C22 – Circadian Rythm PDF

C22 – Circadian rythm Oscillations in the set point of certain values correspond to adaptation to the changing environment.. It is an effort to make the internal environment of the organism independent from the external environment. There are not only circadian rhythms (which last one day), there a...

C22 – Circadian rythm Oscillations in the set point of certain values correspond to adaptation to the changing environment.. It is an effort to make the internal environment of the organism independent from the external environment. There are not only circadian rhythms (which last one day), there are also: -​ ultradian (shorter than one day): The sleep cycle is ultraradian, with each cycle lasting 90mins. Circa means about/approximately, so it is not exactly 24 hours. -​ infraradian (longer than one day) the ovarian cycle lasts 28 days. ​ Hypothalamic Control of Circadian Rhythms—The Suprachiasmatic Nucleus. The suprachiasmatic nucleus (SCN) of the hypothalamus contains about 20,000 neurons and is located above the optic chiasm where the optic nerves cross underneath the hypothalamus. The neurons of the SCN serve as a “master clock,” with a pacemaker firing frequency that follows a circadian rhythm. This pacemaker function is critical for organizing sleep into a recurring 24-hour circadian pattern of sleeping and waking. Lesions of the SCN cause many physiological and behavioral disturbances, including loss of the circadian sleep-wake rhythms. Thus, the SCN directs daily cycles of our physi- ology and behavior that set the tempo of our lives. The SCN adapts and predicts the changed of the day (wake up slightly before sunrise). Cortisol is released in the morning and is at its peak at 8am before decreasing. Light is nit necessary in dictating the rhythm endogenous generation of rythms in the dark. 1.​ Rat experiment An experiment has been done with a rat in a cage with a running wheel and sensors to detect activity. When the rat’s environment has a normal dark-light cycle they have a predictable pattern of activity and sleep which is always broadly the same. During darkness the rat is active, during light it is resting. The lines in the below image represent the activity of the rat. When the rat is entrained in a dark-light cycle, the pattern is reproducible. But when the environment is changed to continuous light there is still a rhythm of approximately 24 hours, but there is a drift and more of a disconnection. Sometimes the activity is longer, sometimes it is shorter, but the rat still maintains period of activity and a period of sleep, but this progressively loses its relationship with the original dark-light cycle. In countries in the north of globe where there have 24 hours of light, circadian rhythms are challenged. But they still stay in the same pattern of activity then sleep over 24 hours, not 1 hour activity then 1 hour sleep for example. The conclusion is that, under constant environmental conditions, circadian rhythms freerun with periods (durations) slightly different from 24 hours. Therefore, light is not irrelevant, the experiment shows that there is an internal generator of rhythms but this rhymicity is linked to environment. There would be no point in having a rhythm that was disconnected from environment as it would defeat its purpose. Light doesn’t generate the rhythm; it is important in entraining the rhythm with the environment. The visual inputs that come to the hypothalamus, are what allow light to be the entrainer.  2.​ Pacemaker system Because the rhythm is endogenously generated, there must be a pacemaker. The pacemaker is modulated correspondinig to information arriving from the environment, by entrainment pathways, such as light. The modulated pacemaker produces a rhythm, an oscillation, that is distributed to organismal functions ybder circadian control, slave oscillators. There must be a structure that generates a rhythm, which has sinusoidal oscillations. The pacemaker is controlled the genetic transcription from the clock gene. It produces specific p° that are more or less produced or degraded: protein is first produced and then degraded in a fixed amount of time. The reduction in amount restarts the process of transcription. Although circadian periods are transiently affected by environment factors, the base value is genetically determined. It based on an autoregulatory feedback loop based on: -​ Clock gene transcription -​ Protein formation -​ Translocatoin of the p° to the nucleus to regulate gene expression. Criteria for the genetic clock components: -​ Amount, or activity of the clock components cycles around 24 hours -​ Phase of the rhythm of the clock component must be reset by the light-dark cycle -​ Adding experimentally clock component mist reset overt rhythms -​ Loss in the rhythm causes a loss of overall rhythm of the body (overt rhythm) -​ Mutation affecting the clock gene causes a loos of rhythm 3.​ Genes and p° involved a.​ Example 1: 1)​ P° complex formed of a CLOCK and CYCLE (form a TF activator) connects w DNA causing the transcription of PER and TIM 2)​ Enough PER and TIM produced will allow a PER-TIM complex 3)​ PER-TIM complex turns the CLOCK-CYCLE off 4)​ After a certain time, PER-TIM are degraded, causing the CLOCK-CYCLE to form again The time decided to degrade PER-TIM decides the length of the cycle  b.​ Example 2 (fruitfly): The CLOCK-CYCLE and PER-TIM loop remains. The p° DBT and CRY regulate the stability of Per and Tim: -​ CRY stabilizes Tim, allowing its degradation -​ DBT stabilizes Per, allowing its phosphorylation for degradation Light acts on DBT and CRY, acting on their stability. DBT is specifically sensitive to light, via a retinal pathway to the suprachiasmatic nucleus. At least 2 interlocked feedback llops are involved in generating rhythms: -​ Negative autoregulatory loop of Per and Tim on their own genes, via inhibition of TF activators CLOCK-CYCLE -​ Positive effect on the p° on the expression of CRY and DBT proteins regulate the stability of TIM and PER 4.​ Circadian Timing The time course of all body functions follows a sinusoid with a period of 24h. This period is organized, in terms of functions, according to the hearth that is rotating with a period of 24h to be part of the environment. The rhythm is endogenously generated, it doesn’t depend on environmental factors. Even if light follows the rhythm of rotation of the hearth, the rhythm is endogenously generated by means of a mechanism based on the synthesis of proteins with a feedback loop controlling the same proteins, it’s the same mechanism with all the possible variables in different cells. Based on studies on drosophila this mechanism was found to be present in all cells, not only in suprachiasmatic clock that is the nucleus of the hypothalamus able to generate endogenously these proteins, it’s entrained by light that has a relevant action on circadian rhythms that, however, are generated by orchestra director, is the clock that controls the period of all other cells. ​ Each cell is supposed to have an internally generated rhythm, to have an organized period within the 24h there can be different phases of the overall period. The phases of the period with respect to a fixed period of it are decided by the internal clock, it gives the others the rhythm by means of modulation of neuronal discharge, it’s generating the rhythm based on clock cycle proteins production and degradation. ​ Light has not a relevant action in determining the cycle of the protein, rather is relevant in determining the duration of the per-Tim complex that defines the feedback onto the cycle genes by acting on other two stabilizing proteins, cry and DBT, to stabilize the complex. So, light can change the duration of the cycle acting on proteins that act on the complex which in turns acts on the synthesis of the proteins. The suprachiasmatic clock in the hypothalamus was studied a lot in the last century and was referred to as the devoted internal clock. ​ In the 1950 was found that rhythms are endogenously generated and there are pacemakers that internally generate rhythms, so they are not externally triggered. ​ the circadian timing system is composed of central neural elements, scientists provided evidence that there was a neural structure acting as orchestra director, central neural elements that function to provide a temporal organization of physiological and endocrine processes and behaviors. This means that the observation was in favor not only of the organization of a hardware of the physiological functions, but also of behavior that is something more complex. Then, other evidences were provided stating that, inside the CNS, in animals and humans this structure was located in the anterior hypothalamus ​ Parallel to this study, there was the discovery of melatonin that is a hormone released following a circadian pathway, it’s overtly involved in the suprachiasmatic clock entrainment. It was the first to be discovered, it’s released following a circadian rhythm. following that, there was the discovery that visual pathways were controlling melatonin synthesis: therefore light has something to do with the release of melatonin because, lacking this information, the circadian synthesis is retained, which means that light is an entrainer but is not the pacemaker, there is not an external factor or variable that induces the circadian rhythm. ​ There was a demonstration that light has a relevant role, even if is not essential, in the circadian rhythm because scientists demonstrate the existence of a private pathway from the retina to the hypothalamus: the retinohypothalamic tract, that goes strictly to the suprachiasmatic clock and entrains it with light. The suprachiasmatic nucleus, given its connections and given the evidence of changes in the discharge of the suprachiasmatic clock in daylight and in seasons, at the end was demonstrated as the master clock. All these discoveries together allow to assess that there is a rhythm endogenously generated by a structure in the brain, in the hypothalamus, defined as the suprachiasmatic clock. ​ It is located anteriorly in the intermediate zone of the hypothalamus and is connected with all the other nuclei of the vegetative system, endocrine system and other cortices. This nucleus is the one that most likely is the master clock which entrains all the others in the circadian rhythm of about 24h. ​ Light is directly traveled from the retina to the hypothalamus through a private pathway, thus light has a very important role in entraining the clock to the environment, and therefore linking it to the environment. The clock is able to generate the 24h rhythm, the problem is to be part of the environment, to link body phases to the environment, otherwise it is useless and even dysfunctional. In fact, it is useful to have an internal clock of 24h period but it must be coherent with the environment, the whole point is to go in harmony with the environment. The light is the strongest parameter regarding the rotation of the hearth on its axis, it’s the main entrainer. The melatonin is a hormone discovered aside, not only related to the light-dark cycle but it has also a connection with the sleep-awake cycle, this hormone more than others is the demonstration of ours oscillations but is not the only one following the circadian rhythm. 5.​ Suprachiasmatic nucleus (SNC) Post-mortem studies on the suprachiasmatic nucleus gave evidence of the fact that it is the master clock. ​ Post mortem studies on human brains have shown that the suprachiasmatic nucleus looks different during the night from the day and in autumn is different from spring, clearly the studies were performed after death. Post mortem study means looking at the suprachiasmatic nucleus at the time of death, when the condition of suprachiasmatic nucleus is frozen with death at different points.  Comparing them, when the person was died in the morning or at midnight or in the afternoon there were differences. Not only with respect to the hours, day or night, but also in seasons. Therefore, the clock must be coherent with the fact that is a structure somehow in communication with the environment. ​ The number of cells producing vasopressin (called vasopressin because it was it discovered in the systemic circulation acting at the level of kidney and vessels, but it is a neurotransmitter and so is related to the posterior hypophysis) is 50% higher during the day than during the night, and in autumn there are 2.5 times more than in spring. The vasopressin is one of the neurotransmitters in the suprachiasmatic clock. ​ These fluctuations coincide with fluctuations of lots of physiological functions, as the amount of sleeping hours per 24h, the testosterone which is low in the morning and high in the end of the afternoon. From all these evidences, scientists assessed that this nucleus changes its aspect from day to night, from autumn to winter and to summer, and when changing it’s not only the aspect but also the content which differs, there are relevant fluctuations in the amount of the production of neurotransmitters and in all the other parameters, they all are oscillating according to the oscillation of the clock. Then scientists had to provide evidences that is a pacemaker. ​ The cells of the the SCN have their own rhythm, when they are grown on a medium they continue to show that rhythm, there even exist cells from other tissues that still show their 24h rhythm after being grown outside the body during 30 years, it means that the internal rhythm is a property of all cells, then they use it differently. Even if a cell has its own rhythm, an internal clock is needed to orchestrate the activities of all the cells as they cannot know what happens outside. Hence, a coordinator is needed to coordinate all the cells of the body, and this is the suprachiasmatic clock. a.​ Master clock activity Looking at the suprachiasmatic nucleus from the outside, there are two sub-sectors: An internal and external part: -​ the ventrolateral core region: o​ Neurons in the core are generally not pacemaker, the whole core structure is not a pacemaker. o​ The neurotransmitter is GABA with the aid of the vasoactive intestinal peptide VIP, these are respectively the main neurotransmitter and neuromodulator. -​ dorsomedial shell region: o​ The shell is the one that generates the rhythm, is composed by intrinsically rhythmic cells.  o​ The neurotransmitter is GABA and the arginine vasopressin AVP is the neuromodulator. The two portions use the same neurotransmitter GABA, what differs in the core and the shell is the neuromodulator: in the core is the VIP and in the shell is the AVP arginine vasopressin. One projects to the other. The core projects to the shell and the shell is the one that generates the rhythm. The conclusion, following this hypothesis, is that all the organs exhibiting intrinsic circadian rhythmicity (at least in some vertebrate species) are multiple pacemakers, the slavers, under the control of the master clock, the suprachiasmatic clock. The rhythm doesn’t need to be induced in the cell, the cell has its own rhythm, it’s only a matter of deciding which will be the phase with respect to one reference frame that is light. In the images is shown the suprachiasmatic nucleus, the shell and the core are marked with a labelled color. b.​ Input and output The two parts of the suprachiasmatic nucleus are the shell and the core. The core projects to the shell and also outside. ​ The first input is the retina, it communicates with the core that communicates with the shell. The retina communicates with direct and indirect pathways: o​ Directly by means of the retinohypothalamic tract, and then from o​ Indirectly by means of the raphe nucleus of the brainstem o​ Indirectly by means of the connection with the lateral geniculate body. ​ Inputs from the neighborhood parts of the hypothalamus. ​ Inputs from the thalamus. ​ Inputs from the limbic cortex ​ Inputs from the brainstem. Therefore, the suprachiasmatic nucleus is receiving every relevant source of information, mainly vegetative but not only.  c.​ SCN neurons The suprachiasmatic neurons are organized as a pacemaker. ​ Individual neurons are born as circadian oscillators coupled by neural connections to form a pacemaker. ​ Each neuron in the shell has its own rhythm, indeed they have to be coordinated via connections between the oscillators. The interaction of these neurons produces a frequency of spikes that has a period less than 24h, about 24h. Studies demonstrated that: ​ Cell culture outside the nervous system displays oscillating properties. ​ GABA is needed in synchronization, this means that a neurotransmitter is needed. ​ Gap junctions and neural cell adhesion molecules participate in coupling neurons giving rise to uniform output. All the elements must be synchronized, the best way is to communicate via GAP junctions to be synchronous. In the fetal life, fetus is showing the circadian rhythm entrained by the mum. This entrainment is not needed to develop the pacemaker properties in the suprachiasmatic clock of the fetus, the fetus is coherent with the rhythm of the mom and the mom entrains it, but in order to develop the suprachiasmatic nucleus of the fetus this entrainment is not needed, it is a primary function genetically determined that doesn’t need an external factor. The entrainment is through melatonin, the mom entrains the fetus through melatonin. 6.​ Circadian oscillations The central clock generates the rhythm that is then transmitted to the slavers at the peripheral clocks. The phases of the different slavers are different. The central clock entrains everyone based on light and other informations, but mainly on light. The entrainment is possible via direct neural connections and also via hormonal signals. The suprachiasmatic clock is in a strategic position and has connections not only with: -​ all the areas of the brain -​ the vegetative system -​ the hypophysis: it can communicate via hormones because the periventricular zone is the one controlling the hypothalamus-hypophyseal axis. 7.​ Light – the zeitgeber Light establishes both the phase and the period if the pacemaker and is the dominant entraining stimulus. The pacemaker is an inaccurate clock which needs to be reset repeatedly. The light-dark cycle sets the exact timing of the pacemaker resetting every morning and evening at the passage between light and dark. Light is the interface between the suprachiasmatic clock, which has control on all the others, and the environment. The circadian rhythm becomes precise with the light, is the light that establishes the duration of the 24h period as the internal rhythm of the cells of the suprachiasmatic clock. The suprachiasmatic clock itself is stretched to 24h by means of the light because the latter is able to change the period via the two proteins stabilizing the per-Tim complex, so light is stretching the “about 24h period” generated by the suprachiasmatic nucleus to a “perfect 24h period”. This is the relevant role of light because in this way the whole body is perfectly adapted to the environment. Light tells us, as humans, in summer and winter, when it is time to change our activities because these phases are entrained by the clock that is internally entrained by the light, that’s why we are so entrained with nature. Animals are not programmed to live dysfunctionally or independently from the environment. This is the idea of functional entrainment, to obtain everything else different from that there is a price to be paid. Therefore, light is the dominant entrainer, it’s called zeitgeber for this reason. Light establishes both the phase and period of the pacemaker, thus it is the dominant entraining stimulus. The pacemaker is an accurate clock and must be reset every day. Light-dark cycle sets the exact timing of the pacemaker resetting it every morning and evening at the transition between light and dark. It means that the parameter of light relevant for the clock is the modulation of luminance, it’s not the tonic fixed amount of light that changes the properties of the clock, what matters is when the light changes in amount so luminance changes, sunrise and sunset are the two crucial moments when the clock is entrained with the environment. A.​ ≠ pacemaker responses to ≠ light conditions Performing an experiment with a rat with the usual time of rest and activity pattern, this rat is then kept in constant darkness. It is expected to have a shift of the pattern, and this indeed is what happens, but the pattern is preserved. Administrating pulses of light, so exposing the rat to light, the question is if the light is able to change the pattern and if the effect of light is the same in the 24h or is different depending on something. Different situations are analyzed in A,B,C,D,E. The amount of light is always the same, but the effect is different depending on when the light is given. -​ In the case A, at rest, it seems that the administration of light does not really have an effect, there is not shift with respect to the pattern of the rat activity and rest cycle. -​ In the case B, going nearer to the activity pattern, there is a shift. -​ In the case C, administrating light in the middle of activity there is a big shift. -​ In the case D, administrating light at the end of the activity period, there is a backward shift. -​ In the case E, administrating light at the very end of the activity period, there is only a slight backward. This means that the pacemaker responds different to light at different time of the day, which means that in the 24h the light effect is different depending on what was the ongoing activity according to the endogenously generated day. Light has a specific window of time when is very efficient as it resets a lot. This means that the sensitivity to light is not the same in different moments of the endogenously generated pattern.  b.​ Eye, photosensor The eye is the only photosensitive organ in mammals, visual pathways are the only way to entrain light. Mammals must rely on the retina. In the eye there are three types of photoreceptors providing redundant inputs to the circadian system. These three main neural pathways are: ​ the retinohypothalamic tract, it connects retinal ganglion cells to the SCN via a monosynaptic pathway, it is very straight as comes from the retina directly, uses glutamate as its main neurotransmitter. ​ The geniculo-hypothalamic tract, it connects the inter-geniculate islet of the thalamus to the SCN via a monosynaptic pathway and uses neuropeptide Y as its main neurotransmitter. ​ The raphe-hypothalamic pathway connects raphe nuclei to the SCN and uses serotonin as its neurotransmitter. The retinohypothalamic tract is the main one, it carries photic informations, the geniculo-hypothalamic also carries photic informations. The raphe-hypothalamic tract carries non photic informations as temperature: During the transition from day to night and also during the day there is an oscillation of environmental temperature, even if the retinohypothalamic tract is not working it’s possible to rely on other parameters as temperature. Normally we rely on every parameter, always the brain asks for confirmation so everything must be coherent. However, mostly we are entrained by the retinohypothalamic tract. In this image are represented ganglion cells, the relevant stimuli are changes in luminance rather than the total amount of light. Color, shape, movement do not matter, any other visual parameter is irrelevant. c.​ Non-photic environment stimuli Although light is the most important entrainer, there are other important informations classified as nonphotic informations: -​ photic information is only the light; -​ non photic are other environmental stimuli as temperature, food availability, physical activities and social contact. TEMPERATURE AND NUTRITIONAL STATE THAT IS NEEDED FOR NON-PHOTIC ENTRAINMENT. TEMPERATURE SIGNALS ARE AVAILABLE FROM COLD- AND WARM-SENSITIVE CELLS ON THE SKIN AND IN THE BODY CORE. HUNGER AND SATIETY SIGNALS ARE AVAILABLE FROM THE BLOOD CONCENTRATION OF NUTRIENTS, TASTE AND SMELL OF THE FOOD BEING INGESTED, GASTRIC DISTENSION, GASTRIC CONTENTS, AND BLOOD LEVELS OF VARIOUS HORMONES SECRETED BY THE STOMACH, BY THE INTESTINES, AND BY FAT CELLS. Physical activity seems counterintuitive as it could be seen as a consequence, actually it is a consequence but is unavoidable because the sleep-awake cycle is unavoidable. Sleep is needed, is something that can’t be chosen. The physical activity forces the system to change the pattern. d.​ Photic environmental stimuli The circadian retina and retinohypothalamic tract are critical to the entrainment, informations are sent to the suprachiasmatic nucleus directly. Indirect informations are sent to the suprachiasmatic nucleus by means of the inter-geniculate leaflet, represented with dashed lines in the picture because it’s not clear how it is connected, for sure it’s an important part of the whole information but the physical connection through which the informations are conveyed to the suprachiasmatic clock hasn’t been found yet. 8.​ Melatonin Seasonal inflences are probably caused by the actions of the pineal gland, producing melatonin. Also called the 3rd eye. When it gets dark, melatonin is produced. Melatonin infleunecs the biological clock, influencing the hypothalamus and therefore the pituitary (influencing metabolism and sexual organs). The pineal gland was referred to as the third eye in the past because it is a gland that releases a hormone, the melatonin, clearly correlated to light. Differently from reptiles and birds, a direct connection of the pineal gland to light is not present in humans, the light must arrive to the pineal gland through the visual pathway so it can’t be considered the third eye. In mammals, when it gets dark the gland starts the production of melatonin, melatonin increases during the dark and decreases during light. That’s why is thought to be the hormone most related to sleep and in some cases it’s thought that it induces sleep. Even if there are not evidences demonstrating this hypothesis, for sure melatonin is correlated to the sleep cycle. This hormone seems to be the interface of the precise pattern of awake and sleep activity according to light and dark in order for this cycle to be perfectly entrained with light during the activity period. Given that melatonin responds to light and the pineal gland releases melatonin more during the night that during the day, this seems to be the intermediate step in order to entrain at least the sleep activity with the dark-light cycle. Probably, melatonin influences the biological clock and this in turn influences the hypothalamus, and in the hypothalamus is hosted the sleep-awake nucleus in the intermediate zone. The hormones produced here, in turns, influence the metabolism of the sexual hormones. As a matter of fact, melatonin is seen as the hormone that influences sleep, it is considered the sleep hormone, but it’s also very interesting for its role in puberty as it’s entraining the activities that result into the development of the final ability to reproduce, so becoming adult. More melatonin means less activity in the suprachiasmatic nucleus and, consequently, weaker activity of sexual organs. Indeed, melatonin is related to sexual hormones. a.​ Production The pineal gland is a very tiny structure located in the center of the brain, it releases melatonin. It was discovered in 1959, not so much time ago. The suprachiasmatic nucleus receives informations regarding light by means of the retinohypothalamic tract and, in turns, releases messengers regarding light to the pineal gland. That’s the way through which the pineal gland is coordinated with the 24h period, the production of melatonin increases up to 10 folds during darkness and falls during the day. b.​ Functions ​ It’s the hormone that promotes sleep: when people have problems in sleeping, pills with melatonin can be administered as it induces natural sleep. Compared with benzodiazepine or other drugs that are sedatives and therefore do not induce a natural sleep, the melatonin is able to induce real natural sleep. Anesthesia during surgery is induced by drugs but is not a normal sleep, rather it’s a reversible loss of consciousness. Even if it’s referred to as sleep, looking at all the possible parameters recorded during sleep and anesthesia there is nothing in common apart from the loss of consciousness. When a patient has problems in sleep, the first thing to do is to try to find a way to re-entrain your own system to push towards sleep rather than forcing the system to lose consciousness without the gain of sleep. Indeed, sleep is something needed to restore the neurotransmitters, the substrates, and to do many other things like cognitive activities. Sleep is not absence of brain activities, for example dream is an important cognitive activity associated to a precise type of sleep, the rem sleep, then there are other activities like the consolidation of long-term memory process. All these essential processes occur during sleep because the brain cannot do it during the activity period as it’s too busy doing something else. Beside its role in the body biological clock, other roles can be related to melatonin: ​ Melatonin is believed to inhibit the hormones that stimulate the reproductive activity, puberty may be initiated by a reduction in melatonin secretion. Thus, the prime mover to induce the events of puberty is melatonin, these events represent the conclusion of growth and the maturation of the reproductive system. The adult is a human being able to reproduce him or herself with acquired reproductive maturity, a physiological process called puberty is needed to conclude growth and to acquire the maturation of the reproductive system. Melatonin seems to be very much involved in triggering the starting point of the system.  ​ In terms of metabolic activity (all the hormones have metabolic activity), melatonin may be effective as antioxidant and correlated to the anti-aging process. ​ It seems also related to immunity, enhancing it. 9.​ Interactions onto the SCN Since the suprachiasmatic nucleus is affected by light, here is possible to see that there’re receptors for neurotransmitters of the retino-hypotalamic (glutamate), for the raphe-hypothalamic (serotonin), for the geniculo-hypothalamic (neuropeptide Y) and then melatonin. In fact, if you postulate that the light via these pathways, the non-photic via other pathways, the melatonin has a role in entraining the suprachiasmatic you must provide evidence of intracellular pathways that can be modulated by these afferences. This is what they discovered. There’re these receptors and pathways that are triggered by them. There’re still some question marks but it can be seen that all the pathways end up in the regulation of the complex which is the complex regulating the pacemaker activity. 10.​Pacemaker output is limited So basically, the suprachiasmatic block communicates with: -​ Preoptic and anterior hypothalamic area which means all the median zone (temperature – autonomic control – sleep – reproduction) -​ Tuberal and posterior hypothalamus (periventricular zone, all the endocrine system) -​ Paraventricularhypothalamic nucleus (autonomic regulation – HPA axis – thyroid – pineal gland) -​ Thalamus and basal forebrain (psychomotor performance – memory –control of reward mechanism and so behaviours) 11.​Circadian rhythms everywhere Here are shown the different functions proving to be oscillating during the 24 hours. For example, urine volume means that also the function of the kidneys oscillates. PTH is not under the control of the axis, it’s a hormone produced by the parathyroid glands which are under the control of the hypophysis. Also, other functions: -​ short-term memory, -​ cognitive performance, -​ subjective alertness, -​ core body temperature. This slide shows that from the very first parameter to the very complex cognitive function there’re in some cases the oscillation of the amount, and in others of the performance which is in the end the result of the function. So, this means that there should be a time of the day where our brain is keener to do something with respect to something else. 12.​3 main parameters Other examples are given by blood pressure, heart rate and temperature. These parameters that are expected to be basically the same all the time, they’re not, in fact they oscillate. It was shown by studies that at certain times of the day are more likely for some pathologies to occur for example heart attack, peak of pressure, labor, … Human beings, sometimes go against these rhythms. For example, night shifts completely change the circadian rhythm. CONCLUSION Circadian rhythmicity is exhibited by many variables simultaneously, and ≠ variables reach their daily peaks at ≠ times of the day. Although circadian pacemaker does not generate each and rhythm individually. The causal connection between ≠ rhythms are not fully known: the body temperature is not caused by either the rhythm of activity if by the rhythm of feeding. Body temperature is under the control of homeostatic control and circadian control. The 2 mechanisms act indep on the effector organs responsible for the regulation of temperature. The circadian system generates the circadian rhythmicity of the body temperature. The thermo-regulatory system restricts this rhythmicity according to a set point and its range of errors. The SCN efference relies on neural connection (mainly other hypothalamic sites) as well on an unidentified diffusible substance. The hypothalamic paraventricular nucleus (PVN) is the main target of the SCN efference for the circadian rhythmicity of the ANS. The dorsomedial hypothalamic nucleus (DMH) is the major target for the efference associated w the behavioural and endocrine rhythms. In many organisms, circadian rhymicity is not present at birth and develops during the early years of the life. It degenerates during old age. Circadian rhythms can be modulated by infraradian rhythms such as the reproductive cycle. The circadian system of males and females do not differ to a great extent.