Sleep 2 PDF - BMS 200

Sleep 2 BMS 200  Clock Genes? What is a clock gene? ▪ An intracellular “time-keeping” system present in most (all?) cells that generate rhythms in biological behaviour ▪ Regulate circadian rhythms, which are the body's natural 24-hour cycles governing physiological and behavior...

Sleep 2 BMS 200  Clock Genes? What is a clock gene? ▪ An intracellular “time-keeping” system present in most (all?) cells that generate rhythms in biological behaviour ▪ Regulate circadian rhythms, which are the body's natural 24-hour cycles governing physiological and behavioral processes like sleep- wake cycles, hormone release, body temperature, and metabolism. ▪ These genes interact through a complex network of feedback loops to generate and maintain rhythmic activity in cells. ▪ These rhythms are usually approximately 24 hours, but usually need input from light-dark cycles to stay entrained (synchronized) ▪ These genes are transcribed and produce proteins on an approximately 24 hour cycle ▪ The following are well-known clock genes: Clock, Bmal1, the “period” genes (Per1, Per2, Per3), Cry1, and Cry2 ▪ The protein products of these genes increase and then decrease over a 24-hour period – the period is likely synchronized via melatonin fluctuations Clock genes in circadian rhythms Are clock genes responsible for the intrinsic rhythms of the SCN (hypothalamic nucleus that receives input from the retina)? ▪ Surprisingly, no – the homeostatic regulation of sleep is not dependent on clock genes or their products in the SCN Are clock genes responsible for intrinsic rhythms in most of the rest of the body (leukocytes, skeletal muscle, brain)? ▪ Yes – and these genes seem to be modified by: Sleep (and sleep deprivation) Hormones (melatonin and others) Clock genes in circadian rhythms How “clinically relevant” are these genes and their daily fluctuations? ▪ Regulate up to 25% of the human genome ▪ Many of the genes are “metabolic” in nature Cell growth/division Energy metabolism, anabolic and catabolic processes Body temperature Perhaps various neurological functions – the hippocampus in particular in association with memory formation “Immunologic functions” Clock Gene Overview - FYI Clock gene synchronization Clock genes can be entrained by a variety of stimuli: ▪ Light-dark cycles ▪ Eating ▪ Exercise Stimuli that can entrain clock genes are called “zeitgebers” Proper “synchronization” of clock genes seems to promote normal physiological processes and be somewhat protective against cardiometabolic disease ▪ People with disrupted sleep cycles are at an increased risk of a variety of cardiometabolic disorders, as well as a modestly increased risk of certain types of cancer (epidemiologic evidence) ▪ Many animal studies show that feeding during “active” (i.e. daylight phases) results in improved insulin sensitivity and reduced adiposity, even in the face of identical caloric intake FYI – state of the evidence re: clock genes Melatonin Melatonin is amphipathic – carried by albumin, diffuses readily across cell membranes A single daily light pulse of suitable intensity and duration in constant darkness can phase shift and synchronize the melatonin rhythm to 24 hours ▪ Higher-frequency (i.e. blue light) is more effective in suppressing melatonin secretion Individuals living in dim light are more sensitive to light, and secrete more melatonin with a smaller “light stimulus” ▪ Blind individuals without light perception show free-running or abnormally synchronized melatonin and circadian rhythms Melatonin can act as a paracrine signal within the retina, Paracrine signaling is a form of cell-to-cell communication in which a cell releases signaling molecules (like hormones or cytokines) that act on nearby cells rather than traveling through the bloodstream to distant targets ▪ enhances retinal function in low-intensity light Melatonin Increases expression of antioxidant enzymes ▪ superoxide dismutase and glutathione peroxidase Blocks Bax proapoptotic activity and reduces caspase 3 Anti-inflammatory and analgesic properties ▪ Inhibits cyclooxygenase (COX) enzyme expression reducing excessive prostaglandin and leukotriene production ▪ May have analgesic properties as well via MT1 and MT2 receptors – reducing pain transmission in dorsal horn neurons Melatonin – additional information Melatonin is a very potent antioxidant, and it seems to be localized in the mitochondria of a wide variety of tissues ▪ Independent of the receptor effects – the hormone itself has antioxidant activity ▪ Unsure of the clinical significance of physiological concentrations of melatonin as an antioxidant – gram per gram, though, it is a better antioxidant than glutathione ▪ Some evidence that melatonin: Is protective against breast and prostate cancer Reduces both systolic and diastolic blood pressure Has been seen (in rodents) to be neuroprotective in ischemic stroke model “Proper” fluctuations in melatonin throughout the day likely improves overall insulin sensitivity and decreases visceral fat mass and hyperglycemia Cardiometabolic consequences of disrupted sleep - summary Increased visceral fat mass Decreased insulin sensitivity and higher incidence of obesity Increased incidence of the metabolic syndrome Dyslipidemia ▪ Lower HDL, elevated triglycerides FYI – state of the evidence re: sleep disruption in humans FYI – state of the evidence re: sleep disruption in humans  Complications of Obstructive Sleep Apnea (OSA) - Overview Associated with premature death ▪ Respiratory events lead to increased sympathetic overactivity ! nocturnal and daytime hypertension ▪ Large intrathoracic negative pressure swings (trying to inspire against an occluded airway) ! alter preload and afterload ! cardiac remodeling and reduced function Increased risk of congestive heart failure as well as supraventricular and ventricular dysrhythmias ▪ Hypoxia ! vasoconstriction and increased right ventricular afterload Formerly thought to be important, however more recent data indicates that most important cause of increased pulmonary vascular afterload is congestion due to reduced left ventricular function Complications of Obstructive Sleep Apnea (OSA) - Overview Associated with premature death ▪ Increased thrombosis and systemic free radical production likely also contribute to mortality Atherosclerosis ! Ischemic heart disease and stroke Hypercoagulability? ▪ Prevalence of atrial fibrillation and atrial flutter also higher in OSA Also contributes to stroke risk ▪ Interestingly, treatment of OSA also improves insulin resistance Improved sleep quality? Sleep Deprivation and Reproductive Health: Testosterone Sleep deprivation decreases testosterone production ▪ Testosterone concentration peaks during sleep Testosterone declines with age (males 45-74) ▪ Poor sleep quality is associated with lower testosterone concentrations ! increased in impact on testosterone levels compared to younger males Sleep Deprivation and Female Reproductive System High levels of melatonin found within ovarian follicular fluid ▪ Protects oocyte from oxidative stress during ovulation ▪ Low levels in follicle correlate with increase ROS and infertility ▪ FYI: IVF outcomes are improved with melatonin supplementation – increase oocyte quality and maturation Sleep: Hormonal and Immune Impacts TSH levels increase during sleep ▪ TSH is reduced during chronic sleep deprivation Cortisol, epinephrine and norepinephrine decrease during sleep GH, prolactin increase during sleep Increased melatonin levels in children help to suppress GnRH secretion from the pituitary ▪ Decline of melatonin production during adolescence is linked to onset of puberty Sleep: Hormonal and Immune Impacts Impact of sleep on the immune system Enhanced production of IL2 and IFN-gamma by T cells during nocturnal sleep and reduction in IL-10 ▪ Nocturnal sleep is associated with shift towards Th1 adaptive immune response; peaks around 3am ▪ Enhanced antiviral and intracellular bacterial response? NK cell count and their activity peak in late morning hours ▪ Blocked if experiencing sleep disturbances IL-6 and TNF (pro-inflam cytokines) increase during the night ▪ IL-6 associated with sleep, while TNF is regulated by other circadian (non-sleep) factors Sleep includes increased GH and prolactin release ! increase T cell proliferation and promote Th1 cytokine activity Sleep: Hormonal and Immune Impacts Summary – Immune: ▪ Impaired sleep may increase the predisposition to infection ▪ Impaired sleep may decrease the effectiveness of vaccination (seen in influenza A vaccinations) ▪ Perhaps greater Th1 (vs. Th2) activity during sleep Sleep and Carcinogenesis Sleep plays a critical role in various physiological processes, and its disruption has been associated with an increased risk of carcinogenesis This is concerning for those with Sleep disorders Shift Workers Sleep and Carcinogenesis Shift work: Circadian genes impact expression of genes associated with cell division and DNA repair ▪ Increased cancer risk in shift workers in epidemiologic studies (breast, prostate, colon, endometrial and non-Hodgkin’s lymphoma) ▪ Circadian disruption is deemed “probable carcinogen” Disorders of sleep: ▪ Increased risk of prostate cancer, but not breast cancer – associated with problem falling or staying asleep ▪ Circadian Rhythms: Gut Microbiome Gut microbiome consists of trillions of microorganisms residing in the gastrointestinal tract, plays a significant role in various physiological processes, even the regulation of circadian rhythms in the host. ▪ Microbes do not appear to express clock genes Gut microbiome may be able to regulate the circadian rhythms of the host In mice fed a high-fat diet, microbiome-dependent changes in clock genes (Per2, ARNTL) were seen within the liver ▪ May be mediated by butyrate production Circadian Rhythms: Gut Microbiome FYI Internal Molecular Clock: ▪ (1) Central pacemakers ▪ (2) Suprachiasmatic Nucleus (SCN) ▪ (3) Auxiliary oscillators Primary clock genes: ▪ CLOCK, ARNTL, PER, CRY Secondary clock genes: ▪ NR1D1, RORA, DBP, PRARGC1A Influence other genes responsible for energy metabolism and other functions Seizures A seizure is a sudden, uncontrolled electrical disturbance in the brain that can cause a range of symptoms, including changes in behavior, movements, feelings, and levels of consciousness. Seizures can vary significantly in their manifestation, duration, and severity, depending on the areas of the brain involved. Seizures Classifications ▪ Focal seizures – originate from one brain region Often due to structural problems ▪ Intact or impaired awareness ▪ Motor or nonmotor at onset ▪ Generalized seizures – arise from and spread rapidly throughout both cerebral hemispheres Often due to cellular, biochemical or structural problems ▪ Motor onset – tonic-clonic or another motor complication at onset of seizure ▪ Nonmotor – absence seizure, sensory, autonomic or emotional symptoms Focal Seizures – Intact Awareness EEG during non-seizure periods of time is typically normal or exhibiting brief epileptiform spikes or sharp waves Arise from: medial temporal lobe or inferior frontal lobe Presentations and progressions vary: ▪ Seizure may start in one region i.e. motor cortex responsible for fingers and spread to include entire hand, patient may experience paresis after the seizures (hours; rarely days) May experience sensory changes or emotional experiences (i.e. déjà vu, fear, detachment) Focal Seizures – Impaired Awareness Impaired awareness ▪ Not necessarily loss of consciousness, but inability to respond appropriately to environmental changes (i.e., conversation) and possible having poor recollection after seizure is done ▪ May experience an aura ▪ May be experience automatism; involuntary, automatic behaviours Can be simple like chewing or complex ▪ Full recovery of consciousness may take seconds, hours or longer Generalized Seizures 1 Typical Absence Seizures ▪ Sudden, brief lapse of consciousness without loss of postural control (seconds in duration) ▪ Typical onset during childhood ▪ May occur 100 times per day – appear as “daydreaming” Atypical Absence Seizures ▪ Lapse of consciousness is longer and more gradual in onset ▪ May include focal and motor symptoms ▪ Usually due to diffuse or multifocal structural abnormalities, which result in additional neurological complications Generalized Seizures 2 Generalized, Tonic-Clonic Seizure ▪ Occur in many different clinical setting because can result from metabolic problems One of the more common types of seizures ▪ Tonic Phase: Tonic contraction of muscles throughout body, “ictal cry”, impaired respiration yielding cyanosis, jaw clenching, increased SNS; lasts 10-20 seconds ▪ Clonic Phase: superimposed periods of muscle relaxation that increase in duration to a maximum of 1 min ▪ Post-Ictal Phase: unresponsive, muscles are flaccid, excess salivation (possibly partially obstructing airway), bladder or bowel incontinence ▪ Gradually regain consciousness after minutes to hours ▪ May complain of headache, fatigue and muscle pain for hours later Generalized Seizures 3 Atonic Seizure ▪ Sudden loss of postural muscles 1-2 sec in duration ▪ Brief impairment in consciousness, no post-ictal confusion Could be as brief as a head drop or a full body collapse Myoclonic Seizure ▪ Sudden and brief muscle contraction of body part or whole body ▪ Can be due to metabolic disorders, degenerative CNS disorders or anoxic brain injury Epileptic Spasms ▪ Predominantly in infants ! brief flexion or extension of proximal and truncal muscles Etiology and Pathophysiology of Seizures: General General knowledge/ observations: ▪ Seizure is a shift from normal balance between excitation and inhibition within CNS ▪ Brain has different seizure thresholds at different maturational stages ▪ Epileptogenesis – transformation of normal brain tissue into a network that is hyperexcitable Include: penetrating head trauma, stroke, infections, abnormalities in CNS development (congenital) ▪ Epileptogenic factors – specific changes that promote lowering of seizure threshold ▪ Precipitating factors – trigger or provoke an episode of seizure (seizures don’t occur 24/7) Include: psychological or physical stress, sleep deprivation, hormonal changes, toxic substances, certain meds, intermittent photic stimulation (video games and strobe lights) Etiology and Pathophysiology of Seizures Almost simultaneous firing of large number of local excitatory neurons ! hypersynchronization of excitatory bursts across large cortical region Individual neuron: ▪ Paroxysmal depolarization shift – long-lasting depolarization of membrane due to influx of extracellular Ca2+ ! triggers voltage gated Na+ channels to open ! influx Na+ ! repetitive action potentials Spike discharge (EEG) – when these action potentials happen in a relatively synchronized manner in sufficient number of neurons ! summation of field potentials Etiology and Pathophysiology of Seizures Spread of activation to surrounding neurons is facilitated by: 1. increase in extracellular K+ which shifts the Nernst potential for potassium Resting membrane potential becomes more positive ! neurons reach threshold more easily 2. accumulation of Ca2+ in presynaptic terminals promoting neurotransmitter release 3. NMDA receptor activation ! additional Ca2+ influx Etiology and Pathophysiology of Seizures: Neonate/ Infant: ▪ Congenital CNS abnormalities, trauma, CNS infection, hypoxic ischemic encephalopathy, drug withdrawal, perinatal injury, inborn errors of metabolism (i.e., pyridoxine deficiency) Early Child: ▪ Febrile seizures Childhood: ▪ Many well-defined epilepsy syndrome present in this age group, often due to idiopathic or genetic causes Adolescents and Adults: ▪ Shift towards acquired due to CNS lesions, head trauma, CNS infection (i.e. neurocystericosis), tumors, illicit drug use or alcohol withdrawal, autoimmune (i.e., antibodies against CNS K+ channels) Etiology and Pathophysiology of Seizures: Etiologies 2 Older Adults: ▪ Cerebrovascular disease (FYI 50% of new cases of epilepsy in >65yo), trauma, degenerative diseases Chronic seizures often appear months or years after the initial stroke Any age: ▪ Metabolic disturbances (electrolyte imbalance, hypoglycemia, hyperglycemia), renal failure, hepatic failure, hematological disorders, endocrine disorder, vasculitis as well as variety of medications Sleep Deprivation and Epilepsy Sleep deprivation can provoke seizures ▪ Cortical excitability increases with time being spent awake ▪ This is especially true for generalized epilepsy BUT not all seizures or epilepsies Epilepsy can affect sleep quality: ▪ Increase wake time after sleep onset (strongest feature of epilepsy) ▪ Reduce REM sleep quality and delay the first REM episode ▪ Change NREM sleep oscillations ▪ Overall disruption of normal sleep  Taenia – worm infestations Tapeworm: ▪ Cattle or pigs become infected by eating contaminated vegetation ▪ Taenia invades muscle and survive for years ▪ Humans get infected by eating undercooked or raw infected meat (beef, pork) ▪ SX: mild abdominal symptoms (attaches to SI and give rise to proglottids which exit via anus and passed in the stool Cysticercosis and Neurocysticercosis Cysticercosis is infection of the muscle (or other tissue) by the larval cysts of Taenia solium (pork tape worm) ▪ Worm was able to penetrate the intestinal wall and disseminate (preference for muscle and brain) Neurocysticercosis is infection of the brain, which is a major cause of adult-onset seizures in low-income countries ▪ Most common parasitic disease of CNS ▪ Complex immune evasion is believed to be the reason it can survive for so long in the brain without sx ▪ Presentation is variable: minimal sx, then suddenly seizures and increased intracranial pressure and possibly death Depends on parasitic load (number of invaders) and location  Neurocysticercosis Pathogenesis MMP-9 polymorphism ▪ Associated with patients who exhibit symptoms (seizures) compared to asymptomatic, yet infected, patients ▪ Increased BBB permeability (MMP-9 remodels and degrades the BBB) ! thought to allow greater influx of immune cells into CNS and thus result in greater inflammatory response ! degradation of the cysticerci AND subsequently greater seizure activity Trypanosoma brucei and Sleeping Sickness Trypanosoma brucei (T.b. gambiense) ▪ Unicellular parasite transmitted by the bite of the tse-tse fly, extra-cellular parasite ▪ Endemic to sub-Saharan Africa (location of the tse-tse fly) Sleeping Sickness 3 years in duration; largely fatal (some problematic treatments exist) ▪ Early phase: parasite is in the bloodstream and interstitial space of a few organs Chronic, intermittent fevers, headache, pruritus, lymphadenopathy, possibly hepatosplenomegaly ▪ Late phase: parasite invades the CNS Sleep disturbance and neuropsychiatric disorders Sleeping Sickness Invade the brain: ▪ Observed in CSF (diagnostic!), but don’t seem to survive there long, may be penetrating BBB directly (unclear) BUT there is no damage in BBB itself ▪ Concentrate in the median eminence and hypothalamic areas Change in sleep architecture ▪ No change in total amount of time asleep! Increased daytime sleep and insomnia at night ▪ Similar features with narcolepsy: SOREM episodes; sudden transition from wake to sleep Excessive daytime sleepiness Sleep fragmentation References Patrick M. Fuller, Joshua J. Gooley, and Clifford B. Saper. Neurobiology of the Sleep-Wake Cycle: Sleep Architecture, Circadian Regulation, and Regulatory Feedback. Journal of Biological Rhythms 2006 21:6, 482-493 “Circadian regulation of sleep-wake cycles” Electrical Activity of the Brain, Sleep–Wake States, & Circadian Rhythms. In: Barrett KE, Barman SM, Brooks HL, Yuan JJ. eds. Ganong's Review of Medical Physiology, 26e. McGraw Hill; 2019. Accessed June 13, 2023. https://accessmedicine- mhmedical-com.ccnm.idm.oclc.org/content.aspx? bookid=2525&sectionid=204291821 CIRCADIAN RHYTHMS Arendt J, Aulinas A. Physiology of the Pineal Gland and Melatonin. [Updated 2022 Oct 30]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https:// www.ncbi.nlm.nih.gov/books/NBK550972/ “Main Function of the Pineal Gland” and “Melatonin Synthesis” and “Control of Melatonin Synthesis: A Darkness Hormone” References Wellman A, Gottlieb DJ, Redline S. Sleep Apnea. In: Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J. eds. Harrison's Principles of Internal Medicine, 21e. McGraw Hill; 2022. Accessed June 13, 2023. https://accessmedicine-mhmedical-com.ccnm.idm.oclc.org/content.aspx? bookid=3095&sectionid=265457102 “Health Consequences and Comorbidities” excluding the Treatments Rao VR, Lowenstein DH. Seizures and Epilepsy. In: Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J. eds. Harrison's Principles of Internal Medicine, 21e. McGraw Hill; 2022. Accessed July 10, 2023. https://accessmedicine-mhmedical-com.ccnm.idm.oclc.org/content.aspx? bookid=3095&sectionid=265447874 “Classification of Seizures” and “The causes of seizures and epilepsy” and “Basic mechanism”, specifically “Mechanisms of seizure initiation and propagation” and “Mechanisms of epileptogenesis” References Gripper LB, Welburn SC. The causal relationship between neurocysticercosis infection and the development of epilepsy - a systematic review. Infect Dis Poverty. 2017 Apr 5;6(1):31. doi: 10.1186/ s40249-017-0245-y. PMID: 28376856; PMCID: PMC5381143. “Background”, “The neurocysticercosis-epilepsy relationship”, “could a genetic predisposition exist?” https://www.cdc.gov/dpdx/taeniasis/index.html “Biology” Nobili L, Frauscher B, Eriksson S, Gibbs SA, Halasz P, Lambert I, Manni R, Peter-Derex L, Proserpio P, Provini F, de Weerd A, Parrino L. Sleep and epilepsy: A snapshot of knowledge and future research lines. J Sleep Res. 2022 Aug;31(4):e13622. “The effects of sleep on epilepsy”, “The effects of epilepsy on sleep structure” and “epilepsy, sleep, brain plasticity and epileptogenesis” References Choi H, Rao MC, Chang EB. Gut microbiota as a transducer of dietary cues to regulate host circadian rhythms and metabolism. Nat Rev Gastroenterol Hepatol. 2021 Oct;18(10):679-689. doi: 10.1038/ s41575-021-00452-2. “Host circadian clock and the gut microbiota”, “Circadian clocks in mammals”, “microbial control of chronometabolism”, “microbial metabolites” – Very useful and interesting read when you have the time to explore. Recommend: download and save. OPTIONAL: Rosselot AE, Hong CI, Moore SR. Rhythm and bugs: circadian clocks, gut microbiota, and enteric infections. Curr Opin Gastroenterol. 2016 Jan;32(1):7-11. doi: 10.1097/ MOG.0000000000000227. PMID: 26628099; PMCID: PMC4721637 References Irwin MR. Why sleep is important for health: a psychoneuroimmunology perspective. Annu Rev Psychol. 2015 Jan 3;66:143-72. doi: 10.1146/ annurev-psych-010213-115205. Epub 2014 Jul 21. PMID: 25061767; PMCID: PMC4961463. “Psychoneuroimmunologic pathways of immune regulation”, “Immunity during nocturnal sleep: circadian versus sleep processes” and “Sleep disturbance, adaptive immunity, and infectious disease risk” AND “Sleep disturbance and cancer” Rijo-Ferreira F, Takahashi JS. Sleeping Sickness: A Tale of Two Clocks. Front Cell Infect Microbiol. 2020 Oct 2;10:525097. doi: 10.3389/ fcimb.2020.525097. PMID: 33134186; PMCID: PMC7562814. “Sleep and circadian disruption by sleeping sickness infection” References Rijo-Ferreira F, Takahashi JS. Sleeping Sickness: A Tale of Two Clocks. Front Cell Infect Microbiol. 2020 Oct 2;10:525097. doi: 10.3389/ fcimb.2020.525097. PMID: 33134186; PMCID: PMC7562814. “Timing of Sleep”, “Sleep Architecture” Lateef OM, Akintubosun MO. Sleep and Reproductive Health. J Circadian Rhythms. 2020 Mar 23;18:1. doi: 10.5334/jcr.190. PMID: 32256630; PMCID: PMC7101004. “Testosterone, FSH, Progesterone, TSH, LH, Prolactin and estradiol, and impact of melatonin” Tarocco A, Caroccia N, Morciano G, Wieckowski MR, Ancora G, Garani G, Pinton P. Melatonin as a master regulator of cell death and inflammation: molecular mechanisms and clinical implications for newborn care. Cell Death Dis. 2019 Apr 8;10(4):317. doi: 10.1038/s41419-019-1556-7. PMID: 30962427; PMCID: PMC6453953.