HYPOTHALAMUS and EPITHALAMUS
Aim: To provide a structural basis for understanding the neural control of the 'milieu interne' via the autonomic &
endocrine systems, and associated somatic behaviour; of the biological clock; reproductive functions; sleep-wake cycle,
control of appetite, growth & metabolism
Points highlighted in bold are ‘core’
Specific core learning objectives at the end of this lecture and associated reading you should be able to:
outline the principal nuclei of the hypothalamus, their main connections and functions
explain how hypothalamic neurons influence feed-forward control on the activity of the anterior pituitary gland
explain how the hypothalamus and epithalamus control the diurnal rhythm of body activity
explain how peripheral hormones can feed-back to influence the activity of hypothalamic neurons
explain how higher neural centres can influence the activity of hypothalamic neurons
Staying alive requires constant monitoring of the milieu interne and making the appropriate homeostatic adjustments; it also
requires the ability to respond to and to anticipate the demands of the external world.
The hypothalamus therefore receives information both from the internal and external environment, and has its own
receptors for a number of parameters. All our responses have three components: somatic, autonomic and endocrine. The
hypothalamus controls both the autonomic and endocrine responses. Sherrington called it the ‘head ganglion of the
autonomic nervous system’. It also determines the hormonal output of both the anterior and the posterior pituitary.
Finally it is very important for homeostasis that the responses are controlled - hence the extensive feedback systems.
HYPOTHALAMUS
Small bilateral masses of grey matter below the thalamus, lying on either side of and flooring the III ventricle.
(4cm3 neural tissue; 0.3% of brain - enormous influence for its size)(derived from diencephalon)
Walls: III vent. & floor forebrain below hypothalamic sulcus from lamina terminalis to mid-brain.
Gross subdivisions:
anterior to posterior: chiasmatic, tuberal, and posterior regions
Cytological structure: consists of diffuse cell groups with more or less formed nuclei; many small cells with short
projections; few major myelinated fibre bundles.
EPITHALAMUS
A small area of the post. wall of III ventricle, above the origin of the aqueduct .
It comprises the pineal gland – source of the hormone melatonin; innervated by postganglionic sympathetic fibres
which control the diurnal secretion of melatonin (at night). It also contains the pretectal area, important for the
pupillary reflex, the posterior commissure, and the habenular nuclei.
Pineal
Principal hypothalamic nuclei/areas [with ‘core’ functions][there are few differences among mammals]
Preoptic area - just anterior to hypothalamus, but functionally connected to it.
Anterior hypothalamic area - involved in: osmotic control, drinking (with OVLT, SFO); temperature control (heat loss)
Suprachiasmatic nucleus - biological 'clock'
Supraoptic nucleus (magnocellular neurosecretion - oxytocin & vasopressin)
Paraventricular nucleus
magnocellular - oxytocin & vasopressin (not all project to posterior pituitary)
parvocellular neurosecretion - corticotrophin-releasing hormone (CRH); thyrotrophin-releasing hormone (TRH)
Periventricular cell groups - a number of neuropeptides acting on anterior pituitary - e.g. somatostatin
Arcuate nucleus - origin of portal dopamine (to control prolactin); growth hormone-releasing hormone;
receptors for many appetite-controlling hormones including leptin, insulin, pancreatic polypeptide, which act via
arcuate neuropeptide Y (NPY) and alpha MSH; (see lecture on appetite control)
Median eminence/infundibulum - neurohaemal zone where parvicellular neurons discharge into portal capillaries.
Medial basal hypothalamus - loose term used to describe site of gonadotrophin-releasing hormone (GnRH) neurons.
Ventromedial nucleus - senses metabolites (glucose, free fatty acid); regulates feeding & metabolism; ‘satiety centre’
Dorsomedial nucleus
Lateral tuberal nucleus (large in man, source of wide GABA projections (c.f. raphé, locus coeruleus)
Lateral hypothalamic area (large in man) – ‘feeding centre’
Posterior hypothalamic area - central control of sympathetic activation
Mamillary body - mamillary nuclei receive from fornix, project to anterior thalamus - Papez circuit.
Periventricular organs
Sites around the third ventricle where the nervous system interacts with the vascular system without a blood-brain barrier.
Site of release of neurohormones into the systemic (neurohypophysis) or pituitary portal circulation (median eminence).
Neurohypophysis - extension of the hypothalamic floor formed by magnocellular neuron axons; oxytocin, vasopressin
Median eminence (tuber, infundibulum) floor and pituitary stalk part of the neurohaemal area; releasing factors
Organum vasculosum of the lamina terminalis (OVLT) and subfornical organ (SFO) both involved in osmotic regulation.
Large fibre bundles
There are few of these, most tracts are
diffuse and non-myelinated. Most
contain fibres passing in both directions.
Fornix: reciprocally connects hippocampus (subiculum) to the hypothalamus (esp. mamillary body) and septum
Stria terminalis: thin bundle of fibres
from amygdala, running with the
caudate nucleus to hypothalamus,
epithalamus and septum.
Ventral amygdalofugal path: mass of
fibres from amygdala (ventrolateral)
which crosses base of forebrain to
hypothalamus
Mamillothalamic tract: distinct bundle
from mamillary nucleus to ant nucleus
of thalamus (part of ‘Papez circuit’)
Medial forebrain bundle : (bad name
as it is neither a single bundle nor very
medial). Main route for fibres passing
between midbrain and septum, giving
fibres to hypothalamus at every point.
Periventricular fibre system: fibres
running posteriorly from tuberal and
post. regions to the midbrain and
hindbrain
Hypothalamo-hypophyseal tract: the
axons of neurosecretory neurons passing
to median eminence and neurohypophysis (oxytocin & vasopressin)
Neural connections
These are largely reciprocal and unmyelinated.
Afferents to hypothalamic nuclei are derived (indirectly) from:
- sensory receptors:
retina - pass directly to the suprachiasmatic nucleus; indirectly influence most parts including the pineal
olfactory -pass directly to lateral hypothalamic 'feeding centre'; indirectly via amygdala, nucleus accumbens (reward)
cutaneous - pass indirectly to hypothalamus (eg pain & stress response; nipple suckling & lactation)
visceral -mostly via nucleus of solitary tract (some are direct)
- brain stem:
noradrenaline fibres from the locus coeruleus
5-HT fibres from the raphé
fibres conveying visceroception from the nucleus of the tractus solitarius
fibres from periaqueductal grey associated with nociception
- 'higher' centres most of which are ‘limbic’ structures:
from hippocampal formation via fornix and via medial septum - complex sensory stimuli
from amygdala and piriform cortex via ventral amygdalofugal path, stria terminalis
from septum
from orbitofrontal cortex in particular, via mediodorsal nucleus of thalamus
Intrinsic sensitivity of hypothalamic neurones
Many hypothalamic neurons respond not only to synaptic inputs
but also directly to a variety of physiological variables.
osmotic pressure: osmosensitive neurons especially in the
antero-ventral hypothalamus
temperature: thermosensitive neurons in the anterior hypothalamus; involved in fever
plasma glucose, FFA: neurons sensitive to metabolic
substrates in ventromedial nucleus; involved in
feeding/stress; contain AMP-kinase
hormones: many hormones affect the hypothalamus as part of
feedback loops (eg cortisol, T3) or to influence certain
functions (eg sex steroids). Hypothalamic stimulation must
be able to override negative feedback (eg stress).
Efferents from the hypothalamic nuclei
The hypothalamus exerts control over the endocrine system, the autonomic nervous system, and some very basic somatic
behaviour (eg drinking, feeding)
Neuroendocrine control: exerted directly on peripheral organs via posterior pituitary (release of vasopressin &
oxytocin), and indirectly via release of neurohormones into hypothalamo-hypophysial portal vessels to control the
anterior pituitary.
Neural control: fibres descend via the medial forebrain bundle to control brainstem autonomic centres:
pretectal & Edinger-Westphal (III) nucleus; dorsal motor nucleus of X;
sympathetic preganglionic neurons in (T1-L2) spinal cord; parasympathetic preganglionic neurons in sacral (S2-4)
cord (these come largely from the paraventricular nucleus)
mamillothalamic tract to anterior thalamus, cingulate cortex, and thence to motor planning areas - motor output.
Some fibres pass to the choroid plexus to influence production of CSF.
The paraventricular nucleus, which comprises many different sorts of neuron, appears to act as an integrative centre for
many different hypothalamic functions. There is an increasing interest in its role as a centre controlling appetite/feeding.
Vasculature of hypothalamus and pituitary
The internal carotid gives sup. & inf. hypophyseal arteries; the inferior supplies only the posterior pituitary; the
superior supplies the hypothalamus including the primary capillary plexus in the median eminence, from which long
and short portal veins pass to the anterior pituitary carrying the releasing factors which give feed-forward control on
the secretion of anterior pituitary hormones.
Ependyma of III ventricle
The ependyma lining the wall of the third ventricle poses little barrier to materials
Tanycytes in the wall of the ventricle have processes which end on portal capillaries of the median eminence.
Sexual dimorphism
There is quite marked sex dimorphism of some hypothalamic nuclei (including the suprachiasmatic). There is currently
considerable interest in the role of differences in some small hypothalamic nuclei in determining sexual orientation.
There may be some plasticity in the adult.
Functional roles
Osmotic and blood volume control
The hypothalamus contains osmoreceptors and
receives information from the brainstem concerning
blood volume.
A rise in plasma osmotic pressure or a fall in blood
pressure or blood volume all stimulate the release of
vasopressin from the magnocellular neurons and also
behaviour.
In hypothalamic diabetes insipidus vasopressin is not
secreted and large amounts of dilute urine are
excreted.
Control of reproductive function
During reproductive life, GnRH neurons in the
medial basal hypothalamus secrete circhoral pulses of
GnRH into the portal system to elicit LH and FSH
secretion. Feedback of gonadal steroids occurs at both
the hypo-thalamic and pituitary levels to influence the
frequency and the amplitude of the pulses.
Kallman’s syndrome is a failure of GnRH neurons to
migrate from the nose into the hypothalamus and thus
failure of GnRH secretion.
Stress also inhibits GnRH release.
Oxytocin is released from the posterior pituitary during childbirth in response to stretch of the cervix (Ferguson
reflex) and during lactation in response to suckling. Now thought to be very involved in bonding (autism)
Hypothalamic dopamine is the principal controller of the release of prolactin from the anterior pituitary. Suckling
causes a reduction in the release of DA and therefore an increase in the secretion of prolactin. Prolactin release is also
increased by stress.
Control of growth
The hypothalamus exerts control on growth by the pulsatile secretion of both GHRH and somatostatin which
stimulate and inhibit secretion of pituitary growth hormone. (See below effects on metabolism)
Control of metabolism
The hypothalamus influences metabolism by the secretion of thyrotrophin releasing hormone which activates the
hypothalamo-pituitary-thyroid axis to release thyroid hormone. This in influenced by temperature receptors in the
anterior hypothalamus, by nutrient status, and by feedback of thyroid hormones.
CRH and therefore cortisol is released in hypoglycaemia - see glucocorticoid effects of cortisol
GHRH and therefore GH is also released in response to hypoglycaemia for the metabolic effects of GH. (separate
lecture on growth & metabolism)
Expression of stress and control of the autonomic nervous system
Any stress causes both the activation of the sympathetic nervous system (posterior hypothalamus) and also the
release of corticotrophin releasing hormone which activates the HPA axis and secretion of cortisol. Glucocorticoids
feed back at the pituitary, hypothalamus and limbic system.(separate lecture on stress axis).
All these endocrine responses are accompanied by appropriate responses of the autonomic nervous system
(separate lecture on control of ANS).