4 3 Circadian Rhythms Many rhythmic behaviors are regulated by pacemaker cells which have an endogenous rhythm that cause them to fire action potentials at regular intervals without any sensory or otherwise neural input There are many ion channels that can contribute to this spontaneous activity Pacemaker cells can control physiological processes and behaviors imparting rhythmicity to these complex outputs All animal genomes contain the components of a molecular clock This is a set of genes that regulate their own expression via negative feedback as the genes are expressed and translated into proteins they inhibit further transcription Over time the proteins will be degraded which will relieve inhibition and allow transcription to resume Thus protein levels will automatically oscillate rising and falling at regular intervals due to negative feedback Not all cells in the body express the genes for the molecular clock However in all human tissues investigated so far we have found some cells that do These peripheral clocks have protein levels that rise and fall with an endogenous rhythm of about 25 hours this pattern underlies circadian rhythms The downstream targets of the molecular clock proteins vary with cell type In the case of neurons the molecular clock may make the neuron fire differently during the day and during the night Other cells may release hormones on a day night cycle The list of molecules that fluctuate with circadian rhythmicity is growing rapidly and they are associated with as many processes and behaviors including the sleep wake cycle diabetes depression cardiovascular disease and cancer If left to operate autonomously these peripheral clocks throughout the body will become unsynchronized as will the processes that they control How can we coordinate all of these peripheral clocks which are distributed throughout the body in all of the tissues and organs In the brain there are neurons that express the molecular clock genes and function as a central clock In these neurons the molecular clock proteins affect the excitability of the membrane leading to neurons that spontaneously fire action potentials during the day and are silent at night The neurons of the central clock have connections to many tissues in the body synchronizing their rhythmic activity In most vertebrates the central clock is located in neurons of the pineal gland a small region located on the dorsal back as opposed to front side of the brain close to the surface These neurons have axons that project to many tissues throughout the body so as they rhythmically fire action potentials these tissues will be rhythmically stimulated The pineal gland also coordinates peripheral clocks by releasing the hormone melatonin into the bloodstream which binds receptors on target tissues to synchronize their activity In mammals the central clock is located in the suprachiasmatic nucleus SCN a cluster of neurons in the hypothalamus Like the pineal gland which is buried deep in the mammalian brain the SCN neurons project to many tissues including the pineal gland which then connects to other tissues and coordinates the system wide release of melatonin into the circulation As you can see in the figure below there is a huge list of hormones and target tissues that are under circadian control and this list is surely incomplete How does the molecular clock work There are many genes involved in the molecular clock see Figure 1 from a review by Zhang and Kay 2010 https utexas instructure com courses 1099761 files 34731924 download verifier DW4t3tvFZblBXgBNnvQI3gOalrUJXiV7DXaiEYqM wrap 1 https utexas instructure com courses 1099761 files 34731924 download verifier DW4t3tvFZblBXgBNnvQI3gOalrUJXiV7DXaiEYqM wrap 1 https utexas instructure com courses 1099761 files 34731924 download verifier DW4t3tvFZblBXgBNnvQI3gOalrUJXiV7DXaiEYqM wrap 1 but the theme is that clock genes encode proteins that act as transcription factors These transcription factors regulate expression of a variety of genes including their own The primary roles of five of these genes is illustrated below Note that genes are written in lower case and italicized proteins are written in all upper case We can describe rhythmic behaviors in terms of how often they cycle period and how much they change amplitude The graph below illustrates these concepts Recall that the endogenous rhythm of the molecular clock in humans is approximately 25 hours this period varies between taxa But our circadian rhythms have a period of roughly 24 hours This discrepancy is due to sensory input that modifies our endogenous rhythm which you were introduced to in the last lesson In invertebrates some of the clock proteins are sensitive to light This causes them to degrade so the clock protein levels build up during the night then steadily decay during the day In this way the endogenous rhythm of their cells is entrained to light the period will match that of the light dark cycle the animal lives in Most vertebrates have a light sensitive protein called melanopsin in the neurons of their pineal gland When light hits the melanopsin it changes conformation and initiates a G protein coupled cascade that depolarizes the membrane By entraining the neurons of the pineal gland to the environmental light dark cycle all of the peripheral clocks are synchronized to this new period Recall that the pineal gland in mammalian vertebrates is buried deep in the brain where it cannot receive light Instead of the pineal gland mammals express melanopsin in some cells of their retina When light enters the eye it activates these retinal cells which synapse onto neurons of the SCN adjusting its endogenous rhythm to the light dark cycle thus entraining the mammal to light Although light is the most common entrainment cue animals can be entrained by a variety of sensory input especially in the absence of light The mechanisms underlying these entrainment processes are not well understood For example research labs that study endogenous rhythms by keeping animals in complete darkness must be careful not to feed the animals at the same time every day or open the lab door at the same time every day as the animals can learn to entrain to these sensory cues Another word for an entrainment cue is the German word zeitgeber literally translated to time giver A common way to illustrate a rhythmic process or behavior is an actogram Each horizontal line corresponds to two 24 hour periods and each line represents the
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