CHRONOBIOLOGY.pptx

Chronobiology

1. CHRONOBIOLOGY Presenter: Dr.S.Chandana , 1 st year postgraduate Chair person: Dr.Rufus , Assistant Professor, Dept of Psychiatry, Andhra Medical College

2. SCHEME OF PRESENTATION Introduction Circadian pacemakers Molecular Clockwork Resetting the circadian clock Retinal photoreceptors Extra SCN Zeitgebers Sleep and circadian rhythm Seasonality and circadian rhythm Psychiatric disorders and circadian rhythm Circadian rhythm and pharmacotherapy

3. Chronobiology is the study of biological time It is derived from the greek ( chronos meaning time and biology is the study or science of life ) The rotation of the Earth about its axis imposes a 24 hour cyclicity upon the biosphere. Organisms have evolved to occupy geographical niches that can be defined by three spacial dimensions and also evolved to occupy temporal niches that are defined by the fourth dimension of time

4. A broad range of frequencies exist throughout biology ranging from millisecond oscillations in ocular field potentials 17 year cycle of emergence seen in the periodic cicada( Magicicada spp.)

5. HISTORY OF CHRONOBIOLOGY TIME PERIOD CONTRIBUTOR DISCOVERY 4 th century BC Androsthenes Ship captain serving Alexander the Great Described the diurnal leaf movements of Tamarind tree 18 th century/1729 Jean-Jacques d’Orteus de Mairan French scientist Documented 24hr patterns in the movement of plant leaves 18 th century/1751 Carl Linnaeus Swedish botanist Designed flower clock using certain species of flowers Early 20 th century Anthonia kleinhoonte Erwin bunning Rhythmicity appears to be endogenous in nature by plant studies

6. TIME PERIOD CONTRIBUTOR DISCOVERY 1918 Szymanski Animals are capable of maintaining the 24 hr activity patterns in the absence of environmental cues 1959 Franz Halberg Father of American Chronobiology Coined the term ‘Circadian’ Auguste forel Circadian rhythms noticed in the rhythmic feeding time of bees 1970 Ron Konopka Seymour benzer Isolated the first clock mutant in DROSOPHILA MELANOGASTER and mapped the period gene 1994 Joseph Takahasi Discovered the first mammalian ‘clock gene’ using mice

7. The most extensively studied and best understood biological rhythms is Circadian rhythms that have a period of about one day A defining feature of circadian rhythms is that they persist in the absence of time cues and are not simply driven by the 24-hour environmental cycle Circadian rhythm can be Diurnal Nocturnal Crepuscular

8. Circadian rhythms in human body: Sleep-wake cycle Body temperature Behavior Feeding Drinking Hormonal levels ( e.g : melatonin)

9. ZEITGEBER: An environmental agent or event that provides the stimulus for setting or resetting endogenous circadian clock of an organism Derived from german ( zeit =time and geber =giver) The environmental parameter that most reliably corresponds to the period of Earth’s rotation is the change in the illuminance associated with day-night cycle

10. Circadian axis of mammals can be divided into three distinct functional components A master pacemaker situated in Suprachiasmatic nucleus A photoreceptor input to SCN that originates in the eye The myriad of rhythmic outputs that provide insight into the clockwork of the circadian pacemaker.

11. Human suprachiasmatic nucleus.Top:Nissil stain of section through the human hypothalamus.SCN indicated by arrows located dorsal to optic chiasma Bottom:Autoradiograph of same section ,specific binding of radioiodinated analogue of melatonin indicated by darkening of the SCN

12. CIRCADIAN PACEMAKERS Anatomy: SCN is the master oscillator Peripheral oscillators are found in wide range of peripheral tissues like kidney ,liver , lung and other sites in brain Neurons of SCN are among the smallest neurons in the entire brain ,they possess short dendrites Every neuron in SCN is immuno-positive for GABA SUBDIVISIONS: core -defined by presence of calbindin-positive neurons , surrounded by shell

13. AFFERENT PROJECTIONS: AFFERENT PROJECTIONS NEUROTRANSMITTER FUNCTION Retino -hypothalamic tract(primary afferent input) Glutamate (Modulator :PACAP) Conveying photic information from retina to SCN Ipsilateral intergeniculate leaflet(subnucleus of lateral geniculate complex) to SCN Secondary indirect pathway :Retina to IGL to SCN NPY Encoding environmental luminance Midbrain Raphe to SCN(5HT1B & 5HT7) Serotonin Modulates light effect on SCN function

14. EFFERENT PROJECTIONS : Suprachiasmatic nucleus Paraventricular nucleus(autonomic division) Medial forebrain bundle Spinal cord (T1 &T2 level) Cholinergic preganglionic sympathetic neurons Adrenergic postganglionic sym. neurons within superior cervical ganglion Pinealocytes Norepineprine GABA

15. OUTCOME: Increased melatonin synthesis occurs when SCN activity is low This anti phasic relationship is established by the GABAergic sign-changing synapse at PVN Melatonin receptors on SCN likely provide feedback mechanism by which the anti phasic relationship is maintained and possibly reinforced

16. Exposure to light elicits two distinct effects on daily melatonin profile. 1)light acutely suppresses elevated melatoni levels immediately decreasing them to baseline levels. 2)light shifts the phase of the circadian rhythm of melatonin synthesis.

17. Second efferent pathway SCN PVN(parvicellular neurons) CRH ACTH adrenal gland(zona fasciculata) release of cortisol. Serum levels of cortisol show strong circadian component,being highest in the morning hours(6 am to 8 am),just as melatonin approach baseline

18. MOLECULAR CLOCKWORK

19. Many of these molecular components were initially discovered in the fruitfly , Drosophila melanogaster, leading to the discovery of mammalian orthologs The mammalian circadian clockwork consists of interacting positive and negative transcriptional and translational feedback loops The expression of multiple homologs of Drosophila period gene and cryptochrome genes are positively regulated by the binding of Clock-Bmal1 heterodimers to E-box enhancers in the promoters of these genes

20. The products of Per and Cry genes translocate back into the nucleus and repress their own transcription which constitutes the negative feedback limb Light directly influences the molecular clock via its impact on the expression of Per2,which has either phase advancing or delaying effects on feedback loop Clock-Bmal1 also activates expression of the orphan nuclear receptor gene Rev- Erba

21. The gene product of Rev- Erba inturn translocates into the nucleus and represses transcription of Bmal1 gene through Rev- Erb / Ror response elements in Bmal1 gene promoter Bmal1 subsequently heterodimerizes with Clock and again activates expression of Per,Cry and Rev- Erba genes This derepression (activation) of Bmal1 gene ,subsequent heterodimerization with Clock, and activation of Per,Cry and Rev- Erba genes constitute the Positive feedback limb

22. Post translational modification Phosphorylation of some Per proteins by casein kinase Histone acetylation

23. RESETTING OF CIRCADIAN CLOCK The mean circadian period generated by human SCN is of about 24.18 hours To maintain proper phase relationship of behavioural and physiological process ,circadian clock should be reset in a regular basis within a context of 24 hours a day Bilateral removal of eyes-incapable to reset circadian clock

24. Photic sensitivities of visual and circadian systems are different VISUAL system CIRCADIAN system DYNAMIC RANGE 14 Log units 3 Log units Activation threshold Less Higher Duration of light stimuli required less longer Photoreceptor input Layer of rods and cones Retinal ganglion cells Principal task To construct a spatio -temporal representation of environment Measurement of ambient illumination

25. NOVEL CLASS OF RETINAL PHOTORECEPTORS Retinal Ganglion cells are the circadian photoreceptors These intrinsically photosensitive cells project directly to SCN and also IGL,olivary pretectal nuclei Contain melanopsin Few in number Represent 1-2% of all retinal ganglion cells in rodent retina

26. Retinal ganglion cells in a flat mounted mouse retina,labelled by Indirect Immunoflorescence with an antibody against melanopsin.Note the photoreceptive net formed by overlapping dendritic arbors

27. These cells are less sensitive to light compared to rods and cones of visual system They require light stimuli of relatively long duration to be activated FUNCTION: Light induced circadian phase shifting knockout study in mice-photoreceptor mediating the residual sensitivity are likely to be rods and cones

28. EXTRA SCN ZEITGEBERS FOOD-has the ability to entrain the circadian rhythm in the absence of the master clock METHAMPHETAMINE-synchronizing the stimulus in the periphery EXERCISE-shifts heart rate and clock gene expression rhythms These may provide novel treatment targets in efforts to stabilize or shift circadian rhythms

29. SLEEP AND CIRCADIAN RHYTHMS Sleep is the integrated product of 2 oscillatory processes 1 st process is Sleep homeostat :arises from the accumulation and dissipation of sleep debt 2 nd process is governed by circadian clock:controls daily rhythm in sleep propensity or arousal

30. Chronotype is dictated almost exclusively by circadian process of sleep regulation Morning and evening chronotype loosely reflect advanced and delayed circadian rhythms relative to environmental light cycle Morning larks tend to awaken earlier and experience core body temperature minimum at earlier clock time relative to those who are labelled as evening types

31. SEASONALITY Many organisms are capable of synchronizing physiology to seasonal cycles to maximize survival E.g. precise seasonal cycles in reproduction Large mammals-sheep-long gestation period- short day breeders ,conceive in fall ,birth occurs in spring Hamsters-short gestation period- long day breeders ,conceive in spring ,give birth in summer Circannual rhythms tend to persist in the absence of seasonal cues with endogenous periods of one year

32. CIRCADIAN RHYTHMS IN PSYCHIATRIC DISORDERS SEASONAL AFFECTIVE DISORDER: Characterised by recurrent major depressive episodes followed by periods of remission or change to mania or hypomania,that recur on a seasonal basis SAD is diagnosed as MDD, bipolar 1 or bipolar 2 disorder with the specifier “with seasonal pattern” in DSM-5 The seasonal pattern criteria include

33. Regular temporal relationship between the onset of major depressive episodes and a particular time of the year Full remissions (or a change to mania or hypomania)also occur at a characteristic time of the year Two major depressive episodes meeting criteria A and B have occurred in the last 2 years and no nonseasonal episodes have occurred in the same period Seasonal major depressive episodes substantially outnumber the nonseasonal episodes over the individual’s lifetime

34. The most prevalent form of SAD has an onset in the late fall and early winter and remits in the late spring and early summer referred as winter SAD or winter depression Prevalence rate is 4 to 9% Women are 4 times as likely to be affected compared to men 20% of population have subsyndromal symptoms Twin studies identified a heritability of 29 to 43 % for seasonality

35. SYMPTOMS: Increase in sleep rather than decrease Hyperphagia Increase in weight Heightened sensitivity to interpersonal rejection Leaden feeling in the extremities

36. The gold standard treatment for winter SAD is light therapy A typical prescription for light therapy involves 45 to 90 minutes daily exposure to a broad spectrum ultraviolet filtered white light source of relatively high irradiance(5000-10000 lux) CBT is equally efficacious for acute treatment and prophylactically to reduce reccurences

37. NONSEASONAL UNIPOLAR DEPRESSION AND CIRCADIAN RHYTHMS Individuals with depression are more likely to be evening chronotypes and often have delayed rhythms and reduced peak amplitude of melatonin and core body temperature CLOCK and CRY genes have been found to be associated with depression diagnosis Circadian control of sleep is a potential avenue to improve long term outcomes in depression as sleep improvement is an important marker for lower recurrence rates

38. Chronotherapies for the improvement of sleep include Wake therapy , advancing sleep phase , bright light therapy and melatonin administration Administration of agomelatine 5 hours prior to bedtime can advance rhythms and improve mood. The practise of using these therapies with anti-depressant medications shows promise for achieving rapid response

39. BIPOLAR DISORDER AND CIRCADIAN RHYTHMS Circadian abnormalities have been suggested as a potential important etiological mechanism in the development of BPAD CLOCK 19 mice models suggest the importance of circadian modulation of dopaminergic activity within VTA in BPAD Depression is associated with a phase delay and mania associated with phase advance Stabilization of these rhythms may help in preventing or reducing the further episodes Interpersonal Social Rhythm therapy was developed due to the observation that irregular daily routines resulting in circadian dysregulation precipitates mood disorders

40. Other psychiatric disorders that may improve in response to light therapy include Post partum depression Pre-menstrual dysphoric disorder Bulimia nervosa ADHD Disordered sleep due to Traumatic brain injury

41. CIRCADIAN SLEEP DISORDERS Advanced sleep phase syndrome It is a pathological extreme of the morning lark phenotype FASPS(autosomal dominant familial form) They exhibit striking 4 hour advance of sleep-wake rhythm They typically fall asleep at 7.30 pm and spontaneously awaken at 4.30 am appr Affected individuals have SNP in PER2 gene

42. Delayed sleep phase syndrome: A circadian sleep disorder in which the individual’s internal body clock is delayed with respect to external day-night cycle A length polymorphism in a repeat region of PER3 gene is associated with morning chronotype while short allele associated with evening chronotype

43. Irregular sleep-wake Disorder: Characterized by at least 3 sleep episodes per 24 hour period ,irregularly from day to day Occurs in elderly people with dementia,ASD,traumatic brain injury Free running/Non-24 hour Sleep-Wake Disorder: Circadian sleep disorder in which an individual falls sleep later each day Generally the delay is about 1-2 hrs corresponding to a circadian cycle of 25-26 hrs but some individuals with Non-24 hour exhibit a longer delay Chronotherapeutics are often first line of treatment in Circadian rhythm sleep wake disorders

44. CIRCADIAN DESYNCHRONY One’s circadian clock is being desynchronized from local time Occurs in jet lag and shift work SHIFT WORK SCHEDULE : When a person works against the natural day-night cycle ,they would suffer from disruption of circadian rhythm

45. JET LAG: There would be a phase difference when a person travels through different time zones In jet lag,the clock is slow to reset so that after time zones have been crossed the endogenous signals for sleep and wakefulness do not match the local light-dark cycle Symptoms include reduced alertness,day time fatigue,loss of appetite, reduced cognitive skills and disruption of sleep/ wakefullness

46. SOCIAL JET LAG : desynchronization of one’s circadian clock with social environment. people who naturally exhibit delayed sleep wake patterns ,able to sleep on their normal delayed pattern on weekends but are forced to wakeup earlier during work days

47. MEMORY,AGING AND NEUROCOGNITIVE DISORDERS The importance of circadian alignment in normative memory performance is established by animal studies As humans age and normative age related memory problems begin , individuals experience shortening of circadian period as well as phase advances resulting in earlier wake up time and bedtime and decrease in the amplitude of most circadian rhythms

48. Age related circadian changes are exacerbated in age related neurocognitive disorders like alzheimers The amount of disruption in activity rhythms has also been associated with severity of neuropathology Dysregulated Circadian rhythms have been found to predate the occurrence of dementia or clinical diagnosis of AD

49. OTHER CIRCADIAN CLOCK ASSOCIATED PATHOLOGIES Cancer :Epidemiological studies have shown women working night shifts have shown elevated risk of breast cancer Metabolic syndrome Cardiovascular diseases

50. CIRCADIAN RHYTHMS AND PHARMACOTHERAPY TCA’s and SSRI’s reduce the elevated nocturnal body temperature in depression while enhancing the circadian amplitude Lithium causes lengthening of circadian period Short acting BZD’s( triazolam and brotizolam )have been shown to reduce light induced expression of clock genes per1 & per2 in SCN. Recreational drugs of abuse (MDMA )-serotonin neurotoxin, also affect circadian system.

51. A Nobel prize in the field of physiology/medicine was awarded to Dr.Jeffrey Hall,Dr.Michael Young and Dr.Michael Rosbash in 2017 for their discovery of molecular mechanisms controlling circadian rhythms RECENT STUDIES: Blue –blocking glasses as additive treatment for mania for improving sleep It is an evolvement from dark therapy and builds on the discovery of blue light sensitive retinal ganglion cells that signals daytime to brain

52. REFERENCES Kaplan and sadock’s comprehensive textbook of psychiatry-Tenth edition Kaplan and sadock’s synopsis of psychiatry-Eleventh edition Shakya P, Roy SN, Deep R. Chronobiology: Discovery of the molecular mechanisms of circadian rhythm. J Mental Health Hum Behav 2018;23:69-71 Henriksen TEG, Grønli J, Assmus J, Fasmer OB, Schoeyen H, Leskauskaite I, Bjorke- Bertheussen J, Ytrehus K, Lund A. Blue-blocking glasses as additive treatment for mania: Effects on actigraphy-derived sleep parameters. J Sleep Res. 2020 Oct;29(5):e12984. doi : 10.1111/jsr.12984. Epub 2020 Jan 21. PMID: 31967375 .

53. THANK YOU