Neuroendo Flashcards
What does ‘anorexigenic’ mean?
Inhibiting food intake
What does ‘orexigenic’ mean?
Driving food intake
What are neurohormones?
Hormones produced and secreted by neurones
What is neurosecretion?
Neuronal release of chemical agents into the circulation
What is the difference between neuro-secretory cells and neurones?
Neuro-secretory cells…
- Require more mitochondria
- Peptidergic; peptide is synthesised in the cell body as an inactive precursor
Where are neuro-secretory cells found?
Neurohypophysis
Infundibular system
What is excitation/ secretion coupling?
Depolarisation via action potentials at the neurosecretory terminals -> hormone secretion
How do we know whether potassium or calcium is most important for neurosecretion?
Potassium:
Stick pituitary gland in a potassium bath -> depolarisation -> vasopressin release
Calcium:
Treatments that raise calcium influx cause hormone release
Agents blocking calcium influx interfere with secretion
greater extracellular calcium stimulates vasopressin release.
What are the stages of neuroendocrine transduction?
- Action potential
- Depolarise axonal terminal
- Increase intracellular calcium
- Vesicular fusion
- Exocytosis of granular contents
- Amplitude of release is proportional to frequency of action potentials.
What is a neuronal reflex?
Unbreakable pathway where a particular stimulus always results in a particular action.
What are examples of 3-tier neuroendocrine systems?
HPG
HPT
HPA
What are examples of 2 tier neuroendocrine systems?
Growth hormone
Prolactin
Describe the blood supply of the pituitary gland
Superior hypophyseal artery - median eminence and pituitary stalk
Inferior hypophyseal artery - posterior lobe and anterior lobe
These arteries are connected by the trabecular artery.
Describe the venous drainage of the pituitary system
The arteries drain into the venous sinuses which carry stuff from both lobes out into the body
What are hypophyseal hormones?
Hypothalamic hormones controlling the pituitary
What is oxytocin?
Small hormone consisting of nine amino acid peptides and one internal disulphide bridge.
Where does oxytocin come from?
Posterior pituitary
- Synthesised as a pro-hormone (in neuronal cell bodies) in magnocellular neurones.
- Packaged into neurosecretory granules and transported down neurones where it’s released into the blood from specialised terminals.
What are ‘neurophysins’?
Carrier proteins within neuronal secretory vesicles that have no biological effects in circulation.
What are the specialised terminals that release oxytocin?
Neurohypophysis
Neural lobe
Pars nervosa
How is oxytocin stored?
Within the dendrites of magnocellular neurones
What are the endocrine (peripheral) actions of oxytocin?
Milk ejection in lactating animals
Uterine contraction during parturition
Oxytocin endocrine actions in males
What are the central/ neuromodulator (behavioural) actions of oxytocin in mammals?
Post-partum maternal behaviour
Pair bonding in monogamous social species
Social interactions
What are the arguments in favour of oxytocin as a ‘morality drug’?
- Correlates with level of perceived trust (measured via monetary games)
- Increases trust and generosity in donors within a trust experiment
- Increases perception of attractiveness and trustworthiness
What are the arguments against oxytocin being a ‘morality drug’?
- Plasma oxytocin isn’t always properly tested or corrected for (overestimated or mistaken for similar molecules)
- Oxytocin is normally undetectable and it remains unknown how secretion is triggered.
- Monetary games can measure risk more than trust
- No evidence that intranasal administration increases intra-cerebral concentration.
- How do you accurately measure morality?
Describe the milk ejection reflex
Myoepithelial cell contraction after pulsatile oxytocin release
-> positive expulsion of milk
How is the milk ejection reflex regulated?
Input from sensory neurones in nipple
Afferents via spinal cord -> mesencephalon
Afferents via diencephalon -> hypothalamus
Increase firing rate in oxytocin neurones in supraoptic nucleus/ paraventricular nucleus
Synchronised discharge of oxytocin -> ejection
What is vasopressin?
Small hormone made of nine amino acid peptides with one internal disulphide bridge
What is the difference between structures of oxytocin and vasopressin?
Two amino acids
What is the role of vasopressin?
Regulation of plasma osmolarity (through water conservation) Vascular regulation (increases arterial blood pressure)
What is the difference between the release of oxytocin and vasopressin?
Oxytocin - released as needed
Vasopressin - released in bursts (phasic); release is proportional to when the stimulus persists
What is the pathophysiology of diabetes insipidus?
Decreased AVP release results in increased water excretion
What is the treatment for diabetes insidious?
Deaminovasopressin (DDAVP)
Usually intranasal administration
What are common studied behavioural effects of vasopressin in mammals?
Aggression
Anxiety
Maternal behaviour
Pair bonding
Why is it important to avoid extrapolation of animal studies onto humans?
Voles and mice have varying results in studies oxytocin and vasopressin.
If there’s variation in species you’d assume to be very similar, how do you expect to do it from a mouse to a human?
How is the paraventricular nucleus organised?
Parvocellular neurons - produce CRH and vasopressin
Magnocellular neurons - produce vasopressin and oxytocin
How does vasopressin act to increase arterial pressure?
Increased vasopressin release
Increased binding to V1a receptors on smooth muscle cells -> increased blood pressure
What is the normal osmolarity of plasma?
280-295mOsM
What happens to vasopressin in hypo-osmotic plasma?
Reduced vasopressin release -> decreased water retention
What is the permeability of water through tubule cell membranes?
Usually permeable through basolateral membrane and impermeable though apical membrane
Where are aquaporins in tubule cell membranes?
Normally stored in membrane vesicles within the cell
Basolateral = aquaporin 3
Apical = aquaporin 2
How does vasopressin change water movement across tubule cells?
Makes the apical membrane more permeable via the aquaporin 2 receptor .
Water can then move down the osmotic gradient, into the blood.
How is blood osmolarity usually monitored?
Central osmoreceptors
What is the ‘adenohypophysis’?
Anterior pituitary
What is the anterior pituitary responsible for releasing?
Thyroid stimulating hormone Adrenocorticotropic hormone Follicle stimulating hormone Luteinising hormone Growth hormone Prolactin
How are hormones from the anterior pituitary gland released?
Pulses; rate of release is regulated through negative feedback
How can episodic pulses of hormone release be regulated?
Circadian rhythms
Reproductive cycles
Seasonal rhythms
What is the difference between circadian rhythms and seasonal rhythms?
Circadian - suprachiasmiatic nucleus is the ‘master clock’
Seasonal- particular points in the year usually act to suppress rhythm generators. The change could be to do with photoperiods (therefore melatonin release), food intake etc.
Where are oxytocin and vasopressin released from?
Posterior pituitary
What is the origin of obesity with respect to energy imbalance?
Increased energy intake
Decreased energy expenditure
= positive energy balance
How do genetics contribute to obesity?
Thrifty genotype- our genes are probably predisposed to storing excess energy
How does policy contribute to obesity?
High density calorie foods are often cheaper than healthy food
Health inequality - poorer individuals less able to afford healthy food and therefore more likely to become obese
How is appetite positively regulated?
Stomach releases ghrelin prior to meal
Hypothalamus increases release of orexigenic peptides, NPY and Agrp which down-regulate POMC and CART
How is appetite negatively regulated?
Small intestine releases PYY3-36 and GLP-1 which project to the hypothalamus
Hypothalamus increases release of POMC (a-MSH) and CART which down-regulate NPY and Agrp
What would happen if you got rid of the hypothalamic centres involved in appetite?
Destroy PVN, VMN or DMN -> obesity
Destroy lateral hypothalamic area (LHA) -> anorexia & weight loss
What is the phenotype of the db/db mouse?
Obese. Crazy appetite, increased energy intake and expenditure
Diabetic. The more obese you are, the more insulin resistant you become
Why is the db/db mouse obese?
Parabiosis with wt mice showed that the wt would stop eating and starve to death.
This means that the db/db mouse has circulating factor (that keeps increasing) but receptors aren’t responsive.
What is the phenotype of the ob/ob mouse?
Obese. Leptin knockout
Ob gene encodes leptin protein
Why is the ob/ob mouse obese?
The ob/ob mouse did not produce any functional leptin.
How is leptin released?
Long term indicator of energy balance; release from adipocytes is proportional to the amount of adipose tissue within the body.
What are the roles of leptin?
Appetite
Hedonistic control of appetite
Reproduction
What is the lipostatic/ adipostatic theory for the long term control of body weight?
Total body weight maintained by regulating total body fat content.
Adipostat = circulating leptin
What is the set point hypothesis for the long term control of body weight?
Leptin controls body weight about a defined level (i.e. the set point) via interaction with the hypothalamus.
Leptin integrates signals with other regulators of food intake to keep energy reserves constant.
Why is the set point hypothesis an explanation for diets being unsustainable?
Dieting means decreasing leptin over time (which the body will try to counteract by increasing starvation signals)
Successful dieters would have to ‘re-set’ their set point through the sustained dieting period.
What are the effects of leptin on energy use?
High circulating leptin means:
- Inhibited food intake -> weight loss
- increased growth
- Increased energy expenditure
- Increased glycaemic control
- Indicator of whether an individual has enough energy for conception
Why is leptin an anti-obesity signal?
The biological impact of leptin is more pronounced when there’s less of it.
Falling serum leptin drives hunger -> reduced energy expenditure & inhibited reproductive competence
Is there a therapeutic potential for leptin?
Leptin blood levels are usually higher in obese individuals, and they also show resistance to it.
Few situations exist where you can replace leptin and weight loss is pronounced (rare genetic disorders).
What are the effects of human mutations in the leptin and leptin receptor genes?
Base deletion maturation -> inactive protein (similar to ob/ob).
Homozygous receptor mutation
Leptin deficiency
Can DNA sequence variations contribute to obesity?
According to Considine et al, no.
Describe signalling through the leptin receptor.
- Phosphorylation of JAK2
- JAK2 cross talks with insulin via IRS proteins
- Calcium influx and release from neurons affected by MAPK pathway
- SOCS3 increases signalling activation and inhibition.
- Phosphorylation of pSTAT3 where there’s more exogenous leptin
How does leptin resistance occur in non-pathological obesity?
Obesity means high circulating leptin
There could be a defect in the leptin signalling pathway
pSTAT3 inhibition means the leptin receptor can’t respond
pSTAT3 is also responsive to stress and inflammation, activation by all the different stimuli may increase resistance
How is it that the hypothalamus can respond to changes in circulating molecules?
The hypothalamus is a circum-ventricular organ which has a leaky blood brain barrier. This means that it is able to ‘taste’ and respond to what’s happening in the blood.
Where can the hormones secreted by food regulating neurones found?
Arcuate nucleus
What is POMC?
Pro-opiomelanocortin
Pre-cursor of the second order signalling hormone alpha- MSH.
What would one expect after centrally injecting alpha-MSH into the brain?
Decreased food intake
What is CART?
Cocaine & amphetamine- regulated transcript
Anorexigenic peptide co-expressed with POMC in arcuate nucleus
How is CART expression regulated?
Circulating functional leptin levels
What is Agrp?
- Agouti related peptide
- Homologue of agouti protein which is responsible for yellow mouse fur
- Melanocortin which is co-expressed with NPY in arcuate nucleus
- MC3 and MC4 receptor antagonist
What is NPY?
Neuropeptide Y
Powerful appetite stimulant
Shares its receptors with PYY, ghrelin and oxyntomodulin.
What cross talk occurs between first order neurons and why is it important?
POMC/ CART neurons inhibit NPY/AGRP for satiety signalling and vice versa for starvation signalling.
Leptin dictates which nuclei are more dominant.
What are the consequences of mouse POMC knockout?
Tian et al. showed that in diet-induced obesity, alpha-MSH expression is reduced
Rats that were resistant to the high fat diet had increased alpha-MSH expression (though its is still less than controls)
What are the consequences of POMC gene mutations in humans?
- Recessive pattern of inheritance
- Red hair (alpha-MSH important in delineating hair colour)
- Hyperphagia
- Obesity
What is the role of melanocortin 4 receptor (MC4R) in second order signalling?
Anything that activates MC4R (like alpha-MSH) reduces food intake.
Therefore when Agrp binds and inhibits MC4R, the result is increased food intake.
What are the consequences of melanocortin 4 receptor mutations in mice?
Agouti and agouti both block melanocortin receptors while alpha-MSH activates them.
Overexpress Agrp or knockout MC4R and you get increased food intake and therefore a fat mouse.
You’ll have a fat yellow mouse if you over expressed agouti.
What are the consequences of melanocortin 4 receptor mutations in humans?
Morbid obesity- most commonly occurring monogenic cause of inherited obesity.
What is the phenotype for melanocortin 4 receptor mutation in humans?
- Hyperphagia (starting from 8 months old)
- Tendency towards tall stature
- Hyperinsulinaemia
- Increased bone density
Where is thyrotropin releasing hormone secreted from?
Paraventricular nucleus
How do we know that Agrp neurons work downstream of leptin
Administer leptin to hypothalamic explants -> increased TRH release
Diminished response in TRH release if Agrp were given.
What is the role of melanin concentrating hormone?
Increased expression during fasting state
Increases food consumption and decreases metabolic rate -> positive energy balance
What are orexins A and B?
- Hypocretins exclusively produced in the lateral hypothalamic area.
- Deficiency results in narcolepsy.
- Its neurons are regulated by ghrelin, leptin and glucose
Wha do studies say about physiological phenotyping of Agrp and NPY?
Gene knock outs:
K/O either - no phenotype
K/O both - non-hypophagic phenotype
Instead of saying they don’t play a role in food intake, it was concluded that they’re so important that compensatory peptides and neurons exist.
Neuron knock out:
Liquet et al - Argp K/O resulted in lean mouse (reduced adiposity)
How does ‘functional mapping’ work?
Investigations of the interaction between neuropeptide hormones and neurones to figure out what pathways are important, the nuclei involved and if there’s a neuronal basis for things like food choice.
What is ghrelin?
Gut hormone responsible for increased food intake
Octanoylation (addition of 8 acyl groups) via GOAT makes it active
How does ghrelin mediate feeding?
Peaks in ghrelin just before meals (therefore drives feeding)
Increased ghrelin secretion in response to negative energy balance to protect from starvation -> dose dependent increase in food intake
What is the main target of ghrelin for driving food intake?
Arcuate nucleus
Also paraventricular nucleus (to lesser extent)
What neurons does ghrelin engage in its target nuclei?
NPY (50% of neurons containing it are ghrelin responsive in Arc)
Why are drugs that increase food intake important?
Conditions like cancer where patients become cachexic
Increasing food intake could increase their life expectancy.
What is D-lys-3-GHRP-6?
Growth hormone receptor antagonist
Ghrelin binds to growth hormone receptor, acting to increase intake
Antagonise GHR and you’d expect decreased food intake which is what happened.
Why are injections not ideal forms of treatment?
Injections reduce compliance
Why is reduced body fat good for obese patients?
Loss in body fat increases insulin’s sensitivity to glucose
What is the role of L cells?
Production and release of oxyntomodulin, PYY and GLP-1 post-prandially.
Tasting changes in gut nutrients.
What are the differences between PYY 1-36 and PYY3-36?
- PYY1-36 increases food intake
- PYY 3-36 (cleaved by DPP4) is the main circulating form and decreases food intake
- They bind to different receptors
What does PYY3-36 bind to?
Y receptor 2
According to Le Roux et al, what observations are made in obese patients after gastric bypass surgery?
- There may be a problem with satiety signalling - defect in gut hormone release while obese
- Increased PYY release in patients after surgery (exaggerated response is larger than in lean controls)
- Implied removal of defect after surgery and compensation for reduced L cell PYY release
What is the difference between PYY 1-36 and PYY3-36 concentrations in fasted and fed stated?
Fasted- increased drive to eat -> PYY 1-36 more abundant in circulation
Fed - increased satiety signals -> PYY 3-36 more abundant in circulation
What receptors does PYY 1-36 usually bind to?
Y receptors 1 and 5
According to Abbott and Koda et al, what is important for PYY3-36 action?
Circulation route
Cut vagus nerve then give PYY3-36 -> blocked satiety
Cut circulatory route to hypothalamus then give - blocked satiety
What are the problems with PYY as a weight loss drug?
Get dose wrong -> emesis
Short circulating half-life, but effects are seen for over 24 hours
What is the difference between oxyntomodulin and GLP-1 with respect to production?
Though coded for by the same gene, they’re processed differently after translation
Where does GLP-1 bind?
GLP-1 receptor on POMC neurone in Arc (and brainstem)
Where does oxyntomodulin bind?
GLP-1 receptor
What is the difference between GLP-1 and oxyntomodulin with respect to function?
GLP-1 reduces food intake by increasing firing rate of POMC neurones
Oxyntomodulin decreases food intake and increases energy expenditure, working on both sides of the energy equation.
What techniques could be used to measure energy expenditure?
Heart rate monitor
Calorimetry
What techniques could be used to establish the site of action of a neurohormone?
- Intranuclear cannulation
- Hypothalamic explants
- Central injection
What is the main problem with oxyntomodulin as a weight loss drug?
Oxyntomodulin is very susceptible to degradation
It is also cleared very quickly; 35% of it experiences renal clearance
How could you make analogues of a hormone?
- Targeted amino-acid substation
- Peptide chain extension
- Side chain derivatization
How do we know that there are cerebral/ neural effects associated with food?
More Agrp/ NPY firing in caged chocolate than accessible in studies of fasted mice (ingestion means release of gut hormones that can send satiety signals)
What are potential steps forward for ‘weight loss’ interventions?
- Combine different drugs to see larger therapeutic effects
- Design foods that provide larger hormone responses
How do growth hormone releasing hormone (GHRH) and somatostatin act on somatotrophs?
G-protein coupled receptors:
GHRH activates adenylyl cyclase by acting on the stimulatory G protein
Somatostatin acts on an inhibitory G protein to inhibits adenylyl cyclase
Why is the growth hormone gene tissue specific?
PIT1 is required
What is the structure of growth hormone?
Single chain protein with 2 disulphide bonds
Major circulating form = 22kD
Minor form = 20kD
Why is growth hormone best taken intraperitoneally?
Half-life = 15 minutes
Can easily be degraded by saliva proteases and stomach.
How is growth hormone stored?
Secretory granules within somatotropin cells, under the influence of growth hormone releasing hormone.
Where is growth hormone produced?
Stomach
Somatotrophs
Neurons in the hypothalamus
What factors stimulate growth hormone secretion?
Arginine
Thyroid hormones
Gonadal hormones
These are all anabolic and protein precursors
What factors inhibit growth hormone secretion?
Cortisol
Glucose
Free fatty acids
How is GH released?
Pulses; concentration varies throughout the day
Most release occurs during REM sleep
When administering growth hormone, what is important to note?
Growth hormone is species specific (though it can now be manufactured by recombinant technology)
What hormones control growth hormone secretion?
Growth hormone releasing hormone (hypothalamic)
Somatostatin (hypothalamic)
Ghrelin (stomach)
How does somatostatin control growth hormone secretion?
Blocks only the final release of stored growth hormone.
Why does GHRH have trophic action within the pituitary gland?
Growth hormone is the major dry weight product of the anterior pituitary
What is the original somatomedin hypothesis?
The effect of growth hormone on longitudinal body growth was mediated solely through liver derived IGF-1.
What adaptations were made to the somatomedin hypothesis?
Extra-hepatic tissues were also capable of expressing IGF-1 and involved in mediating GH action.
It was then updated to suggest that local IGF-1 could be produced by GH action directly on tissues.
Data from tissue specific gene deletion in mice suggest that liver-derived IGF-1 isn’t essential for GH stimulated post-natal growth and development.
What is the interrelation between the secretion of growth hormone releasing hormone (GHRH) and somatostatin (SRIF) for growth hormone secretion?
Reduction in somatostatin mediated inhibition
Episodic GHRH release; maximal concentrations are present during periods of expected growth hormone secretion.
How regularly is growth hormone released?
Every 3 hours
What are the two circulating forms of somatostatin?
SS-14 = 14 amino acids long SS-28 = 28 amino acids long
How is somatostatin formed?
Cleavage from preprosomatostatin to prosomatostatin to somatostatin
What changes in growth hormone pulsatility can be observed after gonadectomy in male rats?
Baseline increased and pulse heights were lower compared to sham controls.
Reversible with testosterone
What hormone is necessary for maintaining the low baseline growth hormone levels in adult male rats?
Testosterone
What changes in growth hormone pulsatility can be observed after gonadectomy in female rats?
Pulse heights were lower, baselines were higher than in male rats.
Add testosterone and male control pulses were recreated.
In the male vs. female rat studies, what effect did gonadectomy have on weight changes?
Male- weight gain decreased
Female - weight gain increased
Describe the growth hormone receptor signalling pathway.
Growth hormone binding causes the receptor (GHR) to dimerise.
Dimerisation causes conformational change so JAK2 moves to the GHR and can activate it via phosphorylation
Activated GHR can then initiate many signalling pathways like STATs, SHC and IRS
What are STATs?
Signal transducer and activator of transcription
Transcription factors found in the cytoplasm when inactive
How do STATs work?
Activated via tyrosine phosphorylation
Phosphorylated STATs dimerise and translocate to the nucleus
Interaction with specific regulatory sequences -> activation or repression in target gene transcription.
What are SOCS?
Suppressors of cytokine signalling
Activated via high GHR activation
How are GH specific cytochromes responsive to GH patterns?
Males - CYP2C11 activation; inhibition of CYP2C12
Females - CYP2C12 activation; inhibition of CYP2C11
What is the role of HNF6?
Induces HNF3-beta which acts with HNF6 to stimulate CYP2C12 promoter activity
What is the role of STAT5b?
Regulating body size
Activated by intermittent plasma GH pulses
Proposed to antagonise HNF6 and HNF3-beta’s stimulation of CYP2C12
Why is growth hormone pulsatility physiologically important?
More effective at stimulating weight gain and growth than continuous exposure
What GH pulsatility qualities maximise growth?
High pulse amplitude
Low baseline levels
Describe growth hormone feedback.
IGF-1 positively feeds back to SRIF and negatively to GHRH and GH.
GH positively feeds back to SRIF, IGF-1 and negatively to GHRH.
SRIF (inhibits GH) and GHRH (stimulates GH) communicate with each other.
What effect does exogenous growth hormone administration have on endogenous secretion and why?
Inhibition of endogenous release via hypothalamic feedback - Wells et al.
Reduced growth
Compare transgenic growth retarded rats with normal controls.
Males - pulse peaks present though not as high. Baseline remains low
Females - Reduced GH, pattern of pulsatility changes
What is the purpose of GC cells?
Cultured pituitary tumour cells which can be implanted back into animals
Allow for high long-term GH exposure in the circulation
What role growth hormone feedback play in NPY expression?
GH administration stimulates NPY neuron activation
What role does NPY play in growth hormone feedback?
NPY administration inhibits GH secretion
How does ghrelin act to stimulate growth hormone?
Acts on the 7-transmembrane domain receptor GHS-R which causes an intracellular calcium increase -> release of growth hormone from anterior pituitary.
What neuron does ghrelin predominantly bind to in the hypothalamus?
NPY (arcuate nucleus)
Why do we need circadian clocks?
More energy efficient for biological processes
Organisms can anticipate changes that are regular, based on environmental cues and predictable
What are the functions of circadian clocks?
Anticipation of regular environmental changes
Internal synchronisation
Synchrony (temporal organisation) within a species
What is the difference between a biological rhythm and a circadian rhythm?
Biological rhythm- process/ action/ function repeated through time like clockwork; often a cause-effect response but not necessarily time dependent
Circadian rhythm- type of biological rhythm but maintained over 24 hours, even when environmental cues change
Give examples of circadian rhythms.
Behavioural - sleep/ wake cycles
Biochemical - glucose uptake, metabolic rate, alcohol degradation
Physiological - core temperature, blood pressure, heart rate, hormones
What are the characteristics of circadian rhythms?
Amplitude - how robust the circadian rhythm is
(half the peak of the rhythm)
Period - one complete cycle in rhythmic variation
What are the different types of circadian rhythms?
Free running - rhythm synced to species specific clock when environmental cues disappear
Entrainment- rhythms synced to specific external cues
What does ‘tau’ mean?
Free-running period of endogenous oscillation which varies between species.
Why is a free-running circadian rhythm useful?
Good for allowing adjustment of the circadian rhythm (e.g. when travelling between countries, you want to adopt different day light hours without lagging)
What does ‘zeitgeber’ mean?
Literally ‘time giver’, it refers to an external cue that circadian rhythms are synced to.
What are examples of zeitgebers?
Main Zeitgeber = light
- Food intake
- Social interactions
- Temperature cycles
What is an actogram?
A graph used to plot circadian rhythms
Black vertical bars = activity
Horizontal lines = double plot of 24 hours
Colour of horizontal lines indicates what type of cycle is being measured:
White = light/ dark (entrained)
Grey = dark/ dark (free-running)
Where do circadian rhythms come from?
Exogenous - responses to a change in environment (driven by environmental rhythms and not internally)
Endogenous - generated by the organism by a self-sustaining biological clock
How is the circadian clock regulated by light?
Light perception in the retina is relayed straight back to the supra-chiasmatic nucleus.
How is it possible that blind people have light entrainment?
Intrinsically photosensitive retinal ganglion cells (ipRGC) are photoreceptors in the inner retina that are distinct from rods and cones (responsible for vision)
What chemical is responsible for the detection of light?
Melanopsin
What would happen if you knocked out the ipRGCs of rats but kept their rods and cones?
Rats would have normal vision but absolutely no sense of circadian entrainment
How can circadian rhythms be linked to technology?
ipRGC overlaps in wavelength sensitivity with technological emissions.
Therefore, being at the wavelength that ipRGCs are most sensitive to, technology can shift your circadian clock.
What are the roles of melanopsin?
Photic entrainment of circadian rhythms
Pupillary light reflex
Light modulation of sleep and mood
Exacerbation of headaches
How does melanopsin mediate the pupillary light reflex?
Under high light intensity, melanopsin supports pupillary vasoconstriction
What is the link between melanopsin and headache exacerbation?
Light perception
Describe the light input pathway
Neural tract from the retina to the supra-chiasmatic nucleus
What is melatonin?
Circadian hormone found in the pineal gland
Half-life = 15-20 minutes
Why is melatonin considered the ‘night hormone’?
It’s almost exclusively secreted in high levels in all biological fluids during dark
How does noradrenaline affect melatonin synthesis?
Melatonin synthesis increases when noradrenaline binds to the adrenergic receptors of pinealocytes
How does light suppress melatonin synthesis?
Light -> SCN stimulation -> PVN inhibition -> melatonin suppression
Where are melatonin receptors found?
- Paraventricular nucleus
- Pars tuberalis of pituitary
- Dorsomedial & ventromedial hypothalamic nuclei
- Medial preoptic nuclei
- Hippocampus
- Cerebral cortex
- Area postrema
- Amygdala
- Retina
What are the systemic effects of melatonin?
- Sends information about the time of day to tissues that need it
- Facilitates sleep
- Lowers body temperature
What are the pharmacological uses for melatonin?
- Insomnia treatment in subjects with circadian disruption
- Used to accelerate entrainment to new time zones (reducing jet lag)
What is the mammalian molecular clock?
Supra-chiasmatic nuclei
What is responsible for making the circadian clock ‘tick’?
Rhythmic transcription-translation feedback loops (TTFL)
If circadian clocks are in individual SCN neurons and peripheral, how are they synchronised to generate a co-ordinated output?
There’s probably a TTFL clock in all cells; work has shown that many tissues express the same genes rhythmically
SCN acts as the central controller for all the individual cells.
How does the SCN communicate with peripheral clocks?
- Hormonal signals
- Rhythmic glucocorticoid
- Metabolic signals
- Behavioural signals
- Signals from autonomic nervous system
What are examples of brain clock outputs?
Sleep/ wake cycles
Feeding behaviour
What are examples of peripheral clock outputs?
- Glucose homeostasis
- Lipogenesis
- Sterol turnover
- Oxidative metabolism
- Respiration
How long does it take to properly re-synchronise to a new light-dark cycle?
1 day for each hour shift
What are adverse consequences of a desynchronised circadian clock?
Faster tumour growth - Filipski et al.
Faster weight gain- Arble et al.
Why do we need sleep?
- Restorative; CSF needs to clear protein metabolites formed in the brain.
- Required to prepare the brain for the next time it needs to wake up
- Cellular cost of learning consumed energy and reduces firing selectivity
- Reducing brain swelling from metabolic waste and reduced interstitial space
How does caffeine keep you awake?
- Adenosine usually binds to neurons causing sleepiness
- Caffeine blocks adenosine binding, keeping you awake
Why do we perform worse when sleep deprived?
Local sleep = force animal to stay awake longer than it should, neurones will sleep independently to the rest of the brain
Stickgold et al. - no matter how much you practice, you won’t learn without sleep
