration for recognizing
corticosteroid ligands. Upon steroid binding, the receptor moves to the nucleus
of the cell and interacts with specific hormone recognition (or response)
elements on the DNA, thereby changing transcription rate.
CRH
neurons of the PVN contain steroid receptors, and glucocorticoids inhibit
transcription of CRH and VP genes through genomic feedback However, numerous
other brain regions also express steroid receptors. These regions, including
the hippocampus exert negative feedback on the brain-pituitary-adrenal axis
through projections to PVN.
Chronic
administration of corticosteroid changes the morphology of field CA3 cell’s
dendrites. These changes may lead to cell death. On the other hand, dentate
granule cells are damaged by a lack of glucocorticoids: there is a dramatic
loss of these cells after adrenalectomy.
Stress
influences learning and memory. Aging and chronic stress can lead to
hippocampus dependent learning deficit via alteration of glucocorticoid
receptors.
The
hypothalamus play an important role in sleep regulation. Lesion of the preoptic
region produces insomnia in rats, wheras chemical or electrical stimulation of
this region causes sleep. In contrast, lesions of the caudal hypothalamus
produces somnolence, suggesting that this region is involved in arousal.
Recently, Saper and colleagues (Sherin et al; 1996), using the localization of
the protein product of the immediate-early gene c-fos, defined the location of
hypothalamic neurons that are active during sleep. These, (presumably
GABAergic) cells, located in the ventrolateral preoptic region (VLPO),
project to the caudal hypothalamic histaminergic cell groups in the
tuberomammilary nucleus (TMN), which promotes arousal and diffusely innervate
the cerebral cortex.
Several cell groups in the hypothalamus (see SUBCORTICAL ACTIVATING SYSTEMS) project diffusely to the cerebral cortex and have been postulated to be important in arousal. Recently, a 130 amino acid containing protein, called hypocretin (orexin) was isolated from the hypothalamus (Sutcliffe et al, 1997). In situ hybridization and immunocytochemical studies revealed that neurons expressing this protein are located exclusively in the tuberal region of the hypothalamus around the fornix. Although it is a restricted group of cells, their projection were widely distributed in the brain, including a diffuse projection to the cerebral cortex. Knockout mice that lack the gene encoding this protein show narcolepsy, indicating that this protein is important in arousal.
Saper suggests that between sleep and wake-promoting brain regions reciprocal interactions exist which results in stable wakefulness and sleep (Fig. 21). Disruption of wake- or sleep-promoting pathways results in behavioral state instability. For example, after lesion of the VLPO, the animals experience much more wakefulness. Similarly, hypocertin-knockout mice or narcoleptic persons fall asleep more rapidly than unaffected individuals.
The
circadian timing system is composed of central and peripheral neural elements.
Critical components include the photoreceptors and visual pathways (e.g
retinohypothalamic tract to the SCN), circadian clocks or pacemakers (such as
the suprachiasmatic nucleus) and output pathways (pineal gland, melatonin) to
couple pacemakers to effectors. SCN neurons are spontaneously active circadian
oscillator even when deprived of the afferent signals. With SCN lesions, the sleep-wake rhythm is
eliminated, but the amount of time spent asleep and awake and the amount of REM
and nonREM sleep is unaffected. Light establishes both the phase and period of
the pacemaker, and thus is the dominant entraining stimulus or Zeitgeber
(time-giver) of the circadian system. The pacemaker can be viewed as a somewhat
inaccurate clock, which must be repetedly reset.
The
circadian system responds to changes in luminance, the total amount of light,
but not to color, shape, movement or other visual parameters. The responsiveness of the circadian system is
not altered in mutant mice with retinal degeneration and nearly complete loss
of rods or cones. Recently, it has been shown that a small percentage (1-2% in
the rodent’s retina) of retinal ganglion cells are light-sensitive, contain a
protein melanopsin, register luminance levels and project to the SCN (Hattar et
al., 2002; Berson et al., 2002). It is suggested that this, separate visual
circuit, running in parallel with the image-forming visual system, encodes the
general level of environmental illuminmation and drives certain photic
responses, including synchronization of the biological clock with the
light-dark cycle, acute suppression of locomotor behavior, control of pupil
size, melatonin release, etc. Only a
subpopulation of retinal ganglion cells project to the SCN and the
intergeniculate leaflet (IGL), a thalamic component of the circadian timer
system. The IGL modulates entrainment by transmitting information about nonphotic
(locomotor) events to the SCN. The
ganglion cell-SCN circuit uses Glu as transmitter, the IGL uses GABA and NPY. A
5HT mediated projection from the raphe nuclei can regulate SCN oscillation.
The
SCN project to the subparaventricular zone and other hypothalamic
neurons and several other nonhypothalamic structures of the diencephalons.
Direct activation of these efferent circuits controls the expression of
circadian rhythmicity. SCN projections have peak daytime firing rates that are
about twice as fast as night rates. However, transplantation studies suggest
that humoral mechanism may play a role in rhythm regulation. In a series of an
elegant experiments, Aston-Jones (2001) have shown that an SCN-Dorso Medial
Hypothalamic (DMH)-locus coeruleus (LC) pathway is necessary for circadian
rythmicity in the LC firing. The transmitter of the DMH-LC may be
orexin/hypocretin. This route may be important in circadian regulation of sleep
and waking.
SCN
ablation results in loss of estrus cycles. The precise timing of the release of
GnRH to produce the LH surge is a function of a series of endocrine and neural
events that lead to proestrus, with the SCN providing the crucial temporal
signal.
In
habitats with marked seasonal variation of temperature and food supply,
survival of species requires seasonal regulation of reproduction. The SCN via
the PVN-intermediolateral column-superiocr cervical ganglion –pineal gland
route provides a pulse of melatonin secretion that faithfully mirrors the
lengths of day and night. Thus, the duration of the melatonin signal
allows the animals to track time on an annual basis.
Melatonin receptors were identified in the SCN,
the midline thalamic nuclei and the pars tuberalis of the anterior pituitary.
Melatonin can affect pacemaker function via its action on SCN cells.
Circadian
function is genetically controlled, and data indicate that function is
maintained by the expression of clock genes that code for specific proteins
that feed back on the nucleus to control their own production.
11. Food Intake (figs. 22-28)
The hypothalamus integrates a variety of sensory
stimuli, both synaptic and hormonal, and modulates autonomic outflow to
viscera.
Although recent work does not
support the conclusion that the VMH
functions as a satiety center, it remains possible that neurons in this nucleus
playing an important role in insulin secretion. It is also clear the SCN influences the temporal
organization of feeding. For example, nocturnal rodents normally feed almost
exclusively during the dark phase of the photoperiod, but rodents whoose SCN is
ablated feed throughout the light-dark cycle.
Leptin is a circulating hormone produced by white adipose
tissue and has potent effects on feeding behavior, thermogenesis and
neuroendocrine response. Leptin regulates energy homeostasis, its absence in
humans and rodents cause severe obesity. Congenital leptin deficiency resulting
from mutations within the leptin gene causes extreme obesity. Moreover, a
mutation in the leptin receptor gene results in morbid obesity, failure to
undergo puberty and decreased level of growth hormone and thyroid hormone.
However, most obese humans do not have mutations in the leptin or
leptin-receptor genes but have high levels of circulating leptin that fail to
prevent obesity. By analogy with diabetes mellitus, these people may have
functional leptin resistance and impaired responsiveness to circulating
leptins.
Within the brain, leptin’s main site
of action seems to be the hypothalamus. Leptin receptors localized to several
hypothalamic nuclei, including, the ventromedial, arcuate, dorsomedial nuclei.
This distribution of leptin receptors is consistent with a large body of
literature implicating the ventrobasal hypothalamus in feeding, as shown by
large lesions of the VMH that produced increased food intake and obesity. An
important target of leptin are also the NPY neurons of the arcuate
nucleus. NPY is a potent stimulator of food intake and leptin inhibit NPY
neurons. Expression of NPY mRNA in the arcuate nucleus is elevated in response
to fasting and in leptin-deficient ob/ob and leptin-resistent db/db mice. In
ob/ob mice and fasted rats, exogeneous treatment with leptin suppresses NPY
overexpression.
Leptin acts directly through hypothalamic long
form leptin receptors. The leptin
receptor have a docking site for janus kinases (JAK), a family of tyrosine
kinases involved in intracellular cytokine signaling. Activated JAK
phosphorylates members of the signal transduction and transcription (STAT) family of intracellular proteins. STAT
proteins, in turn, stimulate transcription of target genes that mediate some of
leptin’s cellular effect. Leptin can affect neuronal firing rate independently
of its tarnscriptional effect. This
response is absent in db/db mice which lack the functional long-form leptin
receptor, and thus cannot activate STAT proteins. Leptin also activate
immediate early genes in specific nuclear groups. Intraveneous leptin activates
several regions thought to be involved in regulation of energy balance, including
VMH, DMH and PVN nuclei. Leptin administration also activates cells in the
superior-lateral parabrachial nucleus that project a CCK containing
pathway to the VMH. Recently a
leptin-inducible inhibitor of leptin signal tarnsduction has been described,
which is rapidly induced in the hypothalamus following systemic leptin
administration.
Leptin
treatment activates neurons in the PVN. The PVN may regulate many of the
responses of leptin, as it has chemically and anatomically specific projection
to brain control sites involved in the maintenance of autonomic and endocrine
homeostasis. The PVN is uniquely
equipped to control activities both in the endocrine, autonomic and somatomotor
systems. It is populated by both magno
and parvocellular neurosecretory neurons, that project to the neurphypophysis
and to the portal system in the median eminence, thus can affect thyroide
hormone, growth hormone and ACTH secretion.
The regulation of the hypothalamo-pituitary adrenal axis, which is
controlled by CRF secreting neurons may be of special importance in this
context. For instance, corticosterone
affects the carbohydrate metabolism, and it is well known that different forms
of stress can influence eating behavior. Leptin regulates both the thyroid and
hypothalamo-pituitary-adrenal axis.
Parvocellular neurons in the PVN also project to the brainstem
parasympathetic and to the sympathetic preganglionic autonomic nuclei in the
medulla and spinal cord. Through these
pathways, the PVN can directly influence the hormone secretion from pancreas
and adrenal medulla as well as somatomotor activities, that may be relevant in
feeding behavior. Leptin receptors are in the PVN, but the highest density of
leptin receptor mRNA is in the ventrobasal hypothalamus, including the arcuate
nucleus. Microinjection of leptin into the arcuate nucleus area results in
anorexic response and icv injection of leptin no longer reduce food intake
after the arcuate nucleus has been destroyed, suggest that leptin effects on
PVN include inputs from leptin-responsive neurons from
arcuate nuclei to the PVN. Leptin signals from the arcuate nucleus are
mediated by NPY and POMC (pro-opiomelanocortin)/CART (cocaine-
and amphetamine-regulated transcript)-containing efferents.
Lesions of
the lateral hypothalamus can cause decreased food intake. Neurons in the LHA, including those that
contain melanin-concentrating hormone (MCH) project to the cerebral
cortex. Ob/ob (leptin deficient) mice have elevated level of MCH mRNA and this
overexpression is normalized by leptin administration. Another peptide, orexin/hypocretin is
found in the perifornical region (PFA) projecting to several areas of the
neuraxis, including the cerebral cortex may be important in mediating leptin
effect. Indeed, orexin icv injection increase feeding behavior. Figures 22-27
summarizes leptin receptor signaling and the various hypothalamic neuropeptide
signaling pathways involved in mediating leptin and insulin action.
Noradrenaline (NA) is synthesized in brainstem locus coeruleus and NTS region (A1
noradrenergic cell group). These areas project both caudally to the spinal cord
and rostrally to the hypothalamus, thalamus and cortex. In some of these
neurons, including those projecting to the PVN, noradrenaline is colocalized with
NPY. Like NPY, injection of noradrenaline into the PVN increases food intake.
The observation of elevated NA levels in the PVN of ob/ob mice may indicate
that increased NA signaling in th ePVN may contribute to hyperphagia induced by
leptin deficiency.
Dopamine.
Feeding effects of dopamine vary with the brain region under study. For
example, mesolimbic dopamine pathways, originating from the SN-VTA that project
to the nucleus accumbens, striatum and cerebral cortex seem to contribute to
the rewarding aspects of palatable food. In contrast, arcuate DA neurons seems
to inhibit food intake. In ob/ob mice the reduced arcuate DA level may
contribute to hyperphagia induced by leptin deficiency.
Serotonin.
Several centrally acting drugs developed for obesity treatment (e.g.
dexflenfluramine) increase 5HT receptor signaling and thereby suppress food
intake, whereas antagonists have the opposite effect. The 5HT2C
subtype is implicated in this process as knockout of this receptor increases
food intake. Leptin increases 5HT turnover and thus it is possible that at
least some of leptin’s weight-reducing effects are mediated through increased
5HT signaling.
According to a recent integrated model (Fig. 28), the adiposity signals, leptin and insulin stimulate a catabolic pathway (POMC/CART) and inhibit an anabolic pathway (NPY/AGRP) that originates in the arcuate nucleus. These pathways project to the PVN and LHA/PFA, where they make connections with central autonomic pathways that project to brainstem autonomic regions that process satiety signals. Afferent input related to satiety from the liver, gastrointestinal tract and from peptides such as CCK are transmitted through the vagus nerve to the nucleus of the solitary tract (NTS), where they are integrated with descending hypothalamic input. Net neuronal output from the NTS leads to termination of individual meals, and is potentiated by catabolic projections from the PVN and inhibted by input from LHA/PFA. Reduced input from adiposity signals (for example during diet-induced weight loss), therefore, increases meal size by reducing brainstem responses to satiety signals.
12. Drinking
Fluid homeostasis is regulated by several
interdependent mechanisms, one of which, i.e. the retention of water by the
kidney mediated by the hypothalamo-hypophysial vasopressin system, was
discussed above. Increased water intake
is another mechanism of replenishing body fluids. Although we often drink spontaneously,
drinking can also be activated by water deficit, i.e. deprivation induced
drinking. Deprivation-induced drinking
is regulated primarily by osmotic changes in the blood or a change in blood
volume, e.g. hemorrhage. The
osmoreceptors for drinking, like the ones regulating vasopressin release, are
located in the OVLT and neighboring medial preoptic area. Drinking in response to reduced blood volume
is initiated by two different mechanisms.
One type of input originates in mechanoreceptors in the pulmonary artery
and the vena cava, and reaches the hypothalamic integration centers for
drinking via the nucleus of the solitary tract.
Another important stimulus is blood-born, i.e. angiotensin II, which
activates the neural circuit for drinking behavior through its action on the
subfornical organ. As indicated above,
the subfornical organ is also an intermediary structure in another important
mechanism for fluid homeostasis, i.e. the place through which blood-borne
angiotensin II (which is released in increased amount in response to reduced
blood volume) can activate the vasopressin system to reduce the loss of water
through the kidney.
13. Temperature Regulation
In order to sense changes in body temperature and
in the surrounding temperature, thermoreceptors are located largely in the skin
(free nerve endings) and in the brain, where thermosensitive neurons are found
primarily in the preoptic-anterior hypothalamic area (PO-AH). The thermosensitive neurons in the PO-AH
sense the temperature of the blood that passes through this richly vascularized
region. Based on this information and
that from various peripheral receptors, neural assemblies both in the anterior
and posterior hypothalamus coordinate the activity needed to maintain the body
temperature within fairly narrow limits.
In response to increased body temperature, hypothalamic neurons initiate
a series of processes that result in heat -loss, including peripheral
vasodilatation and sweating. A drop in
the surrounding temperature leads to a series of events including peripheral
vasoconstriction, piloerection, increased metabolism and shivering in order to
preserve heat. Thermosensitive neurons appear to influence arousal mechanisms
integral to regulation of the sleep-wake cycle. For example, Dennis McGinty and
colleagues have shown that warming the preoptic region during waking suppresses
arousal–related neuronal activity in the caudal hypothalamus and in
magnocellular basal telecephalon neurons that have diffuse cortical
projections. The consequence of this experimental warming include decreased
motor activity, reduced metabolic activity and respiratory rate and enhanced
peripheral heat loss. All these effects are similar to changes that
characterize the onset of sleep.
The preoptic region of the hypothalamus also plays a role in producing fever. Circulating cytokines may act at or near the OVLT to elicit fever, and prostaglandin injection induces fever has been identified in the region surrounding the OVLT.
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