Lect 11-15-23 (circad).pdf

Circadian Timing System Lecture 14; 11/15/23 Fernando Gomez-Pinilla, Ph.D. C144/244 F. Gomez-Pinilla, C144/244; UCLA Circadian Timing System (CTS) • • • • • Cycle of rest-activity Variation of psychomotor performance Sensory perception Secretion of hormones Regulation of temperature Circadian...

Circadian Timing System Lecture 14; 11/15/23 Fernando Gomez-Pinilla, Ph.D. C144/244 F. Gomez-Pinilla, C144/244; UCLA Circadian Timing System (CTS) • • • • • Cycle of rest-activity Variation of psychomotor performance Sensory perception Secretion of hormones Regulation of temperature Circadian timing: environmental adaptation • Adapted to cycles of rest and activity • Diurnal animals vision is the primary sense • Nocturnal animals audition and olfaction dominate perception of environment Every organ or function works on a circadian pattern of activity Circadian timing system (CTS) has three main components • Photoreceptors and pathways transducing entraining information • Pacemakers generating circadian signals • Output pathways coupling the pacemaker to effectors systems. SCN master regulator of CTS • Ablation of visual pathways causes blindness but rhythms are retained. • Output from SCN serves to synchronize slave oscillators • More than 10% of genome in brain, kidney, liver, heart is rhythmically controlled and synchronized by SCN SCN ablation results in loss of circadian function: SCN is the circadian pacemaker Lesion to SCN abolishes rhythms. Animal can still move as the loss is limited to temporal pattern of activity • Some rhythms recover within 4 days after transplantation. No much time for neuronal outgrowth • Transplantation of SCN dissociated cells can restore rhythmicity and period of restore rhythm is determined by donor tissue • Cells do not make connections with surrounding tissue after transplant suggesting that some diffusible signal can drive rhythms. SCN structure and function • Located at the base of the hypothalamus (just on top of optic chiasma) • SCN has 2 parts: dorsomedial (shell) and ventrolateral (core). • Ventrolateral SCN (core) contains the main pacemaker neurons, and receives primary entrainment afferents. • Dorsomedial SCN (shell) is the main source of outputs to the rest of the hypothalamus. • It develops in late gestation in rats Main inputs/outputs to SCN • Retrograde tracers injected into the eye are detected in retinal ganglion cells, SCN, and intergeniculate leaflet (IGL). • Retinohypothalamic tract (RHT) connects the retina with the SCN • Intergeniculate leaflet (IGL, part of lateral geniculate complex) delivers information about some nonphotic events such as motor activity to the SCN. • Raphe nucleus in midbrain densely innervates the core of the SCN via serotonin, and modulates photic entrainment. • Serotonin inhibits the response of SCN to light. Raphe serotonin RHT SCN core receives inputs from outside hypothalamus and projects within SCN (core and shell), and outside SCN to the subparaventricular zone (SPZ) of the hypothalamus Intergeniculate leaflet (IGL) integrates photic and nonphotic information and relies it to SCN (activity promotes phase changes) The SCN affects a wide variety of functions Summary: evidence for pacemaker role of SCN • SCN ablation abolishes circadian rhythms • SCN ablation alters the temporal organization of the function, but the amount of activity remains the same, e.g., the sleep-wake rhythm but not the amount of REM. • SCN maintains its rhythm after being isolated from the rest of the brain. • SCN transplantation restores rhythm of arrhythmic host, imposing rhythm of donor. • Output from SCN serves to synchronize autonomous oscillators (slaves) in cells throughout the body. Light Entrainment of the SCN • • • Specialized retinal ganglion cells containing melanopsin mediate the majority of circadian photoreception in the retina Cones and rods also contribute to circadian photoreception via synapses onto melanopsin containing RGC s Melanopsin containing RGC s integrate light input over a longer time period of around 2 mins vs 1/60th of a second or less for rods and cones. Light is the dominant stimulus for entrainment • System is maximally responsive to 500 nm with a wide range of sensitivity. • System responds only to changes in light intensity and duration. • The pacemaker responds differently to light at different times of the day Projections from melanopsin containing retinal ganglion cells SPZ: subparaventricular zone OPN: olivary pretectal nucleus LG: Lateral geniculate LH: lateral habenula IGL: intergeniculate leaflet Circadian pacemakers are clocks that rely on daily resetting to maintain a rhythm with a 24 hour period. What happens without light input? • Nocturnal animals have an intrinsic period, called tau, of about 23.5 hours and diurnal animals have a tau of about 24.5 hours. • There is adaptive significance for these particular period lengths. They are not a mistake . • Consider what would happen for each of these circadian phenotypes as day length increases in the summer or decreases in the winter. Pineal gland • Relative large gland in lower mammals, reptiles, and birds. • Secretes melatonin • Receives a large sympathetic input from the superior cervical ganglion, which regulates melatonin production. • SNS activity increases at night (darkness) stimulating melatonin through beta 1 adrenergic receptors -- light inhibits melatonin. Do you think beta-blockers prescribed for hypertension might alter melatonin release? Pineal gland interacts with SCN to regulate rest-activity Melatonin • Hormone secreted by the pineal gland in a circadian mode • Affects pacemaker function, e.g., lessen effects of jet lag. • Melatonin receptors have a limited distribution in the mammalian brain (SCN, midline thalamic nuclei, pituitary pars tuberalis). Circadian control of reproduction • Season is main factor in controlling reproduction in most mammal • Day length determines melatonin production • Melatonin production controls seasonal reproduction • ablation of SCN disrupts estrus cycle by affecting release of GnRH from hypoth/pituitary • Melatonin affects the function and size of gonads Photoperiodicity can affect reproduction using melatonin Photoperiodicity regulates melatonin synthesis Circadian rhythms and human health • Relationship between the cellular clocks of different tissues is very important for health. • Short term misalignment of rhythms in tissues is called jet lag which features fatigue, increased accidents, poor memory and concentration. • Long term misalignment of the clocks within a tissue or between different organs of the body is thought to promote/accelerate onset of diseases like diabetes, cancer and heart disease. • Maintaining a constant schedule for sleeping and eating helps the brain and body function their best. Sickening Schedules Good medicine requires good timing More than double the survival rate when treatments administered at optimum time of day. Mood Lighting Phototherapy