Hypothalamus - ahuman.orgahuman.org/svn/ahengine/research/articles/Biological/2012-Hypothal… · Hypothalamus [email protected] Lecture outline • Structural organisation

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[email protected]

Lecture outline

• Structural organisation of hypothalamus– Localisation + nuclei– Input/output pathways

• Physiological function of hypothalamus

Overview of anatomy

chiasmatic tuberal posterior

anteriormedial view

Amygdala

Mamillo-thalamic tract

Dorsal hypothalamic area

Lateral hyothalamicarea Supraoptic nucleus

Optic tract

Ventromedial nucleus

Arcuatenucleus

Median eminence

Lateral tuberalnucleus

Fornix

Dorsomedial nucleus

Amygdala

Medial forebrain bundle

Third ventricle

Overview of anatomycoronal view

Overview of physiological functions

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Overview of physiological functions• Maintenance of milieu interne

• Behaviour

• Memory

Regulation of energy metabolism (food intake, metabolic rate, temperature regulation, growth)

Reproductive function (including milk production, social interactions)

Biological clock, sleep-wake cycles

Control of blood flow (cardiac output, blood osmolarityand renal clearance, thirst regulation)

Overview of physiological functions• Maintenance of milieu interne

• Behaviour

• Memory

Regulation of energy metabolism (food intake, metabolic rate, temperature regulation, growth)

Reproductive function (including milk production, social interactions)

Biological clock (sleep-wake cycles)

Control of blood flow (cardiac output, blood osmolarityand renal clearance, thirst regulation)

Overview of physiological functions

Regulation of the autonomic nervous system

Release of hormonesHypothalamic neurons can release hormones (neuro-endocrine)

Overview of physiological functions• Detection of (changes in)

Blood osmolarity

Blood nutrient levels

Blood hormone levels

Body temperature

Directly and indirectly

Overview of connections• Input from

Retina (retinohypothalamic tract – terminates in SCN)

Olfactory receptors (medial forebrain bundle)

Cutaneous receptors

Higher (limbic) system (hippocampal formation: fornix – to mammillary bodies; amygdala: stria terminalis – to medial hypothalamus)

Viscera

Overview of connections• Output to

Thalamus (via mammillothalamic tract (Papez circuit: cingulategyrus – hippocampal formation – mammillary bodies – anterior thalamic nucleus – cingulate gyrus)) (also mammillotegmental tract to midbrain tegmentum)

Amygdala (from medial hypothalamus)

Midbrain PAG (from medial hypothalamus) (aggression, rage, flight)

Frontal and parietal lobes, habenular nucleus, midbrain…

Blood stream (pituitary)

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Overview of basic functions• Feed-back system

– Hypothalamus corrects deviations from a given set-point:

• measures current value• compares current value

with supposed value• makes adjustments to

achieve supposed value

– helps maintain body homeostasis







• Feed-forward system

– Hypothalamus can over-ride feed-back under special conditions

• Stress responses• Fever (body T set point is

changed to higher T)







• Feed-forward system

– Hypothalamus can over-ride feed-back under special conditions

• Stress responses• Fever (body T set point is

changed to higher T)

• Anticipation

– Hypothalamus adjusts its output to meet future needs

• Insulin secretion prior to food intake

• Look at neuroendocrine functions of hypothalamus

• Look at regulation of non-endocrine functions (ANS) of hypothalamus

Neuroendocrine hypothalamus

• Hypothalamic neurons can act as neuroendocrinecells

• Neurotransmitter = (neuro)hormone is released directly into blood stream

• Site of hormone release is pituitary gland• 2 principal pathways for eliciting hormone release:

– Via the anterior pituitary (adenohypophysis)• 2-tiers process

– Via the posterior pituitary (neurohypophysis)• 1-step process


• Via anterior pituitary(adenohypophysis)– Hypothalamic parvocellular

neurons release releasing or inhibiting hormones into hypothalamo-pituitary portal veins

– Hypothalmo-pituitary portal veins carry these hormones to anterior pituitary

– Anterior pituitary has cells responding to the different releasing or inhibiting hormones

– Responsive cells release or stop releasing hormones in response to binding of hypothalamic releasing or inhibiting hormones into systemic circulation

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neurons secrete releasing or inhibiting hormones into hypothalamo-pituitary portal veins




R I

AnteriorPituitary

Hypothalamus




– Hypothalamo-pituitary portal veins carry these hormones to anterior pituitary



R I

AnteriorPituitary

Hypothalamus







R I

AnteriorPituitary

Hypothalamus






– Responsive cells secrete or stop secreting hormones in response to binding of hypothalamic releasing or inhibiting hormones into systemic circulation

R I

AnteriorPituitary

Hypothalamus

GnRH gonadotrope FSH+LH gonads

CRH corticotrope ACTH

TRH thyrotrope TSH thyroid

GHRH somatotrope GH

Sost somatotrope GH

DA lactotrope prolactin

Rel./Inhib.hormone:




GHRH somatotrope GH

Sost somatotrope GH


Rel./Inhib.hormone:

Ant. Pit.target cell:

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GHRH somatotrope GH

Sost somatotrope GH


adrenalgland

mammaryglands

many cells(bones)

Rel./Inhib.hormone:


Hormone: target:




GHRH somatotrope GH

Sost somatotrope GH


adrenalgland

mammaryglands

arcuate

arcuate

para-ventri-cular(PVN)

arcuate

anteriorHT

many cells(bones)

releasefrom:

Rel./Inhib.hormone:


Hormone: target:


• Via anterior pituitary– Hypothalamic parvocellular





• Via posterior pituitary(neurohypophysis)– Hypothalamic

magnocellular neuronsrelease hormones directly into systemic veins that drain into the systemic circulation

– Hypothalamo-hypophyseal tract (axons of neuroendocrinemagnocellular neurons)

Hypothalamus

medianeminence

posteriorpituitary


• Via anterior pituitary– Hypothalamic parvocellular





• Via posterior pituitary(neurohypophysis)– Hypothalamic

magnocellular neuronsrelease hormones directly into systemic veins that drain into the systemic circulation

– Hypothalamo-hypophyseal tract(axons of neuroendocrinemagnocellular neurons)

Hypothalamus

medianeminence

posteriorpituitary


ADH kidneys

oxytocin mammary gland+ uterus

bonding (autism?)

paraventricular(PVN)

+supraoptic

(SON)

Hormonesreleased:

Hormonetargets:

Releasefrom:


ADH kidneys

oxytocin mammary gland+ uterus

bonding (autism?)

paraventricular(PVN)

+supraoptic

(SON)

Hormonesreleased:

Hormonetargets:

Releasefrom:

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ADH-release

• ADH promotes water retention in kidneys• release is modified when blood osmolarity

changes by more than ~ 1% from set point (~ 280 mOsm/kg)

– Hypotonic conditions inhibit ADH release

– Hypertonic conditions stimulate ADH release

ADH-release

How do cells in supra-optic and paraventricularnuclei know that blood osmolarity has changed?

• Osmosensitive neurons• Intrinsically osmosensitive neurons in OVLT, SFO

and NTS• ADH releasing neurons are intrinsically

osmosensitiveFiring rate of ADH-releasing neurons integrates central and peripheral information and their own osmosensitivity

ADH-release

How do cells in supra-optic and paraventricularnuclei know that blood osmolarity has changed?

• Osmosensitive neurons• Intrinsically osmosensitive neurons in OVLT, SFO

and NTS that directly project to the supraoptic and paraventricular nuclei

Circumventricular organ: brain structure that is devoid of blood brain barrier

How can a cell be intrinsically osmosensitive?

Change in osmolarity will cause cell swelling or shrinking, resulting in increased or decreasedstretch of plasma membrane

Stretch of plasma membrane can gate ion channels

stretch-activated

tethered

indirectly gated

Lumpkin & CaterinaNature 445, 858-865 (2007)

cytoskeleton

cytoskeleton

extracellularmatrix

extracellularmatrix

mechano-sensitiveprotein

ADH-release

TRPV1opens in response to hypertonic stimulus

TRPV4opens in response to hypotonic stimulus

Which is (are) the candidate ion channel(s) involved in osmosensing?

ADH-release



Which is (are) the candidate ion channel(s) involved in osmosensing?Transient Receptor Potential channels of the Vanilloid family (TRPV channels)(non-selective cation channels)

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ADH-release



Which is (are) the candidate ion channel(s) involved in osmosensing?

N-terminal variant

indirect effect

Transient Receptor Potential channels of the Vanilloid family (TRPV channels)(non-selective cation channels)

cell volume(cell shrinking)

Sharif Naeini et al. Nat. Neurosci. 9, 93 - 98 (2006)

membraneconductance

(TRPV1-/-)

Sharif Naeini et al. Nat. Neurosci. 9: 93 - 98 (2006)

membraneconductance

TRPV1

(TRPV1-/-)


Action potential firing rate in response to hypertonic solution

TRPV1


Impaired ADH release in TRPV1 knock-out micein response to hypertonic solution

TRPV1

AVP = ADH

Liedtke & Friedman PNAS;100:13698-13703 (2003)TRPV4+/+ = wild type-/- = TRPV4 knock-out

TRPV4 knock-out mice drink significantly more when infused with ADH-analogue dDAVP (i.e. when water retention is increased, which should result in decreased water intake) than wildtype mice.

TRPV4 channelsopen in responseto cell swelling(indirect effect)in expression systems

ADH-releaseHow does it all come together?

• Increased blood osmolarity causes osmosensitive OVLT neurons to shrink

• TRPV1 channels open, leading to depolarisation and eventually firing of OVLT neurons (graded response)

• OVLT neurons make monosynaptic glutamatergic contacts with supra-optic nuclei neurons

• This promotes firing of ADH-releasing neurons and hence ADH release• ADH releasing neurons are intrinsically osmosensitive

Firing rate of ADH-releasing neurons depends on central and peripheral inputs as well as their intrinsic osmosensitivity

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• Increased blood osmolarity causes osmosensitive (OVLT) neurons to shrink

• TRPV1 channels open, leading to depolarisation and eventually firing of (OVLT) neurons (graded response)

• (OVLT) neurons make monosynaptic glutamatergic contacts with supra-optic nuclei neurons


Firing rate of ADH-releasing neurons depends on central and peripheral inputs as well as their intrinsic osmosensitivity


• Increased blood osmolarity causes osmosensitive (OVLT) neurons to shrink

• TRPV1 channels open, leading to depolarisation and eventually firing of (OVLT) neurons (graded response)

• (OVLT) neurons make monosynaptic glutamatergic contacts with supra-optic nuclei neurons


Firing rate of ADH-releasing neurons depends on central and peripheral inputs (baroreceptors!) as well as their intrinsic osmosensitivity

– Central DI• failure to secrete

ADH, resulting in excess urine output and dehydration

• following pituitary stalk damage (accident)

• Brattleboro rat produces no ADH

Diabetes insipidus Summary of neuroendocrine hypothalamus

• Arcuate GnRH (FSH, LH); GHRH (GH);DA (prolactin)

Reproduction; growth

• PVN CRH (ACTH); TRH (TSH); ADH; oxytocin

Steroid hormone production, energy metabolism, water retention; social behaviours, reproduction

• Ant. HT Sost (GH)Growth

• SON ADH; oxytocinwater retention; social behaviours, reproduction

Summary of neuroendocrine hypothalamus

• Arcuate GnRH (FSH, LH); GHRH (GH);DA (prolactin)

reproduction; energy metabolism

• PVN CRH (ACTH); TRH (TSH); ADH; oxytocin

behaviours, energy metabolism, water retention (blood flow), reproduction

• Ant. HT Sost (GH)energy metabolism

• SON ADH; oxytocinwater retention (blood flow), behaviours, reproduction

Non-endocrine control via the hypothalamus

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• Food and drink intake

• Thermoregulation

• Circadian rhythms

Parasympathetic and sympathetic control





Parasympathetic and sympathetic control





ANS control

Food intake

Food intake

• Lateral hypothalamic area– “Feeding centre” (bilateral lesions: aphagia)– Receives olfactory input via medial forebrain bundle

• Ventromedial nucleus– “Satiety centre” (bilateral lesions: hyperphagia)– Receptors for glucose and free fatty acids

• Arcuate nucleus– Receptors for leptin (adipose tissue) and insulin

Separate lecture on food intake

Food intake





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Food intake





Food intake





Drink intake/Thirst Drink intake/Thirst

• Subfornical organ– contains osmosensitive neurons

– projects to PVN, SON and POA

– stimulation of drinking behaviour (thirst)

other cirumventricular organs also contribute

More in separate lecture

Thermoregulation Thermoregulation • Alert consciousness and normal patterned motor

activities only when CNS temperature ~ 36 - 39°C

• Hypothalamus can stimulate thermogenesis– shivering, piloerection, skin vasoconstriction– behaviours that increase body temperature (or minimise

heat loss)

• Hypothalamus can stimulate heat loss– sweating, skin vasodilation– behaviours that promote body temperature cooling

• Controlled elevation of body temperature (fever) reduces pathogen viability and boosts immune system function

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Thermoregulation • Anterior hypothalamus (POA)

– Lesions cause hyperthermia– Endogenous temperature sensors (warm-sensitive neurons)

• T set-point can be changed by pyrogens, causing elevated core temperature (PGE2 acting on EP3 receptors)

• Posterior hypothalamic area– Lesions cause hypothermia– Involved in sympathetic activation

• Dilation or contraction of cutaneous circulation and control of sweat glands

receive peripheral temperature information (TRPM8, TRPV3, TRPV4)






also receive peripheral temperature information (TRPM8, TRPV3, TRPV4)

• What is the central temperature sensor?

2 current models:1. Heat directly opens ion channel that then

depolarises neuron – AP firing

2. Heat indirectly promotes depolarisation of neuron – AP firing

Thermoregulation


2 current models:

1. Heat directly opens ion channel that then depolarises neuron – AP firing

2. Heat indirectly promotes depolarisation of neuron – AP firing

Thermoregulation

TRPV1

– peripheral or central administration of TRPV1 agonist capsaicin induces hypothermia

– administration of TRPV1 antagonists induces hyperthermia (increased metabolism and reduced heat loss from body surface)

– TRPV1 is expressed in anterior hypothalamus

◄However: TRPV1 knock-out mice have no obvious deficit in body temperature control and TRPV1 channels in anterior hypothalamus are not activated by normal body temperature: TRPV1 is unlikely to be the hypothalamic thermosensor!

thought to be mediated by visceral TRPV1 channels that are tonically active

ThermoregulationTRPV1

– peripheral or central administration of TRPV1 agonistcapsaicin induces hypothermia



◄However: TRPV1 knock-out mice have no obvious deficit in body temperature control and TRPV1 channels in anterior hypothalamus are not activated by normal body temperature: TRPV1 is unlikely to be the hypothalamic thermosensor!


Thermoregulation

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TRPV1

– peripheral or central administration of TRPV1 agonistcapsaicin induces hypothermia



◄However: TRPV1 knock-out mice no obvious deficit in body temperature control; TRPV1 channels in anterior hypothalamus not activated by normal body temperature: TRPV1 unlikely to be hypothalamic thermosensor!


Thermoregulation


still unclear

Thermoregulation










• Posterior hypothalamic area– Lesions cause hypothermia














also receive cutaneous temperature information (TRPA1?, TRPM8, TRPV3, TRPV4)

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Circadian rhythms Circadian rhythms• Suprachiasmatic nucleus

– Sleep-wake cycle, feeding, temperature control, hormone release…..

– direct input from light-sensitive ganglion cells in retina (melanopsin)

(retinohypothalamic tract)

– phototransduction cascade similar to invertebrate one

• TRPC channels (originally cloned from drosophilaphotoreceptors)

• Separate lecture

Mammillary bodies

Mammillary bodies• Role in memory: Korsakoff’s syndrome

» alcohol-induced Vitamine B1 deficiency: damage to mammillary bodies (but also thalamus)

» Symptoms: anterograde and retrograde amnesia, confabulation

• Contain several nuclei with distinct connections

• Head direction cells (lateral nuclei) » fire selectively when animal faces specific direction

in horizontal plane; navigation

• Memory formation (medial nuclei)» connected with hippocampus via fornix and fire at

theta frequency (4-8Hz), which elicits long term potentiation in hippocampus

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Summary non-endocrine hypothalamus• Anterior HT ANS regulation;

endogenous T sensor; osmoregulation (energy metabolism, blood flow)

• SCN circadian rhythms

• Arcuate nucleus food intake

• Ventromedial nucleus “satiety” centre

• Lateral hypothalamus “hunger” centre

• Posterior HT ANS regulation(T sensor)

• Mammillary bodies memory (behaviours?)

Summary non-endocrine hypothalamus• Anterior HT ANS regulation;

endogenous T sensor; osmoregulation (energy metabolism, blood flow)

• SCN biological clock

• Arcuate nucleus food intake

• Ventromedial nucleus “satiety” centre

• Lateral hypothalamus “hunger” centre

• Posterior HT ANS regulation(T sensor)

• Mammillary bodies memory (behaviours?)

energymetabolism

Aggression and the hypothalamus• Neuronal subpopulations of ventromedial hypothalamus cause

aggressive behaviour (Lin et al. (2011) Nature 470:221-226)

“sexually experienced” male C57BL/6N mouse under investigation

Some cells are active duringnumber of different behaviourswhereas others (cell 4) are onlyactive during one particularbehaviour

“sexually experienced” male C57BL/6N mouse under investigation

Some cells are active duringnumber of different behaviourswhereas others (cell 4) are onlyactive during one particularbehaviour

Went on to selectively initiate behaviours by activating certain neurons and showed that neuronsactivated during an attack areinhibited during mating

Sex and the hypothalamus

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Sexual dimorphism of hypothalamusSexually dimorphic nucleus of preoptic area: Interstitial nucleus III

and also other hypothalamic regions

VERY controversial data/ woman

Sexual dimorphism of hypothalamusSexually dimorphic nucleus of preoptic area: Interstitial nucleus III

and also other hypothalamic regions

VERY controversial data/ woman

Documents

Hypothalamus - ahuman.orgahuman.org/svn/ahengine/research/articles/Biological/2012-Hypothal… · Hypothalamus [email protected] Lecture outline • Structural organisation