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A BMS 381 - Developmental neurobiology > Hypothalamus and the circadian cycle > Flashcards

Hypothalamus and the circadian cycle Flashcards

1
Q

What do the neurons of the tuberomammillary nucleus do?

What are these neurons aligned to?

A

Respond to sleep pressure and reduction in sleep pressure

Aligned to the neurons in the SCN that are central regulators of the circadian cycle

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2
Q

What are circadian rhythms?

What are they generated by?

A

24hr rhythms in PHYSIOLOGY and BEHAVIOUR

Generated by MOLECULAR CLOCKS that coordinate internal biology with the external world

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3
Q

What is the main output of the neurons that regulate the circadian clock?

A

Melatonin

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4
Q

What is the function of the circadian clock?

A

1) To ANTICIPATE the regular 24hr ENVIRONMENTAL CHANGES
2) To establish ENDOGENOUS 24hr rhythms (coordinated with the environmental changes)

To ENSURE:
- Physiological and behavioural outputs are APPROPRIATE and OPTIMISED to the appropriate time window each day

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5
Q

What do most cells possess?

A

A molecular clock - that is maintained in synchrony by a MASTER clock in the SCN

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6
Q

What hormones are regulated on a 24hr cycle?

A
  • Melatonin
  • Body temperature
  • Plasma cortisol
  • GH
  • Testosterone
  • Prolactin
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7
Q

What orchestrates the oscillation of tissue-specific metabolic and physiological function?

A

Thousands of clock-controlled genes:
- Between 2-30% of the transcriptome of each tissue displays a circadian rhythm

  • Transcriptome (upregulated/downregulated genes) of a cell can vary hugely on a 24hr cycle –> controlled by the circadian clock
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8
Q

How do we know much about the molecular details/genes of the circadian clock?

A

Through studies in DROSOPHILA

LOF studies in the MOUSE

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9
Q

What underlies circadian regulation?

Describe this

A

Cell-autonomous transcription-translation feedback loops:

1) TF (CLOCK, BMAL1) drive the expression of other genes (Per1/2) and (Cry1/2) y binding to their enhancers
2) Protein products of these genes (Per1/2, Cry1/2) go back into the nucleus to INHIBIT CLOCK and BMAL1
3) Per1/2 and Cry1/2 are then degraded –> CLOCK and BMAL1 build up again

This loop takes roughly 24 hrs

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10
Q

What entrains the circadian clock?

Example

A

Environmental inputs

Daylight:
- Activates CRY proteins –> promotes binding to transcription initiation machinery

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11
Q

When does development start?

A

When group of shh midline cells splits the eye field into 2

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12
Q

Where is the SCN situated in the brain?

What does this mean?

A

VERY close to the eyes, with direct axon tracts between the retina and the SCN

Light coming through the eyes can entrain the master clock in the SCN –> sets the clock for the entire b

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13
Q

How does the SCN entrain the clock for the entire body?

A

Through efferents (nerve connections) to other hypothalamic nuclei and brain regions

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14
Q

What is important about the isolated neurons of the SCN?

A

Dissociated neurons of the SCN maintain their 24hr rhythm:

  • Competent, cell-autonomous circadian pacemakers
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15
Q

Describe the neuronal excitability in the SCN

A

Different at different stages of the circadian cycle

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16
Q

What must occur for the circadian clock to occur optimally?

What is responsible for this?

A

Neurons of the SCN must be PERFECTLY SYNCHRONISED

Vasoactive intestinal peptide (VIP) released from a subset of neurons in the SCN

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17
Q

What is a marker of SCN?

A

VIP

18
Q

How is the development of the SCN understood?

A

By examining the marker of SCN - VIP

19
Q

What controls the terminal differentiation and circadian function of the SCN?

HOW is this seen?

A

Lhx1 (previously met lhx6 and lhx9 in sleep):

Deletion of Lhx1 in the developing SCN:
- Loss of SCN-enriched neuropeptides involved in synchronisation and coupling to downstream oscillators

  • Clock gene expression rhythm persists BUT is damped and highly DISORGANISED –> clock doesn’t work
20
Q

What do the neurons of the SCN form connections with?

What does this mean?

A

OTHER hypothalamic nuclei: PVN, Arc, LH:

  • DIRECTLY regulate neurons involved in SLEEP and ENERGY METABOLISM
  • Synapse on the NPY and POMC neurons of the Arc

Means:

  • SCN governs MANY outputs
  • SCN/Circadian clock is linked to a range of problems with ill-health
21
Q

What can disruption of the intrinsic clock cause?

How?

Shown?

A

Mental health disorders:

  • Bipolar
  • Sch
  • Depression

Due to:

  • Disruption of multiple circadian outputs
  • Disruption of the core circadian clock

Shown through GWAS and SNP analysis

22
Q

Describe differences in the clock in Schizophrenic patients

A

1) FIBROBLASTS - loss of rhythmicity in CRY1 and PER1 expression
2) LEUKOCYTES - decreased/disrupted day expression of CLOCK, PER, CRY

23
Q

Are disruptions to the clock a cause or consequence of mental illness?

A

BOTH:
- Perturbations in one –> exacerbate dysfunction in the other (disruptions in one part of the Hyp –> disruptions in another)

24
Q

What do mouse mutants of the circadian clock show?

How was this shown?

A

Manic behaviours –> shows links between circadian clock and disease pathology

Shown by:
- Mutations in CLOCK –> behavioural profile similar to human mania

  • Increase in DOPAMINERGIC ACTIVITY
  • Hyperactivity, decreased sleep, LOWERED depression and anxiety
  • Increase reward value for cocaine, sucrose

Disruption to the clock is CAUSAL to manic behaviour

25
Q

What can disrupting SCN in mice show?

A

Helplessness, behavioural dispair, anxiety-like behaviour

CAUSAL

26
Q

What is an animal model of depression?

A

SCN-Bmal1-KD

27
Q

What did Russell Foster suggest?

A

Sleep and circadian rhythm disruption is CAUSAL to mental illness (NOT a CONSEQUENCE)

Not have mental illness and then can’t sleep –> can’t sleep - more sucesseptible to mental illness

28
Q

Do social/behavioural aspects LEAD to sleep and mental health problems?

A

IDEA that:
- Intrinsic clock has evolved to be in PERFECT synchrony with the 24hr light-dark clock (intrinsic and extrinsic = synchrony)

  • Synchrony lost –> effects hormonal and physiological signals –> impact on health
29
Q

What is another idea of the cause of depression involving the clock? (other than a direct mutation in a component of the clock)

What does this suggest?

A

ENVIRONMENTAL disruption (eg. by stress) –> same knock on effect

One part of the nervous system –> impacts on another

30
Q

Why is the hypothalamus a good model to see how one part of the nervous system can impact on another?

A

Hypothalamus is an INTEGRATED system:

Can see the effects of manipulation/disruption in one part of the hypothalamic circuit (associated with one behaviour) on ANOTHER part of the circuit (associated with a DIFFERENT behaviour)

31
Q

What is another idea of the cause of depression involving the clock? (other than a direct mutation in a component of the clock)

What does this suggest?

A

ENVIRONMENTAL disruption (eg. by stress) –> same knock on effect

One part of the nervous system –> impacts on another

32
Q

Why is the hypothalamus a good model to see how one part of the nervous system can impact on another?

A

Hypothalamus is an INTEGRATED system:

Can see the effects of manipulation/disruption in one part of the hypothalamic circuit (associated with one behaviour) on ANOTHER part of the circuit (associated with a DIFFERENT behaviour)

33
Q

What is the summary of these studies?

A
  • KNOWN that lack of sleep is associated with poor mental health
  • Now, some evidence that disruptions to intrinsic circadian clock (through mutation/environmental disruption) –> cause poor mental health
34
Q

What does understanding the mechanisms of the clock allow?

A

Understanding of the link between the clock and physiological processes and therefore the central role of the clock in many diseases

35
Q

What may disruptions to the clock also be responsible for?

A

Neurodegenerative diseases
Metabolic diseases
Immune-system diseases

36
Q

Where/how is melatonin produced?

A

In the PINEAL GLAND by the action of SCN (has a direct circuit with the pineal gland)

37
Q

What is melatonin involved in?

A
  • Circadian rhythm regulation
  • BP regulation
  • Immune funciton
  • Detoxification of free radicals
38
Q

What is the function of melatonin?

A

Antioxidant:

- Protects against free radicals that are the byproducts of being exposed to sunlight

39
Q

What is melatonin involved in?

A
  • Circadian rhythm regulation
40
Q

What do animal models of melatonin suggest?

A

Critical to clear free radicals - faliure to do so –> cause mental health and neurodegeneration

A BMS 381 - Developmental neurobiology (17 decks)

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