Hypothalamus and the circadian cycle Flashcards
What do the neurons of the tuberomammillary nucleus do?
What are these neurons aligned to?
Respond to sleep pressure and reduction in sleep pressure
Aligned to the neurons in the SCN that are central regulators of the circadian cycle
What are circadian rhythms?
What are they generated by?
24hr rhythms in PHYSIOLOGY and BEHAVIOUR
Generated by MOLECULAR CLOCKS that coordinate internal biology with the external world
What is the main output of the neurons that regulate the circadian clock?
Melatonin
What is the function of the circadian clock?
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
What do most cells possess?
A molecular clock - that is maintained in synchrony by a MASTER clock in the SCN
What hormones are regulated on a 24hr cycle?
- Melatonin
- Body temperature
- Plasma cortisol
- GH
- Testosterone
- Prolactin
What orchestrates the oscillation of tissue-specific metabolic and physiological function?
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
How do we know much about the molecular details/genes of the circadian clock?
Through studies in DROSOPHILA
LOF studies in the MOUSE
What underlies circadian regulation?
Describe this
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
What entrains the circadian clock?
Example
Environmental inputs
Daylight:
- Activates CRY proteins –> promotes binding to transcription initiation machinery
When does development start?
When group of shh midline cells splits the eye field into 2
Where is the SCN situated in the brain?
What does this mean?
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
How does the SCN entrain the clock for the entire body?
Through efferents (nerve connections) to other hypothalamic nuclei and brain regions
What is important about the isolated neurons of the SCN?
Dissociated neurons of the SCN maintain their 24hr rhythm:
- Competent, cell-autonomous circadian pacemakers
Describe the neuronal excitability in the SCN
Different at different stages of the circadian cycle
What must occur for the circadian clock to occur optimally?
What is responsible for this?
Neurons of the SCN must be PERFECTLY SYNCHRONISED
Vasoactive intestinal peptide (VIP) released from a subset of neurons in the SCN
What is a marker of SCN?
VIP
How is the development of the SCN understood?
By examining the marker of SCN - VIP
What controls the terminal differentiation and circadian function of the SCN?
HOW is this seen?
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
What do the neurons of the SCN form connections with?
What does this mean?
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
What can disruption of the intrinsic clock cause?
How?
Shown?
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
Describe differences in the clock in Schizophrenic patients
1) FIBROBLASTS - loss of rhythmicity in CRY1 and PER1 expression
2) LEUKOCYTES - decreased/disrupted day expression of CLOCK, PER, CRY
Are disruptions to the clock a cause or consequence of mental illness?
BOTH:
- Perturbations in one –> exacerbate dysfunction in the other (disruptions in one part of the Hyp –> disruptions in another)
What do mouse mutants of the circadian clock show?
How was this shown?
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
What can disrupting SCN in mice show?
Helplessness, behavioural dispair, anxiety-like behaviour
CAUSAL
What is an animal model of depression?
SCN-Bmal1-KD
What did Russell Foster suggest?
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
Do social/behavioural aspects LEAD to sleep and mental health problems?
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
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?
ENVIRONMENTAL disruption (eg. by stress) –> same knock on effect
One part of the nervous system –> impacts on another
Why is the hypothalamus a good model to see how one part of the nervous system can impact on another?
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)
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?
ENVIRONMENTAL disruption (eg. by stress) –> same knock on effect
One part of the nervous system –> impacts on another
Why is the hypothalamus a good model to see how one part of the nervous system can impact on another?
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)
What is the summary of these studies?
- 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
What does understanding the mechanisms of the clock allow?
Understanding of the link between the clock and physiological processes and therefore the central role of the clock in many diseases
What may disruptions to the clock also be responsible for?
Neurodegenerative diseases
Metabolic diseases
Immune-system diseases
Where/how is melatonin produced?
In the PINEAL GLAND by the action of SCN (has a direct circuit with the pineal gland)
What is melatonin involved in?
- Circadian rhythm regulation
- BP regulation
- Immune funciton
- Detoxification of free radicals
What is the function of melatonin?
Antioxidant:
- Protects against free radicals that are the byproducts of being exposed to sunlight
What is melatonin involved in?
- Circadian rhythm regulation
What do animal models of melatonin suggest?
Critical to clear free radicals - faliure to do so –> cause mental health and neurodegeneration
