Human Physiology: The Human Body Clock (Bio-5004A/Bio-5104A) PDF

Bio-5004A / Bio-5104A Human Physiology The Human Body clock Circadian rhythms Dr Tracey Swingler [email protected]  Bio-5004A Human Physiology Lecture content 1. Evolution of circadian rhythms- plants/ flie...

Bio-5004A / Bio-5104A Human Physiology The Human Body clock Circadian rhythms Dr Tracey Swingler [email protected]  Bio-5004A Human Physiology Lecture content 1. Evolution of circadian rhythms- plants/ flies/ mammals 2. The master synchroniser of circadian rhythms (SCN) 3. Hormones of the circadian rhythm: Cortisol/ Melatonin 4. Molecular control of circadian rhythm 5. Peripheral tissue clocks 6. How misalignment affects health  Bio-5004A Human Physiology Learning outcomes Understand the concept of circadian function and biological clocks What external cues helps to set the clock. Give examples of circadian rhythms in the body Describe key hormones in circadian rhythm Describe the basic molecular control of circadian rhythm Understand what peripheral clocks are Circadian rhythm: Biological clocks were first described in plants. Sunflowers: begin the day with their heads facing east, swing west through the day, turn back to the east at night. Growing sunflowers anticipate the timing and the direction Indoors, they continue to swing back and of dawn forth for a few days - internal clock. Acting through growth hormones: ⁻ Day: the east sides of their stems grow more rapidly ⁻ Night: the west sides grew faster Prepares plants for: photosynthesis prior to dawn, Turns on heat-protection mechanisms before the Every cell in the plant hottest part of the day appears to have its own Produce nectar when pollinators are most likely clock. to visit. So do humans! ur circadian clock Human physiology is organised around the daily cycle of activity and sleep. ALMOST ALL LIFE ON EARTH uses an internal biological clock: anticipate the changes that result from the light/ dark cycles In the active phase: energy expenditure is higher/food and water are consumed/ organs need to be prepared for the intake/ processing and uptake of nutrients. During sleep: energy expenditure and digestive processes decrease, BUT, cellular repair, toxin clearance, memory consolidation and information processing increases All of these activities needs internal synchronisation a to ensure that biological processes occur in the appropriate temporal sequence. A brief history of circadian time All life on earth has adapted to the rotation of the earth around the sun Predictable changes in the geophysical environment Organisms from algae to people have evolved to keep time with light/dark cycles Different organisms occupy different spatio- temporal niches Physiology anticipates daily cycles - ‘circadian rhythms’. Comes from the Latin circa (about) and dies (day) Sleep/ wake cycle is ONE example of circadian rhythm What is the circadian rhythm? Sleep Alertness Coordination Temperature Endocrine system Cardiovascular This rhythm has evolved to help humans efficiency adapt to changes in our environment and Blood pressure anticipate changes in radiation, temperature, Immune system and food availability. Liver function Without this endogenous circadian clock, Homo Metabolism sapiens would not be able to optimize energy Digestion expenditure. Bone Disruption of sleep and circadian rhythm mineralisation Muscle strength can impact our physiological, emotional, Cartilage turnover cognitive health DNA repair Wound healing More active/ alert at certain times of the day Temperature core drops at night-conserve energy Cardiovascular and muscle strength optical Entrainme nt Circadian rhythms, do not run at exactly 24 hours Longer than 24 hours: without daily resetting we would get up and go to bed about 10 minutes later each day. Light is the leading ‘entrainment’ cue Zeitgeber- time giver The process of daily resetting is called ‘photoentrainment’. mples of a biological rhythm To be ‘circadian’, a biological rhythm must meet these three general criteria: 1. The rhythm has an endogenous free-running period that lasts approximately 24 hours. The rhythm persists in constant conditions, i.e. constant darkness, with a period of 24 hrs. 2. The rhythms are entrainable. The rhythm can be reset by exposure to external stimuli (such as light and heat). Rhythmically co-ordinated 3. The rhythms exhibit temperature biological processes so they occur compensation. They maintain circadian periodicity at the correct time to maximise over a range of physiological temperatures. the fitness of an individual. ying circadian rhythm in drosophila Egg laying by fruit flies Nobel prize in physiology and light dark Medicine, 2017: Molecular mechanism Day 1 Day 2, etc controlling CR in drosophila Begin at same time ENTRAINED Isolated a gene in Drosophila that controls the biological rhythm. The protein accumulates in the cell during the night, Constant light and is then degraded during the day Drosophila displays circadian rhythms in Shift start time FREE-RUNNING physiological and behavioural processes. I.e. always lays eggs in the morning light dark In constant light or constant dark- rhythm is still there but late- FREE RUNNING Begin at same time ENTRAINED Reversable, can be re-set- ENTRAINABLE al features of Biological Clocks in humans The most important entrainment is light 1. Input pathway 3. Output pathway Environme Sensory Physiological output Endogenous circadian rhythms: ntal cues receptors rhythms that last about a day; humans Master last around 24.5 h – free running activity synchroniz er hormone release Examples: activity, temperature, waking and sleeping, secretion of hormones, eating and drinking Zeitgeb feeding er Zeitgeber: a stimulus that resets the others biological clock (eg. bright light, exercise, temperature) - entrained al features of Biological Clocks in humans The most important entrainment is light 1. Input pathway 3. Output pathway Environme Sensory Physiological output Endogenous circadian rhythms: ntal cues receptors rhythms that last about a day; humans Master last around 24.5 h – free running activity synchroniz er hormone release Examples: activity, temperature, waking and sleeping, secretion of hormones, eating and drinking Zeitgeb feeding er Zeitgeber: a stimulus that resets the others biological clock (eg. bright light, exercise, eating)- entrained 2. What controls the physiological output at the cellular level? The master synchroniser: The SCN The SCN: The master synchroniser Studies in the 1990s showed that mice lacking rods and cones and visually blind, could still SCN consists regulate their circadian rhythms to light Retinal of two nuclei hypothalamic Light sensitive photopigment, OPSIN (OPN4): tract role in non-image-forming visual functions Nervous signals Sympathetic and SCN in the hypothalamus: Coordinates via neural parasympathetic and endocrine networks Photopigment psin4 in the retina Hormone signals Allows ENTRAINMENT and SYNCHRONIZATION, to the 24-hour cycle Without the SCN, rhythms in body cells dampen over time, which may be due to Synchronises lack of synchrony between cells physiology according to Day and night Natural daylight Light: combination of various wavelengths across the visible spectrum. Daylight is rich in blue light OPSIN4 triggered by blue wavelengths 480 nm Cortisol Melatonin OPSIN4 suppresses the production of MELATONIN, promoting alertness Blue light also comes from light Alert Sleep bulbs, smartphones, computer screens and tablets. ones of the circadian rhythm: Melatonin Light-> Eyes-> SCN-> Cervical ganglion-> Pineal gland Melatonin- amino acid hormone, derived from tryptophan. Secreted by a PINEAL GLAND- general circulation Melatonin is the main regulator of the circadian rhythm. Cortisol Melatonin Opsin4 - Blue light supresses melatonin biosynthesis Alert Sleepy Melatonin acts through Melatonin receptors, important for sleep/ wake cycles, blood pressure immune function mones of the circadian rhythm: Cortisol 1. Hypothalamus secretes Cortisol is a steroid hormone - corticotrophin- glucocorticoid class produced by the releasing hormone (CRH) adrenal glands 2. The anterior Transported by- corticosteroid-binding pituitary gland secretes globulin adrenocorticotrop hic hormone Normally released in a diurnal cycle (ACTH) Shift work: reversed-cortisol higher at 3. Stimulates the midnight secretion of cortisol from the adrenal Cortisol release is clearly linked to glands. activity patterns As the cortisol levels rise, Also released in response to stress and blocks the release of CRH low blood glucose concentration and ACTH. leads to reduced cortisol levels. coordinates clock in peripheral tissues Studies have shown that many other tissues in the rats including skeletal muscle, liver, and lung generate 24-hour rhythms Gene and protein expression patterns that regulate function of the tissue This rhythm dampens over time when the cells isolated in a dish. SCN maintains control across the body by synchronizing "slave oscillators," which exhibit their own near-24-hour rhythms and control circadian phenomena in local tissue. Zeitgebers Light: the most powerful zeitgeber 1. Light/dark The SCN also responds to more subtle cues such as when we exercise, eat, and socialize with cycle others. Temperature: Fluctuations in environmental 2. Food 3. temperature can help synchronise the body clock Exercis e Social cues: and daily routine play a role in entrainment Physical activity: regular exercise can affect circadian rhythms 4. Temperatur Eating patterns: timing of meals can affect circadian rhythm (particularly related to e metabolism) When these zeitgebers are ill-timed, it can put our body ‘out of time’. ey leaning points ALMOST ALL LIFE ON EARTH uses an internal biological clock to anticipate the changes that result from the light/ dark cycles Other Zeitgebers include- exercise, eating, socialising SCN coordinates all the peripheral clocks throughout the body (neural and hormonal) Melatonin-increased during night, cortisol during the https://padlet.com/tswingler/human- day physiology-introduction- z55csbeylkckqm8v Circadian rhythm: The molecular level Circadian transcriptional–translational feedback loop Clock gene expression Different organisms such as bacteria, plants, fungi, and animals, show near-24-hour rhythms. Circadian rhythms are controlled by "clock genes" that code for clock proteins. 0 12 24 32 480 12 24 32 48 The levels of these proteins rise and fall in rhythmic patterns over 24 hours A transcription-translation negative feedback loop ore circadian genes Core clock genes Regulates genes during the day Metabolism, muscle strength etc Brain and Muscle ARNT-Like 1 Circadian Locomotor Output Cycles Kaput Clock gene expression Regulates genes during the night Reparative 0 12 24 32 48 Period Cryptochrome 0 12 24 32 48 Molecular control of the circadian rhythm mRNA expression Clock Clock BMal BMal 0 12 24 32 48 BMal Clock Clock controlled genes 0 12 24 32 48 E-boxes Molecular control of the circadian rhythm mRNA expression Clock Clock BMal BMal Clock BMal 0 12 24 32 48 Per gene Cry genes BMal Clock Clock controlled genes 0 12 24 32 48 E-boxes Molecular control of the circadian rhythm mRNA expression Clock Per Per Cry Clock Cry BMal BMal Clock BMal 0 12 24 32 48 Per and Cry genes Per Cry BMal Clock Clock controlled genes 0 12 24 32 48 E-boxes cadian dysregulation Shift work Jet lag Light exposure Irregular sleep pattern Medical conditions- neurological condition Lifestyle- caffeine, alcohol Genetic factors Physical repair Psychological repai Cortisol Melatonin dian rhythm disorders: How they can affect health Over time, being out-of-sync with your body clock can increase your risk for obesity, cardiovascular disease, diabetes, gastrointestinal problems, neurodegenerative disorders Caused by gene mutations or environment/ lifestyle Memory consolidation occurs at night Bone mineralisation DNA repair Wound healing As we age our circadian rhythm natural dampens How Can Circadian Rhythm Affect Medical Treatments? Drugs are metabolized by enzymes, which are present in different amounts throughout the day. Many drugs target specific biochemical processes. Therefore, will be most effective if they are present at the time that the processes they target are actively occurring. Certain disease processes have their own timing. Learning outcomes revisited Understand the concept of circadian function and biological clocks What external cues helps to set the clock. Give examples of circadian rhythms in the body Describe key hormones in circadian rhythm Describe the basic molecular control of circadian rhythm Understand what peripheral clocks are Thanks for listening. Any questions? QR