HYPOTHALAMUS and NEUROENDOCRINE SYSTEMS
FOUNDATIONS (01-27-05)
2. Major Fiber Systems of the Hypothalamus
4. Hypothalamic Nuclei
5. Magno- and Parvocellular Neurosecretory System
6. Summary of Hypothalamis Organziation
7. Reflex Control of Vasopressin and Oxytocin Secretion
13. Behavioral State Control
14. Temperature Regulation
The hypothalamus control autonomic,
behavioral and neuroendocrine functions (Plates 2-4).
1. Boundaries and Subdivisions (Plates 5-17)
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.
2. Major Fiber Systems of the Hypothalamus (Plates 18-22)
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 (BST), 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 (Plates 23-30)
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 and innervate lateral and medial zones. In addition, the hypothalamus receive
indirect input from the prefrontal cortex, hippocampal formation and the
basolateral amygdale via the n. accumbens.
Visceral inputs. Viscerosensory
information reaches the hypothalamus via ascending projections of the nucleus
of the solitary tract (NTS), that receives input from the major visceral organ
by way of the glossopharyngeal (IX) and vagal (X) cranial nerves. The NTS is
the first region in the CNS that process information about visceral,
cardiovascular, respiratory functions as well as taste. 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. Neurons in the paraventricular
hypothalamic nucleus and the lateral hypothalamic area receive direct
(synaptic) input from the NTS.
Olfactory inputs. Both the main
and the accessory olfactory bulb (AOB) indirectly provide input to the
hypothalamus. 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. Plate shows how pheromonal information from the AOB
through distinct subnuclei in the amygdale and bed n. of the stria terminalis
reach various medial hypothalamic cell groups to modulate defensive,
reproductive, autonomic and endocrine responses.
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, the
endogeneous circadian clock. A second visual input to the hypothalamus
originate in ventral lateral geniculate body and ends in the subparaventricular
zone and the SCN itself.
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. Another route by which the
hypothalamus receive somatosensory and auditory input is the peripeduncular
area, which lies in the area ventral to the medial geniculate body.
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 (Mei Fang-Cheng
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. A distinct subdivision of the
hippocampus, the subiculum, project through the postcommissural fonix to the
mammillary bodies. 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
basolateral amygdaloid nucleus that receive inputs from the secondary motoer,
cingulated, insular, prelimbic, entorhinal and perirhinal cortical areas
project directly to the VMH. Additional ‘limbic’ input reaches the hypothalamus
via the lateral septum, bed n. of the
stria terminalis, medial
amygdalar nuclei. At the simplest level of analysis, amygdalar input is
involved at elast in the transmission of
olfactory (pheromonal), whereas the hippocampal input is involved in
transmitting information related to exploratory behavior.
Blood-borne stimuli. Information from plasma or CSF reaches the
hypothalamus via input from projections of
Circumventricular Organs (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. In addition, lippophilic hormones such as
gonadal, adrenal steroids, thyroid
hormones, and angiotensin II readily
cross the blood-brain barrier into the hypothalamus, where they may influence
neuronal firing rates and/or the synthesis of neurotransmission related
molecules. A number of molecules related
to metabolism (glucose) act on hypothalamic cells. And finally, osmoreceotors
in the subfronical organ and region of the median preoptic area are sensitive
to ion concentration of the blood to influence thirst and body water
homeostasis.
Hypothalamic Efferents (Plate 27-29)
The main outflow of hypothalamic nuclei are
directed 1) median eminence
(parvocellular neurons influencing the anterior pituitary), 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 originating in 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), various nuclei of the
rostromedial zone of the dorsal thalamus, cerebral cortex
(anterior insular cortex, anterior tip of the cingulate cortex), and brainstem
(NTS, parabrachial nucleus) to
influence various behavioral responses.
Cortical regions receive indirect hypothalamic influences via various thalamic
nuclei, via cholinergic and GABAergic neurons of the substantia innominata and
deep amygdaloid nuclei. Also, there are descending hypothalamic projections to
brainstem areas (dopaminergic ventral tegmental area, serotoninergic raphe,
noradrenergic locus coeruleus, mesopontine cholinergic neurons) that in turn
project to the cerebral cortex. The hypothalamus also projects directly to the
nucleus tractus solitarius and parabrachial nucleus, and may thus ‘gate’ the
flow of specific from the IX and X nerve to the thalamus and cerebral cortex.
Through these relays primarily prefrontal (infralimbic, prelimbic), agranular
insular and ventral subicular areas receive hypothalamic input. The hypothalamus also provides direct input
to the entire cortical mantle. These
hypothalamo-cortical fibers contain MCH, orexin, histamine, GABA (see ASCENDING
MODULATOR SYSTENS)
4. Hypothalamic Nuclei, Areas (Plates 9-17)
Four lines of evidence support
the view that the suprachiasmatic nucleus (SCN) is the dominant
mammalian endogeneous timekeeper. 1)
This nucleus receive afferents directly (retinohypothalamic tract) and
indirectly (via the LGN) from the retina in order to synchronize otherwise
free-running circadian rhythms with the day-night cycle. 2) Lesions of the SCN typically alter only
the temporal organization of a function (see later), the function itself is not
changed. 3) Isolation of the SCN either in vitro or in vivo, does not alter its
ability to generate circadian signal. 4) Transplantation of a fetal SCN into
the third ventricle of arrhythmic hosts with SCN lesions restores circadian
rhythm with a period that reflects donor, not host, rhythm (Moore, 2002). 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 vasopressin and oxytocin 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 subparaventricular zone (SPVZ) is thought to
play a role in amplifying circadian output from the SCN
The supraoptic nucleus (SON) contain vasopressin
and oxytocin and project with similar axons originating in the PVN to the
posterior pituitary.
The anteroventral third ventricle region (AV3V) is a term that encompasses several preoptic subnuclei and the OVLT that is important in osmo-and volum regulation.
The ventrolateral preoptic area (VLPO) is a
recently coined term to define cells that are sleep-active.
The arcuate nucleus (ARC)
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 waking.
The tuberomammillary nucleus (TMN) is located in the caudoventral part of the lateral hypothalamus. Its neurons contain the sleep-active histamin projection system.
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.
Lateral hypothalamic/perifornical(LHA/PFA)
contain several peptidergic cell groups, including orexin/hypocretin,
melanin-concentraing (MCH) neurons, that ate participating in general arousal,
feeding, etc.
5. Magno- and Parvocellular Neurosecretory Systems (Plates 35-45)
Two distinct neurosecretory systems. 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 where these substances are
released into the peripheral circulation.
Vasopressin 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 particular, it is responsible for the
retention of water, which is regulated by the effect of vasopressin on the
distal tubules of the kidneys. Plate
36a shows schematically the mechanism by which vasopressin or oxytocin is
transported, processed, packaged and released in the posterior pituitary.
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.
The parvocellular neurosecretory neurons originating in the preoptic, arcuate, periventricular, paraventricular nuclei transport a variety of releasing and inhibiting hormones to the portal vessels of the median eminence. Fenestrated capillaries loop through the median eminence and coalesce to form long portal vessels that travel along the infundibular stalk where they are continuous with vascular sinuses in the anterior pituitary. These substances 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=dopamine) → Prolactin, MRF (Melanocyte-stimulating hormone Releasing Factor) and MIF (Melanocyte-stimulating hormone release Inhibiting Factor) → MSH (Melanocyte-Stimulating Hormone).
Hormonal and transynaptic regulation. 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 monoaminergic 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.
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. Examples
of feedback regulation of hypothalamic
releasing-hormon producing cells are depicted diagrammatically in case of the
LHRH and CRF regulation.
Characteristics of neurohormone
release. The release of
hypothalamic hormones occurs in a pulsatile manner. Thus, brief pulses of these
hormones generally occur at intervals of 1-2h (ultradian= shorter than
daily rhythms) or circhoral (approx. hourly). The corresponding anterior
pituitary cells respond to each pulse of a hypothalamic hormone with a
corresponding pulse of its pituitary shortly thereafter. It has been suggested
that the pulsatile release of hypothalamic hormones is necessary to prevent the
desensitization of the receptors in the anterior pituitary gland. Along with these ultradian (or circhoral)
rhythms are the circadian or diurnal rhytms of hormonal release. These 24-h rhythms of hormonal release, which
can occur independently of the light/dark cycle (circadian) or are
entrained to the light-dark cycle (diurnal) have been described for all
of the neuroendocrine systems. Circadian rhythms are driven by the SCN.
Finally, longer, yearly (seasonal) cycles of hormonal release is most
apparent for the reproductive axis. Many species are seasonal breeders and are
only sexually active during certain periods of the year.
6. Summary of Hypothalamic
Organization (Plates 31-34)
Magno-and parvocellular
neruosecretory neurons. Neurons
of the magnocellular neuroneurosecretory (vasopressin, oxytocin) are located in
the supraopric (SON), paraventricular (PVN) nuiclei and in the are in between
these two nuclei (often called accessory supraoptic). GHRIH (somatostatin),
TRH, CRH, dopamine and GHRH parvicellular neurons are centered in a more or
less continuous zone that includes the parvicellular paraventricular, anterior
periventyricular and arcuate nuclei of the hypothalamus. In contrast, GnRH
parvicellular neurons are centered more rostrally in the medial preoptic-medial
septal-diagonal band complex. This latter location reflects the unusual origin
of GnRH neurons: they are generated in the olfactory placode and migrate to the
basal forebrain along the terminal and/or vomeronasal nerves. It is thought
that all other magnoc and parvocellular neurons are generayed from the
neuroepithelium of the ventral diencephalons.
Preautonomic cell groups. Several neurons in the parvicellular division of
the PVN and scattered neurons in the retrochiasmatic area and lateral
hypothalamus project directly to all of the preganglionic parasympathetic and
sympathetic cell groups of the brainstem and spinal cord (see Prof. Levin’s
lecture).
The behavioral control column. Recent
analysis (Swanson and coworkers) suggest that there is a distinct nuclei in the
medial regions of the hypothalamus (and midbrain) that plays an essential role
in controlling the expression of motivated behaviors. Special cell groups in the preoptic, anterior
hypothalamic, paraventricular, ventromedial-tuberal and premammillary nuclei
control expression of ingestive (food and water intake) defensive and
reproductive behaviors (see Swanson’s scheme for more details).
Hypothalamic visceromotor pattern generator
(HVPG) network. A high resolution PHAL analysis of axonal connections (Sawnson and coworkers) suggests the
existence of a visceromotor pattern generator network in the periventricular
region of the rat hypothalamus (HVPG). Six nodes identified thus far include
the dorsomedial nucleus and five small nuclei in the preoptic region
(anteroventral and anterodorsal preoptic, parastrial, median preoptic, and
anteroventral periventricular). Aside from its location between the
neuroendocrine ‘motor’ zone (periventricular mango- and parvocellular neurons)
and the medial hypothalamic behavior control column (see above), two other
primary features characterize the HVPG network. First, each HVPG nucleus
generates a pattern of terminal fields that differentially targets a unique set
of hypothalamic neuroendocrine motoneuron pools, and of preautonomic parts of
the paraventricular nucleus. Second, the six HVPG nuclei are massively
interconnected themselves. The idea of the HVPG is similar to motor pattern
generators that control locomotion, chewing, swallowing and eye movements. In
principle, a central motor pattern generator may be defined as a local circuit
network that generate a basic response pattern that is intrinsic to the network
and that is modulated by neural inputs from the
cerebral hemispheres, sensory systems,
behavioral state-related cell groups, and the hypothalamic behavior or
motivation control column. It is
envisioned that this HVG network coordinate the complex endocrine and autonomic
visceromotor responses to various physiological (for example hot or cold
environment) and psychological (e.g. restraint) challenges. Also, it is
suggested that the endogeneous circadian rhythm generator, the suprachiasmatic
nucleus influences visceromotor responses via the HVPG, rather than via direct
input to neuroendcorine motorneuron pools or to the preautonomic neurons in the
PVN.
Model of hypothalamic organization. According to Swanson’s analysis, it appears that
the behavior control column has ‘descending’ projections to brainstem
somatomotor and sometimes autonomic regions and ‘ascending’ projections to the
tahalamo-cortical loop, but little if any direct input to the neuroendcorine
motor zone. Instead the behavioral control column projects in a highly topographic
way to the adjacent visceromotor pattern egenrator network, which in turn
issues a complex set of projections to various combinations of neuroendcorine
motorneuron pools and to preautonomic cell groups in the PVN. This arrangement
is in a position to allow fro the coordinate expression of somatomotor,
autonomic and neuroendcorine responses that are appropriate for specific
classes of motivated behavior (ingestive, reproductive and defensive).
7. Reflex Control of Vasopressin and Oxytocin Secretion (Plates 45-49)
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.
The vasopressin gene encode a 145 amino acid
prohormone that is packaged into neurosecretory granules of the magnocellular
neurons. During axonal transport of the granules from the hypothalamus to the
posterior pituitary, enzymatic cleavage of the prohormone generates the final
products: VP, neurophsyin and a carboxy-terminal glycoprotein. When afferent
stimulation depolarizes the VP-containing neurons, the three products are
released into capillaries of the posterior pituitary. 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 plasma 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.
Effectors.
Circulating VP maintains extracellular fluid balance by acting a) at the kidney,
where it stimulates (through VP receptors) 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 Osmo- Chemo 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. The signal from arterial baroreceptors,
cardiopulmonary receptors and peripheral osmoreceptors (in 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. An excitatory influence on vasopressin release
is provided by carotid body chemoreceptors and peripheral osmo- and
stretch[pressure]-receptors. 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. However, the cholinergic input eventually reach VP neurons in
the SON through inhibitory local GABAergic neurons.
Clinicopathology. The
lack of VP results in a condition known as diabetes insipidus (DI, Brattleboro
rats), 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 (Plate 38).
8. Central and peripheral control of
osmo- and volume regulation. Thirst. Drinking (Plates 50-51)
Body fluid homeostasis is directed at
achieving stability in the osmolality of body fluids and the volume of the
plasma. Such homeostatic regulation is promoted by several mechanisms intrinsic
to the physiology of body fluids (intar-extracellular) and the cardiovascular
system. For example, the osmotic movement of water across cellular membranes
rapidly buffers changes in the osmolality of extracellular fluid. Similarly,
the movement of fluid across capillary membranes buffers acute changes in
plasma volume, as does venous compliance and compensatory alterations in the
kidney glomerular filtration rate. Nevertheless, changes in body fluid
osmolality and plasma volume maybe so large that additional mechanisms must be
recruited to maintain homeostasis. These responses include central control of
water and sodium excretion in urine through specific actions of hormones, and
the central control of water and sodium consumption motivated by thirst and
salt appetite (Striker and Verbalis, 2002).
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, near the anterior
wall of the 3rd ventricle (AV3V).
Additional evidence suggests that the SFO and OVLT and the magnocellular
neurons themselves may be sensitive to changes in extracellular osmolality and
sodium concentration. Additional osmo-
or Na receptors are located in the area postrema that project to the NTS. NTS afferents reach the AV3V region also
through the parabrachial area. Afferents
from the bed nucleus of the stria terminalis to PVN, SON serve to integrate
central cardiovascular and "limbic" information.
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-borne, when blood pressure falls, the kidneys release renin into the
bloodstream. Renin triggers a biochemical cascade that produces angiotensin II
(ANGII, Plate 37-38), which activates the neural circuit for drinking behavior
through its action on the subfornical organ.
The subfornical organ is 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. The neural pathways connecting the SFO and AV3V with
magnocellular cells in the SON and PVN have been identified, and use ANG II as
transmitters.
When body fluid is hyperosmolal, adaptive behavior includes not only drinking and conserving water, but also excreting sodium and avoiding the consumption of additional osmoles. Endogeneous natriuretic agents promote urinary sodium loss after an administered sodium load. One such agent is the hormone atrial natriuretic peptide (ANP), which is synthesized in the atria of the heart and released when increased intravascular volume distends the atria. ANP is also synthesized in central neurons of the hypothalamus. Another is the hormone oxytocin. Like VP, OT is secreted from the posterior pituitary in proportion to induced hyperosmolality. OT is as potent in stimulating natriuresis as VP is in stimulation antidiuresis. Renal Na+ retention is mediated largely by aldosterone secreted from the adrenal cortex. The secretion of aldosteron is stimulated by ANGII and ACTH. Note that aldosterone can eliminate Na from urine, whereas VP primary effect is antidiuresis. Circulating oxytocin also inhibit salt appetite.
9. Brain-Pituitary Gonadal Axis (Plates 52-55)
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.
Sexual behavior involves a number of general
(e.g. respiratory and cardiovascular) and specific (e.g. erection, ejaculation,
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 (luteinizing) and FSH (follicle stimulation) from the pituitary
gonadotropes into the peripheral bloodstream, where they direct gamete
production, as well as gonadal (testosterone in male and estrogen and
progesterone in female) hormone production. In male, LH is responsible for
steroidogenesis and FSH for spermatogenesis. These hormones bind to their respective
LH or FSH receptors, which are G-protein-coupled receptors found in target
tissues of the ovary and testis.
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. 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 GABA, CRF, substance P (SP), neurotensin (NT), Beta-endrorphin (B-END). It is possible that GnRH neurons coordinate their pulses via some signals at the level of the median eminence where the GnRH terminals converge. Alternatively, afferents contacting GnRH neurons may release their transmitters in a pulsatile manners, and this may be a way of coordinating the widely scattered GnRH perikarya to release pulses of GnRH in a coordinated manner.
Sex steroid hormones. Sex steroid hormones are synthesized from the precursor cholesterol in a multistep process. Cholesterol is first converted to pregnenolone, which is converted to progesterone. Progesterone serves as a precursor for the synthesis of testosterone. Testosterone is the major steroid hormone in males and serves as a precursor for 5alfa-dihydrotestosterone, which is responsible for mnay of the masculinizing effects of steroids in males and for 17B-estradiol, which is the primary estrogen responsible for sexual behavior in females. The sex steroid hormones bind to their receptors which are localized intracellularly in the cytoplasm and/or the nucleus. The binding of a steroid hormone to its receptor, and subsequent receptor dimerization in the nucleus, allows these transcription factors to bind to specific sites on the promoter of the target gene. This enables the receptor-ligand complexes to induce or repress gene transcription in their target tisseus.
Pulsatile stimulation of the pituitary
by GnRH is necessary to maintain normal function of pituitary gonadotropes.
When GnRH is infused continuously, the GnRH receptor in the pituitary is
downregulated and gonadotropin secretion is inhibited. 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. 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.
A key event in the regulation of cyclic
ovarian function is the midcycle gonadotropin surge. The dominant follicle responds to FSH and LH
by greatly increasing estradiol synthesis in the last few days of the
follicular phase. The sustained high levels of estradiol act at the
hypothalamus and pituitary to cause a positive feedback effect such that
a large outpouring of LH and FSH is released from the pituitary. This very high
levels of LH and FSH released during the surge trigger the final maturation of
the ovum within the dominant follicle and trigger ovulation of that follicle.
Both the magnitude and the duration of elevated estradiol are critical for the
induction of the gonadotropin surge. Estradiol elicits positive feedback by
acting at the level of the hypothalamus to increase GnRH release and at the
level of the pituitary to increase gonadotrope sensitivity to GnRH. The
mechanism of the estradiol positive feedback action is unknown. It is possible that the ‘switch’ between
estrogen negative and positive feedback onto GnRH neurons in females may be
mediated by different transmitters that inhibit or stimulate, respectively GnRH
cells depending on their exposure to various levels of estrogen. Also,
measurement of GnRH release during the surge is not pulsatile,
suggesting, that the surge may involve a GnRH release mechanism that is
distinctly different from the normal, pulsatile GnRH release mechanism.
Although the hypothalamo-pituitary system plays a critical role in producing
the midcycle gonadotropin surge, the timing of events in the ovarian cycle
clearly is regulated by the ovaries.
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 et al., 1997). 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. There are several mechanisms for estrogen actions: 1) estrogen may
cooperate with nerve growth factor (NGF). For example both estrogen and NGF
receptors are expressed in the same basal forebrain neurons and estrogen and
NGF mutually enhances the binding of each other to its receptors. 2) Estrogen
induced dendritic changes are related to increased expression of NMDA receptors
and estrogen also enhanced LTP. 3)Estrogen may act as antioxidant disrupting
free radicals and protect beta-amyloid exposure induced cell death. These findings may explain the mild
beneficial effect of estrogen-treatment in Alzheimer’s disease.
The HPA axis is a key player in an animal’s
response to stressful stimuli. Other participants in the stress response are
the adrenal medulla, which produces noradrenaline and adrenaline and the
sympathetic 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 median eminence, 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).
Adrenocorticotropic hormone. ACTH derives from the
cleavage of a precursor protein, proopiomelanocortin (POMC), in the
corticotropes. POMC is cleaved to a number of smaller peptides, including
B-endorphin, B-MSH, gamma-MSH. ACTH is the primary effector of the stress
axis. ACTH through the systemic
circulation binds and activate its receptors on the surface of cells of the
adrenal cortex. The ACTH receptor is a member of the melanocortic family of
receptors. It is a seven transmembrane domain G-protein-coupled receptor
expressed primarily in adrenal cortex. The binding of ACTH to its receptor
activates adenylate cyclase and cAMP production. In response to receptor
activation, adrenocortical cells synthesize glucocorticoids (corticosteroids:
corticosteron in rats; cortisol in humans).
Pulsatile and circadian release of CRH and
ACTH. Concentration of circulating glucocorticoids and ACTH show a
circadian rhythm (Plate 55). 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 mRNA levels precedes
the increase in glucocorticoid release by several hours. A similar pattern of
glucocorticoid release is seen in rats, with highest levels when animals are
awakening (in the case of rats, this is in the evening) and lowest level in the
morning. SCN lesion abolishes the CRH rhythm. Food intake, or the anticipation
of eating is a major factor in controlling the CRH cycle. The feedback of
glucocorticoids onto brain and pituitary negatively regulates the synthesis of
CRH and ACTH: therefore, this neuroendocrine system is a classical negative
feedback loop. 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.
Various neural inputs regulate CRH secretion. Basal activity of the brain-pituitary-adrenal axis oscillates: CRH is released in a pulsatile manner from terminals in the median eminence, 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.
Glucocorticoids. Corticosteroids are necessary for normal fetal
development. Enzymes in the liver, GI
system, lungs and adrenal medulla are stimulated by glucoocrticoids. There, glucocorticoids alter glucose metabolism
and energy use (glucocorticoids promote the production of glycogen synthetase).
Glucocorticoids exert effect on cardiovascular system, causing elevation in the
heart rate, BP in close coordination with the autonomic NS. In general, their role is to mobilize energy
stores and to improve cardiovascular tone. Glucocorticoids also modulate immune
responses and inhibit cytokine production, thereby inhibit inflammatory
responses.
CRH
regulation through glucocorticoid receptors. 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 translocates 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 via a GABAergic link in the bed n. of the
stria terminalis on the brain-pituitary-adrenal axis through projections to
PVN.
Pathology
of the HPA axis. The negative
feedback loop of CRH-ACTH-glucocorticoids is kept in a delicate balance. In
response to stress, there is a large increase in the activity of the stress
axis, but the system is downregulated rapidly by negative feedback from the
glucocorticoids to the brain and pituitary gland, causing it to return the
output of the stress axis to basal levels. However, the stress axis can be
disrupted by psychological stressors such as mood disorders that can
chronically disregulate the HPA axis (PTSD). Hyperadrenocorticism (Cushing
syndrome) is concomitant with immunosupression, osteoporosis, muscle
atrophy. Underactivity of the stress axis (Addison syndrome) is
characterized by increased susceptibility to inflammatory and autoimmune
disease, muscle weakness and changes in skin pigmentation. Stress influences learning and memory.
Aging and chronic stress can lead to hippocampus dependent learning
deficit via alteration of glucocorticoid receptors. 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. Moreover,
neurogenesis in the adult dentate gyrus also appears to be glucocorticoid
dependent.
11. Central control of food intake
(Plates 61-64)
Food-intake
is a complex process in which various hypothalamic neurons [PVN, arcuate,
ventromedial and lateral hypothalamic–perifornical neurons (LHA, PFA)] are
participating that integrate sensory inputs from the viscera and influence
autonomic outflow to viscera. Similarly a host of transmitters (noradrenaline,
serotonin, dopamine) peptides (NPY, CART) and blood- borne substances (insulin,
leptin) with their receptors on various hypothalamic neurons are involved in the central regulation of
food intake.
According to a recent integrated model, the adiposity signals, leptin
and insulin stimulate a catabolic pathway via POMC/CART neurons and
inhibit an anabolic pathway (NPY/AGRP) both originating 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 gastrointestinal tract
(gastric distension), from gut peptides such as CCK (which is secreted during
meals) are transmitted through the vagus nerve to the nucleus of the
solitary tract (NTS), where they are integrated with descending
hypothalamic input from leptin/insulin sensitive neurons. Also, the NTS is the
site where sensory input from the viscera is integrated with input from the
taste buds. Net neuronal output from the NTS leads to termination of individual
meals, and is potentiated by catabolic projections from the PVN and inhibited
by input by anabolic input from LHA/PFA.
Arcuate nucleus. 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. Leptin signals in the arcuate nucleus are
mediated by POMC (pro-opiomelanocortin: alpha MSH) and CART
(cocaine- and amphetamine-regulated transcript)-containing efferents that are
activated by the action of leptin.
Alpha-MSH and CART are potent catabolic peptides, and when either is administered
locally in the 3rd ventricle, animals eat less food, have increased
energy expenditure, and lose weight. The other type of arcuate neuron
influenced by adiposity signals synthesizes neuropeptdie Y (NPY) and
agouti-related protein (AGRP). Both
peptides are potent anabolic compounds in that the administration of either
into the 3rd ventricle results in hyperphagia, reduced energy
expenditure and weight gain. Neurons containing NPY and AGRP express both
leptin and insulin receptors and the local administration of either insulin or
leptin near the arcuate nucleus reduces the synthesis of both NPY and AGRP.
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. Endogeneous levels of
NPY in the arcuate-PVN system normally peak when daylight ends and nocturnal
activity begins, which is also the time when rats typically eat their largest
meal of the day.
Paraventricular nucleus. 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. 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 treatment activates neurons in
the PVN. The PVN may regulate many of the responses of leptin, it receive
projections from leptin-responsive neurons of the arcuate nucleus and has
chemically and anatomically specific projection to brain control sites involved
in the maintenance of autonomic and endocrine homeostasis. Oxytocin secreted from PVN neurons
but projecting within the CNS rather than to the pituitary has also appetite suppressive effect.
Plates show the localization of NPY and POMC (alpha
MSH) neurons in the arcuate nucleus and their projections to oxytocin, CRH and
TRH neurons in the PVN (which causes anorexia). Arcuate POMC axons also contact
orexin and MCH neurons in the LHA/PFA areas whose action increase feeding.
Plate 50 shows the putative mechanism of obesity and anorexia in leptin/insulin
deficiency and increased leptin/insulin signaling, respectively. Reduced
leptin/insulin levels in the brain during diet-induced weight loss increases
activity of anabolic pathways that stimulate eating. Increased leptin level by
inhibiting NPY and facilitating alpha-MSH neuronal systems results in anorexia.
Ventromedial hypothalamic nucleus
(VMH). Although
recent work does not support the conclusion from early lesions studies that VMH
functions as a satiety center, VMH neurons are rich in insulin and leptin
receptors that mediate adiposity signals.
Lateral hypothalamic (LHA) and
Perifornical (PFA)
areas. Lesions of the lateral hypothalamus (LHA) can cause decreased
food intake. These animals show akinesia
and sensory neglect. In this respect, rats with lateral hypothalamic lesions
resemble human patients with Parkinson’s disease that has been attributed to
the degeneration of dopaminergic neurons of the nigrostriatal system. Large
lesions in the LHA interrupt the ascending dopaminergic fibers from the ventral
midbrain. Similarly, selective demage to the dopaminergic neurons with 6-OHDA
also produces akinesia, sensory neglect in association with loss of 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 projecting to several areas of the
neuraxis, including the cerebral cortex may be important in mediating leptin
effect. Administration of MCH or orexin into the brain stimulates food intake.
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. Leptin concentration in
plasma is directly proportional to adiposity. Congenital leptin deficiency
resulting from mutations within the leptin gene causes extreme obesity (ob/ob
mice). Moreover, a mutation in the leptin receptor gene (db/db mice) 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. Administering leptin to ob/ob mice, or to normal animals,
causes them to eat less and loose weight. Hence, leptin appears to function as
a negative feedback signal to the brain. When fat stores increase in adipose
tissue, more leptin is secreted and enters the brain, causing a greater
inhibition of foood intake and loss of body fat. When circulating leptin levels
are low, feeding and other anabolic responses are disinhibited. In this way,
leptin acts to promote the maintenance of a relatively stable body weight over
long intervals.
Within
the brain, leptin’s main site of action seems to be the hypothalamus.
Figure shows that the effect of leptin
is mediated through leptin receptors localized in several hypothalamic nuclei,
including, the ventromedial, (VMH) arcuate and dorsomedial nuclei. The complex
physiological effect of leptin can be explained by the fact that
leptin-responsive neurons in these regions project to hypothalamic neurons in
PVH, LHA and subparaventricular zone. These neurons in turn with their further
projections to the cerebral cortex, autonomic preganglionic neurons and the
pituitary gland can effect various endocrine, autonomic and behavioral
responses .
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 transcriptional 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 transduction has been described, which is rapidly induced in the
hypothalamus following systemic leptin administration.
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
the PVN 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.
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 SCN) 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. Ablation of the SCN
results in also a loss of rest-activity rhythm, estrus cycle and reproductive
capacity in rats. 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 without
SCN feed throughout the light-dark
cycle.
Genetically controlled molecular clock. Individual SCN neurons maintained in cell culture
have a rhythmic electrical activity that approximates a 24 h cycle. Mammalian
circadian rhythms are maintained intracellularly by interlocking positive and
negative-feedback control of the transcription and subsequent translations to
protein of about a dozen of clock genes (Plate 52a, b) that reliably recur at
precise times over 24-h cycles. These molecular signals can be read by
cytoplasmic mechanisms in SCN cells and translated into cellular events such as
changes in membrane potential and cell firing rate. Such signals, in turn, can
be transmitted to connecting neurons and ultimately to those neuronal
structures that control physiological processes with a circadian rhythmicity.
Evidence suggests that GABA, gap junctions and neural cell adhesion molecules
participate in the coupling of individual SCN neurons that underlie pacemaker
function. Interestingly, SCN cells show increased electrical activity during
the daytime in both nocturnal and diurnal mammals, thus SCN activity signals
inactivity in nocturnal animals (rats, mice) and activity in diurnal species such
as humans. In humans, however, secretion of corticosteron take place opposite
to that observed in the rat, so the signal of the SCN to the human PVN and
other hypothalamic targets will be interpreted in a different way.
Synchronization
of the biological clock with the light-dark cycle. The circadian rhythms of
physiology and behavior are driven by the molecular clock as indicated above. To be ‘useful’,
these clocks must be synchronized to the day-light cycles of the real world.
The primary environmental synchronizing cue is the natural cycle of light and
dark. In fish, amphibians, reptiles and birds there are specialized circadian
photoreceptor cells located in several places in the brain. These cells respond
to light that penetrates the skin, skull and overlying brain tissue, and their
output signals act directly on clock centers in the brain. In these animals,
eyes are not necessary for synchronization to the day-night cycle. Mammals have specialized photoreceptors in
the retina. 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 repeatedly reset. It free runs with a period that is slightly off
24 h in the absence of light-dark cycle. The light-dark cycle sets the exact
timing of the pacemaker and it is best understood by looking at the phase
response curve (PRC) of the pacemaker to light (Plates 53A 54B). The PRC shows
that the pacemaker responds differently to light at different times of the day.
It is typically reset each day in the morning and the evening at the
transitions between light and dark. Photic
stimulation of SCN cells in the early subjective night cause phase delay,
whereas such stimulation late in the subjective night causes phase advance.
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 to light 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 that project to the SCN and the lateral geniculate body
(specifically to the intergeniculate leaflet (IGL) are intrinsically
light-sensitive, contain a photopigment melanopsin (an opsin based
photopigment), and register luminance (Hattar et al., 2002; Berson et al.,
2002). These same cells also contain the peptide PACAP (pituitary
adenyl-cyclase-activating peptide). These cells respond electrically to light
in isolated retinal preparation in which synaptic transmission is blocked. 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 synchronization of the biological clock with the light-dark cycle. This
‘new’ light-detection system influences also to pupil’s response to
light and suppression of melatonin secretion produced by light.
Melanopsin-deficient mice could still be entrained to a L/D cycle, still
exhibited phase-shifting in response to pulses of white light and responded
with changes in circadian period when they were switched from constant darkness
to constant light, but these responses
were severely attenuated, indicating the critical role of melanopsin in circadian photoentrainment. These
melanopsin-deficient animals had also a diminished pupillary light reflex at
high irradiance. It is suggested that the full dynamic range of the pupillary
response and other components of the circadian mechanisms could be accounted
for by the rode/cone, melanopsin and cryptochrome
(another photopigment present in the inner retina and SCN) systems acting
together.
The IGL modulates entrainment by transmitting
information about both photic and nonphotic (locomotor) events to the SCN. The retinal ganglion cell-SCN circuit uses
glutamate as transmitter, the IGL uses GABA and NPY. Perfusion of NPY into the
SCN or IGL stimulation produces phase response curve with phase advances during
subjective day and phase delays during subjective night. Serotoninergic neurons
of the midbrain raphe densely innervate SCN neurons. Raphe neurons are
state-dependent; they fire regularly during waking, slowly during SWS, and not
at all during REM sleep. During waking visual stimulation acutely increases the
activity of SCN neurons. Serotonin inhibits the SCN response to light. Data
suggest that serotonin acts between the retina and pacemaker mechanisms within
SCN neurons.
Specific receptors and signaling
pathways in entrainment. The rhythms of SCN cell firing depends on specific membrane
receptors, signaling pathways and the timing of various neuromodulators as they
relate to circadian phase. For example, cholinergic mechanisms that involve the
activation of M1 muscarinic receptors in the SCN are involved in resetting the
circadian clock only during the subjective night. Similarly, SCN cells are most
sensitive to melatonin feedback at subjective dawn. Second-messenger cascades
lead ultimately to the intranuclear phosphorylation of
cAMP-responsive-element-binding protein (CREB) and the subsequent downstream
transcription of clock-related genes.
Output of SCN neurons control various rhythms The SCN project to the subparaventricular zone
(SPVZ) 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 also suggest that in addition to synaptic, humoral
mechanism may play a role in rhythm regulation. The
SCN uses several means to regulate circadian rhythm of hormonal secretions: 1)
by direct contact with neuroendocrine neurons, for example those containing
GnRH and CRH; 2) by contacting neuroendocrine neurons via intermediate neurons,
for example those of the medial preoptic area and dorsomedial hypothalamic
nucleus (Saper) and 3) by projections to the autonomic PVN to influence the
autonomic nervous system (for example in the case of melatonin regulation).
Estrous cycle In female mammals, reproductive events occur in cycles, called
estrous cycles. The estrous cycle in the rat is four days long and culminates
on the day of proestrus in a mid-afternoon surge of release of LH. The timing
of the LH surge is precise and results in ovulation followed by receptivity to
males the subsequent night. The surge in LH production results from GnRH
release from the median eminence into the portal circulation. 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. SCN ablation results in loss of estrous cycles and
reproductive capacity.
Melatonin regulation. In habitats with marked seasonal variation of
temperature and food supply, survival of species requires seasonal regulation
of reproduction. The circadian timing system of these animals uses production
of the pineal hormone melatonin to measure day length as a means of predicting
seasonal changes. The SCN via the PVN-intermediolateral column-superiocr
cervical ganglion (SCG)–pineal gland routes control melatonin secretion that
faithfully mirrors the lengths of day and night. For example, in all mammals,
the activity of SCG neurons innervating the pineal increases at night. The
release of norepinephrine from axon terminals acts through beta-adrenergic
receptors to stimulate melatonin synthesis and release. At night, exposure to
light through the retinohypothalamic tract via GABAergic projection from SCN to
PVN inhibits SCG activity and thereby
quickly stops the production of melatonin.
In the mammalian brain, 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. For
example, melatonin can lessen the symptoms of jet lag and in elderly people,
the disruption of sleep as a consequence of alteration of the pacemaker
function.
According to a well-established model of sleep
regulation, the timing of sleep and wakefulness is regulated by two processes:
a sleep homeostatic process that is increases during waking and decreases
during sleep and a circadian process. The sleep homeostatic process is
partially due to accumulation of various metabolites, like adenosine. The circadian signal arises from the SCN: in
day-active animals, this signal increases throughout the day and then declines
during the night. In a series of elegant experiments, Aston-Jones et al. (2001)
have shown that an SCN-Dorsomedial 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.
It is also suggested that the SCN provides arousal-promoting input to
hypocretin neurons, which project upon the neocortex and subcortical arousal
areas (Moore, 2002).
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 diffusely innervate the
cerebral cortex and promotes arousal. The SCN also projects to the sleep active
VLPO cells that in turn inhibit the ascending arousal systems. Recent studies (Deboer et al., 2003) suggest
that the vigilance state also influence
the neuronal activity of the SCN, although the precise mechanisms of this
effect remains to be investigated.
Several cell groups in the hypothalamus (see SUBCORTICAL MODULATORY 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.
Patients with Huntington chorea (HD) as well as R6/2 mice (which mimic many of the features of human HD exhibit progressive loss of orexin neurons. Orexin neurons also project to the SCN and in R6/2 mice there is a progressive disruption of circadian behavior as characterized by the marked alteration in the expression of mPer2 and mBmal1 clock genes. These findings could explain the markedly increased daytime sleepiness and night wakefulness of HD patients.
Saper suggests that between sleep and wake-promoting brain regions reciprocal interactions exist which produces a flip-flop switch (Plate 63). 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.
12. 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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