Principal circadian oscillator in mammals

Subhadeep Dutta Gupta M.Phil Scholar

Department of Neurophysiology, NIMHANS

tg

Introduction:

• Physiological processes exhibit cyclic variation over time, ranging from

hours to years.

• This feature is ancient and ubiquitous.

• Types of biological rhythms:

-- Ultradian rhythm : shorter than a day

-- Circadian rhythm : occurs once a day

-- Infradian rhythm : occurs monthly

-- Circannual rhythm : occurs yearly

Circadian Rhythm:

• Physical, mental & behavioral changes that follow a roughly 24 hr

cycle responding to light & darkness of the organism.

• Latin word: ‘Circa’ means around and ‘diem’ means day.

• Very essential for survival of organisms under natural conditions.

Historical background:

• Greek poet Archilochus (675–635 BC) : author of the oldest written record

of observations in circadian physiology.

• Androsthenes of Thasus (4th century BC): recorded his observations of daily

movements in plant leaves.

• Jean-Jacques de Mairan (1678-1771) : daily rhythms may be endogenously

generated ………. Mimosa pudica

• Augustin Pyramus de Candolle (1778–1841) : period of the rhythm slightly

shorter than 24 hours ………. existence of endogenous circadian rhythm.

h• John Davy (1844) : recorded his own body temperature in the morning

and evening every day for 9 consecutive months.

• Rogers & Greenbank (1930) : reported the existence of a daily rhythm

of growth in colonies of bacteria (Escherichia coli).

g• Nathaniel Kleitman, (1938) : physiology of sleep and circadian rhythm

Kleitman at work in Mammoth Cave, Kentucky (150 feet underground).

Properties of Circadian rhythm:• A rhythm with a periodicity ~ 24 hours, even in the absence of external time

cues (Zeitgebers) [called a free-running rhythm].

• Reset by changes in environmental conditions, most notably the daily light-dark

and temperature cycles.

• Have an invariant period length over a wide range of physiologically relevant

temperatures.

-- Nat Rev Genet. 2005 Jul; 6(7): 544–556

Entrainment:

Concept of circadian oscillator:

• Biological processes occurring within many cells and tissues that have

the capacity to oscillate with a wide variety of periodicities.

• They show peak-to-peak intervals, or periods of activity.

• Circadian oscillators, express periods of ~ 24 hours and form the

circadian biological clock.

Basic parts of circadian clock:

• An input pathway -- receives environmental cues and transmits

them to the circadian oscillator.

• A circadian oscillator -- keeps circadian time and activates output

pathways, &

• Output pathways -- control various metabolic, physiological and

behavioural processes.

-- Fed. Proc.1979 (38), 2570-2572

Hierarchy of circadian system:

-- Nature Reviews Neuroscience (13) 2012, 325

Suprachiasmatic Nucleus:

• The central oscillator, or master clock, is located in the

Suprachiasmatic Nucleus (SCN).

• Small bilateral nuclei located in the rostral hypothalamic region,

superior to the optic chiasma.

-- Paxinos & Watson,The Rat Brain; 5th Ed

Location:

Location:

Time course of circadian development:

Evidences for SCN as principal circadian pacemaker:

• Site of termination of a critical entrainment pathway.

• Ablation of SCN abolishes circadian rhythm in many functions

viz.. Sleep-wake cycle.

• Isolated SCN neurons maintain circadian control of firing rate.

• Transplantation of fetal SCN into the 3rd ventricle of an

arrhythmic host with SCN lesion re-establishes rhythmicity.

-- Brain Res Rev; 2005; 49(3):429-54.

Anatomy of SCN:• Two major subdivisions in mammals:

A) Dorsomedial (Shell)

B) Ventrolateral (Core)

• Each SCN has a volume of less than 0.3 mm3.

• Each SCN houses approx 10,000 (in rats)-50,000 (in human) neurons.

DM (Shell)

VL (Core)

3V

OC

k

Gap junction between SCN neurons.

-- Neuroscience, 2004; 123: 87–99.

Connections of SCN :

Afferent pathways:

-- Textbook of Circadian Physiology 2nd Edn

f• Other inputs from:

Limbic system

Pretectum

Paraventricular thalamic nucleus

u Efferent pathways:

-- TRENDS in Neuroscience 2005 (28) 3.

Hamster

Mouse

Rat

Firin

g ra

te (H

z)

Circadian time (hour)

8

0 12 24

Circadian variation in firing rate of SCN neurons:

8

012 24

8

0 24

Circadian rhythmicity in the SCN cells has been documented by electrophysiological recording.

Functional properties of SCN neurons:

-- Journal of Comparative Physiology ,2004; 190: 167–171

h• Greater proportion of rhythmic cells in the shell region than in

the core region (Nakamura et al., 2001).

• The RMP of SCN neurons is approximately –50 mV.

• Firing rate:

-- Subjective day : 8 Hz

-- Subjective night : 2 Hz (Saeb-Parsy & Dyball, 2003)

Firing pattern of SCN neurons:

• Most cells fire regularly, but some fire

irregularly.

• Contradictory role of GABA - both

excitatory and inhibitory (Wagner et al.,

1997).

Single cell activity in brain slices of Rattus norvegicus exemplify the regular and irregular firing patterns of SCN neurons.

-- Journal of Neurophysiology, 2004; 91: 267–273.

Activity of isolated SCN neurons:

• Circadian variation in firing rate of four

individual neurons in a dissociated culture system

of SCN cells from the laboratory rat.

• The overall period of the circadian oscillation

generated by the SCN is the average of the

period of the various cells.

-- Neuron, 1995; 14: 697–706.

Neurochemistry of SCN: Major Neurotransmitters:

GABA

Arginine Vasopressin

Vasoactive Intestinal Polypeptide

Other neurotransmitters:

Gastrin-releasing peptide

Somatostatin

Thyrotropin-releasing hormone

Angiotensin

Nitric oxide

Neuromedin U

Neurochemical subdivision

-- Physiol Rev, 2010 (90): 1063-1102

Interaction with the Pineal Gland:

-- Neurology 2008 (71), 594-598

What makes the clock tick?

A simple molecular loop

Molecular circadian clock in mammals:

--- TRENDS in Pharmacological Sciences 2013 (34), 11;605-619.

hh Clinical Implications

Circadian clock: Ageing and Cognitive functions.

-- Nature Reviews Neuroscience (13) 2012, 325

Circadian clock-dependent regulation of neurodegeneration:

-- Nature Reviews Neuroscience 2012 (13), 325

Circadian clocks as tumor suppressors:

-- Nature, 2003 (3) 350- 361

Circadian disorders:

• Common in elderly, blinds, and individuals with hypothalamic,

pituitary, or optic tumours.

Circadian sleep disorders

-- delayed or advanced sleep phase syndrome

Shift Work disorder

-- insomnia during their off hours and hypersomnolence during

their work hours.

-- gastrointestinal discomfort

j Seasonal Affective Disorder/ Winter Depression

• Depression

• Lethargy

• Hypersomnia

• Weight gain

• Carbohydrate cravings

• Anxiety

• Inability to concentrate and focus.

So……let there be ‘LIGHT’:

• Bright light exposure (10,000 lux ; 30-120 minutes/ day)

• Effective for patients suffering from:

-- Sleep disorder

-- Seasonal Affective disorder

-- Bipolar disorder

-- Neuropsychobiology 2011;64:152–162

Chronotherapy:

• Use of circadian cycle in therapeutic application.

• Medications prescribed a/c to the patient’s rhythm to maximize

effectiveness.

• Reduces side effects.

• Effective in hypertension, asthma & depression.

f 17th January, 1995 ----- Kobe earthquake, Japan

In mice & catfish, drastic increase in locomotive activities during

sleep and active periods before the earthquake began.

Role of SCN in those animals’ perception??

-- Bioelectromagnetics 2003; 4(24):289-91

Bibliography:

• Eskin, A. (1979). Identification and physiology of circadian pacemakers. Fed.

Proc. 38, 2570-2572.

• Circadian rhythms from multiple oscillators: lessons from diverse organisms.

Nat Rev Genet. 2005 Jul; 6(7): 544–556.

• Jobst, E. E., Robinson, D. W. & Allen, C. N. Potential pathways for intercellular

communication within the calbindin subnucleus of the hamster

suprachiasmatic nucleus. Neuroscience, 2004; 123: 87–99.

• Burgoon, P. W., Lindberg, P. T. & Gillette, M. U. (2004). Different patterns of

circadian oscillation in the suprachiasmatic nucleus of hamster, mouse, and rat.

Journal of Comparative Physiology 190: 167–171.

g• Saeb-Parsy, K. & Dyball, R. E. J. (2003). Defined cell groups in the rat suprachiasmatic

nucleus have different day/night rhythms of single-unit activity in vivo. Journal of

Biological Rhythms 18: 26–42.

• Kononenko, N. I. & Dudek, F. E. (2004). Mechanism of irregular firing of suprachiasmatic

nucleus neurons in rat hypothalamic slices. Journal of Neurophysiology 91: 267–273.

• Welsh, D. K., Logothetis, D. E., Meister, M. & Reppert, S. M. (1995). Individual neurons

dissociated from rat suprachiasmatic nucleus express independently phased circadian

firing rhythms. Neuron 14: 697–706.

• Bell-Pedersen, D., Cassone, V.M., Earnest, D.J., Golden, S.S., Hardin, P.E.,Thomas, T.L. and

Zoran, M.J. (2005) Circadian rhythms from multiple oscillators: lessons from diverse

organisms. Nat Rev Genet, 6, 544-556.

• Young, M.W. and Kay, S.A. (2001) Time zones: a comparative genetics of circadian clocks.

Nat Rev Genet, 2, 702-715.

• Saper, Scammell & Lu. Hypothalamic regulation of sleep and circadian rhythms. (2005)

Nature (437) 1257-1263.

h• Saper, Lu Chou and Gooley. TRENDS in Neurosciences Vol.28 No.3 March 2005.

• Golombek DA, Bussi IL, Agostino PV. 2014 Minutes, days and years: molecular

interactions among different scales of biological timing. Phil. Trans. R. Soc. B 369:

20120465.

• Nakamura, W., Honma, S., Shirakawa, T. & Honma, K. (2001). Regional pacemakers

composed of multiple oscillator neurons in the rat suprachiasmatic nucleus.

European Journal of Neuroscience 14: 666–674.

• Reciprocal interactions between the suprachiasmatic nucleus (SCN) and melatonin.

Neurology 2008 (71), 594-598.

• Mouse circadian rhythm before the Kobe earthquake in 1995. Yokoi S, Ikeya M, Yagi

T, Nagai K. Bioelectromagnetics 2003 May; 4(24):289-91.

• Gerald Pail Wolfgang Huf.Bright-Light Therapy in the Treatment of Mood Disorders

Neuropsychobiology 2011;64:152–162.

• Textbook of Circadian Physiology,2nd Edition, Roberto Refinetti.

d Feynman’s Conjecture:

“The brain should have a master oscillator, like that found in a computer, that is responsible for coordinating the timing of all bodily activities”.

-- Richard

Feynman

h

THANK YOU