55. Integrative Role of the Hypothalamus (HT)

Question 1

Does the hypothalamus work by feed-forward or feed-back?

Answer 1

• It works mostly by feedback, where it takes measurements of the current value and compares it with what it should be
• However, it can also work by feed-forward when it overrides feedback mechanisms in times of stress or fever
• It can also anticipate (e.g. insulin release before a meal)

Question 2

What are the two pathways by which the hypothalamus can lead to hormone release?

Answer 2

• Via the anterior pituitary (adenohypophysis -> This is a 2-tier process
• Via the posterior pituitary (neurohypophysis) -> This is a 1-step process

Question 3

What are the names for the anterior and posterior pituitary?

Answer 3

• Anterior -> Adenohypophysis
• Posterior -> Neurohypophysis

Question 4

What are neuroendocrine cells?

Answer 4

Hypothalamic cells that release hormones directly into the bloodstream.

Question 5

Describe the process of hormone release using the hypothalamus and anterior pituitary.

Answer 5

• Hypothalamic parvocellular neurons secrete releasing or inhibiting hormones into hypothalamo-pituitary portal veins
• Hypothalamo-pituitary portal veins carry these hormones to anterior pituitary
• Anterior pituitary has cells responding to the different releasing or inhibiting hormones
• Responsive cells secrete or stop secreting hormones in response to binding of hypothalamic releasing or inhibiting hormones into systemic circulation

Question 6

What are the main releasing and inhibitory hormones produced by the hypothalamus that act on the anterior pituitary?

[IMPORTANT]

Answer 6

Releasing:

• GnRH
• GHRH
• TRH
• CRH

Inhibitory:

• Somatostatin
• Dopamine

Question 7

For the main releasing hormones produced by the hypothalamus that act on the anterior pituitary, state:

• Release site
• Target cell
• Hormone released by anterior pituitary
• Target of the anterior pituitary hormone

Answer 7

Question 8

For the main inhibitory hormones produced by the hypothalamus that act on the anterior pituitary, state:

• Release site
• Target cell
• Hormone released by anterior pituitary
• Target of the anterior pituitary hormone

Answer 8

Question 9

What are the each of the main releasing and inhibitory hormones produced by the hypothalamus (that act on the anterior pituitary) released from?

Answer 9

• Arcuate nucleus -> GnRH, GHRH, Dopamine
• Paraventricular nucleus -> CRH, TRH
• Anterior hypothalamic nucleus -> Somatostatin

Question 10

Describe the process of hormone release using the hypothalamus and posterior pituitary.

Answer 10

Hypothalamic magnocellular neurons release hormones directly into systemic veins that drain into the systemic circulation.

Question 11

What are the main hormones released via the posterior pituitary?

Answer 11

• ADH
• Oxytocin

Question 12

For the main hormones produced by the hypothalamus that are released via the posterior pituitary, state:

• Release site
• Targets

Answer 12

(Both nuclei produce both hormones)

Question 13

What is the posterior pituitary made of?

Answer 13

It is made of hypothalamic neurons, so it really a part of the hypothalamus.

Question 14

What is the name for the axon tract that passes from the hypothalamus to the posterior pituitary and into the blood?

Answer 14

Hypothalamo-hypophyseal tract

Question 15

Which hormone is most implicated in social bonding?

Answer 15

Oxytocin -> It is released when gazing into each others eyes.

Question 16

What is the main role of ADH?

Answer 16

Promotes water retention in kidneys.

Question 17

What triggers ADH release?

Answer 17

• It is released in response to hypertonic conditions.
• A change in release is triggered when blood osmolarity changes by more than ~ 1% from set point (~ 280 mOsm/kg)

Question 18

How can the supraoptic and paraventricular nuclei in the hypothalamus detect changes in blood osmolarity?

Answer 18

• They receive input from intrinsically osmosensitive neurons in the circumventricular organs (OVLT and SFO) and the nucleus tractus solitarius (NTS)
• The supraoptic and paraventricular nuclei are also osmosensitive but are less well understood

Question 19

What are the two main circumventricular organs you need to know? What are circumventricular organs?

Answer 19

• Organum vasculosum of the lamina terminalis (OVLT) and subfornical organ (SFO)
• Circumventricular organs are parts of the brain that are devoid of a blood brain barrier, so they can sample the blood and detect changes

Question 20

How can a cell be intrinsically osmosensitive?

Answer 20

• A change in osmolarity will cause cell swelling or shrinking, resulting in increased or decreased stretch of plasma membrane
• This causes opening/closing of membrane ion channels via:
  
  • Direct stretch-activation of the ion channels
  • The ion channel being tethered to the ECM or the cytoskeleton, which causes it to open as the cell stretches
  • Indirect activation of the ion channels via a mechano-sensitive

Question 21

What channels are responsible for osmosensing in the circumventricular organs?

Answer 21

• TRPV1 -> Opens in response to hypertonic stimulus
• TRPV4 -> Opens in response to hypotonic stimulus (indirect effect)

Question 22

Give some experimental evidence for the importance of TRPV1 channels in osmosensing in the paraventricular organs.

[EXTRA]

Answer 22

(Naeini, 2006):

• Used normal mice and TRPV1 knockout mice
• In both groups, cell shrinking was observed upon hypertonic conditions
• However, in the knockout group, there was no change in cell permeability, action potential firing or ADH secretion

Question 23

Summarise the steps that lead to ADH release.

Answer 23

• Circumventricular organs (OVLT and SFO) contain cells that shrink in response to a hypertonic environment
• This leads to TRPV1 channels opening, which leads to depolarisation and therefore action potential firing
• These neurons release glutamate onto neurons in the supraoptic and paraventricular nuclei
• This leads to ADH release
• The supraoptic and paraventricular nuclei are also intrinsically osmosensitive AND they receive inputs from peripheral receptors (such as baroreceptors)

Question 24

What is central diabetes insipidus and what causes it?

Answer 24

• Failure to secrete ADH, resulting in excess urine output and dehydration
• It can occur following pituitary stalk damage (e.g. in a car crash)

Question 25

What are the 4 main neuroendocrine nuclei in the hypothalamus? What is the function of each?

Answer 25

* Arcuate nucleus * Paraventricular nucleus (PVN) * Anterior hypothalamus * Supraoptic nucleus (SON)

Question 26

What functions does the hypothalamus control via the autonomic nervous system?

Answer 26

* Food and drink intake * Thermoregulation * Circadian rhythm

Question 27

Summarise the different parts of the brain involved in controlling food intake.

Answer 27

* Lateral hypothalamic area * “Feeding centre” * Receives olfactory input via medial forebrain bundle * Ventromedial nucleus * “Satiety centre” * Receptors for glucose and free fatty acids * Arcuate nucleus * Receptors for leptin (adipose tissue) and insulin More info later.

Question 28

What is the consequence of bilateral lateral hypothalamus lesions?

Answer 28

Aphagia (inability or refusal to eat)

Question 29

What is the consequence of bilateral ventromedial nucleus lesions?

Answer 29

Hyperphagia (excessive desire to eat)

Question 30

Summarise the different parts of the hypothalamus involved in control of thirst.

Answer 30

* Subfornical organ * Projects to PVN (paraventricular nucleus), SON (supraoptic nucleus) and POA (preoptic area) * This leads to stimulation of drinking behaviour (thirst) * Note: Other cirumventricular organs also contribute More info later.

Question 31

What are the roles of the hypothalamus in thermoregulation?

Answer 31

* Stimulating thermogenesis * Shivering, piloerection, skin vasoconstriction * Behaviours that increase body temperature * Stimulating heat loss * Sweating, skin vasodilation * Behaviours that promote body temperature cooling * Inducing fever

Question 32

What parts of the hypothalamus are involved in thermoregulation?

Answer 32

* Anterior hypothalamus (especially pre-optic area) * Involved in response to hyperthermia * Posterior hypothalamic area * Involved in response to hypothermia

Question 33

What are the current models for how the anterior hypothalamus detects heat?

Answer 33

There are two proposed models: * Heat directly opens ion channel that then depolarises neuron, leading to AP firing (i.e. same principle as peripheral temperature sensing by TRP channels) * Heat inactivates leak potassium channels, which leads to slight depolarisation and therefore promotes AP firing

Question 34

Which part of the hypothalamus determines the body temperature set point? How can this set point be changed?

Answer 34

* Anterior hypothalamus * Set point can be elevated by pyrogens -\> PGE2 acting on EP3 receptors

Question 35

Do the central thermoregulation centres also receive input from the peripheral thermoreceptors?

Answer 35

Yes

Question 36

What parts of the hypothalamus are involved in circadian rhythms?

Answer 36

Suprachiasmatic nucleus

Question 37

How is the suprachiasmatic nucleus involved in control of circadian rhythms?

Answer 37

The SCN receives direct input from light-sensitive ganglion cells in retina (melanopsin-containing) via the retinohypothalamic tract. More info later.

Question 38

Give some experimental evidence relating to jet lag. [EXTRA]

Answer 38

(Yamaguchi, 2013): * Knock-out of vasopressin V1a and V1b receptors causes resistance to jet lag (in mice).

Question 39

Draw a diagram to show where the mammillary bodies are.

Answer 39

Question 40

What is the role of the mammillary bodies?

Answer 40

Memory

Question 41

Give some experimental evidence for the role of the mammillary bodies. [EXTRA]

Answer 41

Korsakoff’s syndrome: * This is an alcohol-induced Vitamine B1 deficiency that leads to damage to the mammillary bodies (but also thalamus) * The symptoms are anterograde and retrograde amnesia, as well as confabulation * This shows that the mammillary bodies are involved in memory

Question 42

What are the roles of the different nuclei in the mammillary bodies? [EXTRA?]

Answer 42

* Lateral nuclei * Contain head direction cells * These fire selectively when animal faces specific direction in horizontal plane so they are used in navigation * Medial nuclei * These are involved in memory formation * They are connected with the hippocampus via the fornix and elicit long term potentiation

Question 43

What are the 7 main non-endocrine nuclei in the hypothalamus? What is the function of each?

Answer 43

* Anterior hypothalamus * Suprachiasmatic nucleus * Arcuate nucleus * Ventromedial nucleus * Lateral hypothalamus * Posterior hypothalamus * Mammillary bodies

Question 44

What part of the hypothalamus is involved in aggression?

Answer 44

Ventromedial hypothalamus

Question 45

Give some experimental evidence for the ventromedial hypothalamus being involved in aggression. [EXTRA]

Answer 45

(Lin, 2011): * Measured action potentials in various cells in the ventromedial hypothalamus * Recorded what these action potentials were in response to * Found that some cells fired at the same time as the mouse displayed aggressive behaviour * This suggested that these cells are responsible for controlling aggression * To show that these cells are having a direct effect, optogenetics can be used and a mouse can be made to act aggressively towards an inanimate object, like a glove

Question 46

Summarise the functions of each of the hypothalamic nuclei you need to know.

Answer 46

* Suprachiasmatic nucleus (SCN) * Biological clock * Anterior hypothalamus * Thermoregulation and Fever * Posterior hypothalamic area * Fear and Aggression * Supraoptic + Paraventricular nucleus * Posterior pituitary secretion of oxytocin & ADH * Median eminence + Arcuate nucleus + Paraventricular nucleus * Control of appetite * Metabolic rate * Anterior pituitary * Ventromedial nucleus * Satiety centre * Lateral hypothalamus * Hunger centre * Mammillary body * Memory * Circumventricular organs (Organum vasculosum of lamina terminalis (OVLT) + Subfornical organ (SFO)) * Thirst + Osmoreception

Question 47

Where does the hypothalamus have neural outputs to?

Answer 47

Brainstem and spinal tract (amongst others)

Question 48

How does the hypothalamus control the eye?

Answer 48

Provides a major parasympathetic drive of CNV₁, causing pupillary constriction and increased lacrimation when activated by bright light (as a part of the pupillary light reflex)

Question 49

How does the hypothalamus control osmotic regulation and cardiovascular function?

Answer 49

* Controls secretion of ADH and sympathetic control of the adrenal secretions (with aldosterone being the desired signal) and renin release from the kidney itself. * Controls vasoconstriction (neurally) (mediated by α₁ adrenoreceptors and noradrenergic stimulation via the sympathetic nerves that follow the blood vessels of the body)

Question 50

How does the hypothalamus control the digestive system?

Answer 50

* It increases peristalsis * It increases salivation * Control over the alimentary system is parasympathetic down the vagus nerve and enteric nervous system, although the HPA axis is also involved. Influences include the neurogenic cephalic phase of digestion, where gastrointestinal hormone (especially histamine and gastrin, to increase H⁺ secretions of the stomach) are increased in preparation for the consumption of food in response to hunger stimuli coupled with the sight/smell/feel of food nearby. Increased hunger signals from the lateral nuclei of the hypothalamus can also lead to increased gastrointestinal motility, potentially linked with the mass movement, housekeeping process of the distal gut. [CHECK]

Question 51

How does the hypothalamus control the genital system?

Answer 51

* Erection in males being induced by parasympathetic supply to the S2-4 nerves * It also controls emission

Question 52

How does the hypothalamus control the urinary system?

Answer 52

Control is largely sympathetic, influencing renin secretions and local control, as well as providing ADH as appropriate.

Question 53

How does the hypothalamus controll aggression?

Answer 53

Idk, it does.