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Alexandra Ahlschlager and Katelynne Au Presentation Date: October 25, 2023 Outline: A review of vagus nerve stimulation as a therapeutic intervention Introduction (Background, Purpose of Article, and Hypotheses) The Vagus nerve connects the CNS to autonomic control centers, originating in the brains...

Alexandra Ahlschlager and Katelynne Au Presentation Date: October 25, 2023 Outline: A review of vagus nerve stimulation as a therapeutic intervention Introduction (Background, Purpose of Article, and Hypotheses) The Vagus nerve connects the CNS to autonomic control centers, originating in the brainstem and branching to innervate visceral organs. Vagus Nerve Stimulation (VNS) currently treats epilepsy and depression, regulating autonomic tone via neck-accessible electrodes. Due to its anti-inflammatory properties, VNS also holds the potential for treating autoimmune and inflammatory disorders. This review covers VNS applications, including potential medical uses beyond epilepsy and depression (the article’s “hypotheses”). Main Results (the actual review portion) Current Uses Epilepsy: An alternative to antiepileptic drugs to treat partial onset seizures. Expecting mothers with treatment-resistant epilepsy can minimize drug exposure to the fetus, while the pediatric population who are susceptible to anxiety and depression while taking antiepileptics can avoid these psychological effects with VNS. Involves a battery-powered stimulator with an electrode around the left cervical vagus. The mechanism of action is unknown, but evidence suggests it may reduce the activity of highly excitable regions (limbic system/thalamus) and regulate downstream release of norepinephrine and serotonin. Depression: Used as a supplemental treatment and for those who have not responded to at least 4 different pharmaceutical antidepressant treatments previously. For expecting mothers, VNS has been shown to avoid the risks of low fetal birth weight and preterm delivery commonly seen with SSRIs. Alters medial and prefrontal cortical transmission to moderate release of serotonin and norepinephrine. Potential Uses Sepsis: VNS may prevent sepsis by regulating inflammation and balancing PNS and SNS responses. Research explores VNS use with neonates vulnerable to sepsis. Pain Management: VNS complements fibromyalgia pain treatment. It may also relieve migraines and episodic cluster headaches. Obesity/Diabetes: VNS may curb food cravings and prevent excess weight gain. Vagal tone alteration in diabetes affects inflammation and metabolic issues. VNS may lower blood glucose. Stroke/TBI: VNS lowers TNFa, indicating cytokine regulation and therapeutic potential for stroke and TBI. Anti-inflammatory properties and influence on ACh levels may modulate injury and inflammation. Rheumatoid Arthritis (RA): VNS may modulate RA, possibly via α7 nAChR, in chronic synovial inflammation. Cardiovascular Disease: VNS influences cardiovascular control, preventing aortic stiffening and reducing inflammation in hypertension. It is linked to reduced inflammation, lowering coronary artery disease risk. VNS improves heart function, reduces infarct size, and modulates inflammatory markers. Lung Injury: VNS plays a role in pulmonary inflammation. Vagotomy worsens ventilator-induced lung injury. VNS reduces injury by decreasing inflammation and apoptosis; it may also protect against simultaneous gut injuries. Conclusion (Discussion and Interpretation) Emerging evidence suggests VNS can mitigate inflammation in various autonomic and inflammatory disorders, expanding its potential uses. The understanding of VNS's actions is still evolving, requiring further analysis and focused research on autonomic tone modulation. The vagus nerve plays a crucial role in the immune response, and manipulating vagal tone may lead to the application of minimally invasive therapeutic options. Advances in Enteric Neurobiology: The “Brain: in the Gut in Health and Disease Enteric Neurobiology ❖ the study of the enteric nervous system, which is a complex network of neurons and other cells found in the gastrointestinal tract. ➢ Enteric neurons, glia, EECs, immune cells ❖ Plays a crucial role in digestive, immune, hormonal, and metabolic processes ❖ Functions independently of CNS, meaning it can regulate various digestive processes ➢ Peristalsis and release of digestive enzymes ❖ ENS communicates bidirectionally with the CNS via gut-brain axis Zebra Fish, model system for investigating the ENS ❖ Conservation of genetic and cellular processes involving neurogenesis between zebrafish and humans ❖ Enteric Neural Progenitor Cells (ENPCs) drive neurogenesis in the ENS ➢ Ensures the maintenance and repair of the ENS How ENS is maintained in the healthy adult gut? ❖ There is continual neuronal turnover which maintains the adult ENS ➢ Adults myenteric neurons can be lost at a significant rate, yet the regenerative nature of the ENS which allows for myenteric ganglia to be maintained. Enteric Neuroepithelial Interactions ❖ Enteroendocrine Cells (EECs) sense the luminal enviro. of the gut via the cell surface receptors for nutrients, microbial products, and host signaling molecules ❖ Enterochromaffin Cells (ECs) express voltage ion channels that regulate serotonin release in the body, triggering the peristaltic reflex circuit upon mucosal deformation ❖ Bidirectional communication via the synapses between intestinal mucosal fibers and adjacent EECs Neuron-Glia interactions within the ENS ❖ Ablation of GFAP-expressing enteric glia suggested that they are essential for the maintenance of the intestinal epithelium ❖ Role of enteric glia (supporting enteric neurons) → communicate via glial signaling, release of signaling molecules act on neighboring neurons and influence activity, and help regulate GI function ➢ Additionally, neuron-glia interactions contribute to the repair of damaged neural tissue and provide support structurally and functionally (metabolism specifically) Enteric Neuroimmune Interactions ❖ Enteric neurons interact w/ immune cells (macrophages) to maintain gut health and respond to challenges ❖ Muscalaris Macrophages (MMs) maintain gut homeostasis by secreting BMP2 (neurotrophic growth factor that acts on enteric neurons) and phagoctyosing mature neurons ❖ Enteric Neurons in turn control MM numbers through the production of CSF1 (macrophages-specific growth factor) Aging and Neuralinflammation ❖ Effects of aging on the ENS includes: (1) enteric neuronal loss, (2) degeneration, (3) neuronal hyperexcitability, and (4) neuroinflammation aka inflammaging ➢ All of these can contribute to age-related gastrointestinal disorders ❖ There are multiple processes that have been proposed for cause of inflammaging (alterations in gut microbiota and elevated interleukin-6 levels) ❖ Also with age, there is MM behavior change and change in intestinal microbiota composition, these two disrupt ENS structure and function. Methods of Evaluation of Autonomic Nervous System Function Introduction The autonomic nervous system (ANS) regulates involuntary physiological processes. This paper reviews methods for assessment of ANS function, focusing on techniques for the diagnosis and treatment of cardiovascular diseases. Stimuli that change blood pressure are considered sympathetic modulation and stimuli that change heart rate are considered parasympathetic modulation. Tests of Autonomic Cardiovascular Reflexes Valsalva Manoeuver (Involves involuntary forced expiration against a resistance) ● Used to calculate valsalva ratio (longest RR interval ÷ shortest RR interval) ○ RR interval is the time between two successive R-waves Deep Breathing (Subject breathes at a rate of 6 breaths per minute) ● Used to calculate two different values 1. Difference between average of the largest accelerations in heart rate during inspiration and average of the largest decelerations in heart rate during expiration 2. Expiratory-inspiratory ratio (longest RR interval during expiration ÷ shortest RR interval during expiration) Isometric Handgrip Test (Subject squeezes a handgrip dynamometer for 3-5 minutes) ● Results are presented as difference between highest measured diastolic blood pressure and average diastolic blood pressure while at rest Cold Pressor Test (Subject immerses their hands or feet in cold water for 60-90 seconds) ● Results are presented as the rise in diastolic blood pressure Head-Up Tilt Test (Subject lays on special motorized table to gradually assume an upright posture) ● Allows for assessment of autonomic regulation during long-term orthostatic challenge Orthostatic Test (Subject starts laying down, then stands up) ● Used to calculate 30/15 ratio (maximum RR interval ÷ shortest RR interval) Mental Arithmetic (Subject performs serial subtractions) ● Results are presented as the increase in systolic blood pressure Baroreflex Sensitivity Testing (Nerve endings in the carotid sinus and aortic arch that are stimulated by changes in arterial pressure) ● 3 methods: pharmacological stimulation, neck suction, and noninvasive methods Analysis of heart rate variability (HRV) ● HRV based on the observation of RR intervals fluctuating around a mean value ○ Fluctuations based mainly on interactions between the sympathetic (slow and long-lasting) and parasympathetic nervous system (quick and transient) Measurements of neurotransmitter levels Noradrenaline Spillover Rate (Intravenous infusion of titrated NA→tissue secretes NA into plasma→tissue clearance of this NA minus plasma NA value = noradrenaline spillover rate) ● Sympathetic nervous system activity is assessed through the measurement of plasma or urine noradrenaline (NA) concentration Microneurography ● Use tungsten microelectrodes to record sympathetic nerve activity in muscle and skin Testing of Sudomotor Function (ANS control of sweat glands and their response to stimuli) ● 3 tests: Thermoregulatory Sweat Test, Sympathetic Skin Response (SSR), and Quantitative Sudomotor Axon Reflex Test (QSART) Outline of Dysautonomia: Its Symptoms, Etiology, Pathophysiology and Diagnosis Autonomic dysfunction, or dysautonomia, refers to dysfunction of the autonomic nervous system, which includes the afferent and efferent pathways of the sympathetic, parasympathetic and enteric nervous system. Symptoms of dysautonomia are numerous and encompass dysregulation of essential involuntary physiological processes such as tachycardia, constipation, incontinence, impotence, hyperhidrosis, vision problems, insomnia, and vertigo. Dysautonomia is usually a manifestation of an underlying disease that leads to damages of the nerves within the autonomic nervous system. • The etiology of dysautonomia can be either hereditary or acquired. Familial dysautonomia is an autosomal recessive genetic disorder caused by a mutation of the ELP1 (Elongator Complex Protein 1) gene on chromosome 9, which disrupts neuronal functions of the ANS. Familial amyloidosis is another inherited disease whose first symptoms usually include postural/orthostatic hypotension. Neuropathic amyloidosis is caused by misfolding proteins around neurons that aggregate into distinctive fibrillar forms with a beta-sheet structure which cannot be broken down by protease enzymes. • More often, dysautonomia is non-hereditary and due to underlying diseases that interfere with normal ANS functioning. Hyperadrenergic postural tachycardia is a form of postural orthostatic tachycardia syndrome (PoTS) that results from excessive sympathetic tone in the heart during postural changes, whereas postural/orthostatic hypotension is caused by insufficient or delayed adjustment in blood pressure after postural changes. Normally SNS increases heart rate and produces vascular bed constriction, leading to an increase in blood pressure. This in turn is detected by vagus nerve baroreceptors in and around aortic arch. Visceral afferents in the vagus then stimulate vagal PNS efferents which then slow down heart rate. Postural/orthostatic intolerance could occur when this process is not robust against posture induced hemodynamic changes, which results in insufficient oxygenated blood reaching the brain and tachycardia. Dysautonomia could also arise from autoimmune disorders like autoimmune autonomic ganglionopathy, where antibodies against the ganglionic nicotinic acetylcholine receptor in SNS and PNS induce abnormal immune responses that impair neurotransmitter receptor activities in ANS. Trauma, neoplasia, HIV and Lyme infection, alcoholism and Parkinson’s disease could all develop dysautonomia as their symptoms. Another common cause of dysautonomia is diabetes mellitus, where hyperglycemia damages both nerve fibers and surrounding vasa nervorum in ANS. • Reflex syncope, or vasovagal syncope, is another dysautonomic condition characterized by fainting due to some triggering stimulus like sight of blood or stress. The nucleus tractus solitarii of the brainstem is activated directly or indirectly by the triggering stimulus, resulting in simultaneous enhancement of PNS vagal tone in the heart and withdrawal of SNS tone in blood vessels. These two factors lead to bradycardia and low blood pressure, resulting in syncope. Some researchers argue that reflex syncope is not a disease but rather a vestigial trait that shares similar neural mechanisms as tonic immobility in many animal species. • Diagnosis of postural hypotension requires sustained reduction of systolic blood pressure of at least 20 mmHg within three minutes of standing or head-up tilt to at least 60 degrees on the tilt table, which is a motorized device that simulates postural changes of the human body. Similarly, postural tachycardia’s diagnosis requires sustained heart rate increment of 30 bpm within 10 min of standing up. Sweat tests are often used to diagnose SNS disorders such as small fiber neuropathy, where quantitative sudomotor axon reflex test (QSART) is used to evaluate postganglionic sympathetic functions of the pure small nerve fibers of the dermal tissue by measuring the amount of sweat produced under electrical and norepinephrine stimulation. References Sánchez-Manso JC, Gujarathi R, Varacallo M. Autonomic Dysfunction. [Updated 2023 Aug 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430888/ Alboni P, Alboni M. Vasovagal Syncope As A Manifestation Of An Evolutionary Selected Trait. J Atr Fibrillation. 2014 Aug 31;7(2):1035. doi: 10.4022/jafib.1035. PMID: 27957092; PMCID: PMC5135249. References Elizabeth Clem, Andersen Chu “Acupuncture Enhances Gastrointestinal Motility…” Sepsis → systemic inflammation → GI tract is main target organ and stress response center - Mainly mediated by inflammation → destroy intestinal epithelium and immune response, lead to GD, increases intestinal permeability so bacteria go into walls, sepsis increases Gastrointestinal dysfunction → Common after endotoxemia (bacteria die, release toxins into blood), occurs with sepsis and together they have poor prognosis and high mortality - Abdominal distension, vomiting, diarrhea, intestinal dyskinesia, stress ulcer, GI bleeding - Current western treatment: antidiarrheal, analgesic, laxative, promote gastric motility Acupuncture → To stimulate healthy qi, strengthen homeostasis, regulate immunity with needles - Simple, easy, low-cost, and doesn’t have to be absorbed through GI lining - Studies show improved GI function with sepsis, post-op recovery, and less inflammation Aim of study → Confirm clinical effects of acupuncture for treating patients with septic GD Participants → 36 control, 37 study; all septic with GD Control → Follow guidelines for sepsis treatment, also fluid resuscitation, anti-infection, protection of GI barrier mucosa, reduction of GI mucosal permeability, observed for 1 week Study → Received approved treatment like above then also acupuncture, observed 1 week - Used 7 acupoints, mainly along Ren channel, and some along leg and foot Gastric dilation, and max volume and pressure → Barostat device to maintain gastric V and P - Get scores of distension, epigastric pain, nausea, vomiting when V at 200, 300, 400 ml - 0 = no symptoms, 1 = mild, 2 = moderate, 3 = severe symptoms - Scores decreased for both after treatment, decreased more for study group - Max V (when pain began) and P increased after treatment, increased more for study ANS function → baseline ECG; use barostat for ECG at max V (before and after treatments) - HF showed downward trend for both → expanding V reduces tension of vagus nerve so vagus wasn’t able to stimulate GI function as much - LF and VLF showed upward trend for both → expanding V increase tension of sympathetic nerve so it can inhibit GI function even more - Acupuncture group made vagus trend less downward, and sympathetic less upward Infection index → Blood sample for white blood cell, C-reactive protein, procalcitonin levels - Decrease for both groups, study wasn’t any better, showing the decrease was from comprehensive treatment (anti-infection, fluid resuscitation, ventilation, etc.) Overall → Acupuncture enhances GI motility, peristalsis, and ANS function of GD with sepsis ‭Joshua Chan and Oris Chen‬ ‭Background:‬ ‭●‬ ‭Dehydration stimulates thirst and vasopressin (VP) secretion.‬ ‭●‬ ‭Ingested water takes time to impact plasma osmolality (Posmol).‬ ‭●‬ ‭Early signals are crucial for osmoregulation.‬ ‭●‬ ‭Prior dog studies suggest VP inhibition might relate to swallowing, not Posmol.‬ ‭●‬ ‭Previous rat studies imply visceral receptors, possibly in intestines, hepatic portal‬ ‭vein, or liver, detect water absorption pre-Posmol changes. Damage to vagal‬ ‭afferents in rats disrupts normal water intake reduction during thirst, emphasizing‬ ‭the role of peripheral receptors.‬ ‭Hypothesis:‬ ‭●‬ ‭Water ingestion will cause rapid inhibition of VP secretion in rats‬ ‭Main Results:‬ ‭●‬ ‭Rats were given 5 minutes to drink water, isotonic solution, or nothing‬ ‭●‬ ‭Within 20 minutes after drinking plasma osmolality remains the same for all 3‬ ‭●‬ ‭Rats that drank water showed significant decrease in concentration of plasma‬ ‭oxytocin and plasma vasopressin‬ ‭Discussion:‬ ‭●‬ ‭Small gastric NaCl loads stimulate VP secretion and thirst without Posmol‬ ‭changes.‬ ‭●‬ ‭Early signals may not directly relate to osmolality but could be linked to hepatic‬ ‭vagotomy or area postrema, providing an anticipatory system for osmoregulation.‬ ‭Our Interpretation:‬ ‭●‬ ‭Concur with the hypothesis that early, non-osmolality-related signals significantly‬ ‭inhibit VP secretion and thirst during water ingestion in rats.‬ ‭●‬ ‭Alternative: Sensory cues related to drinking may contribute to the inhibitory‬ ‭effect on VP secretion. The rapid VP decrease could be due to direct dilution in‬ ‭the gastrointestinal tract rather than an anticipatory signal from peripheral‬ ‭receptors.‬ ‭Relation to Lecture Topics:‬ ‭●‬ ‭Osmoreceptors in vascular organ of lamina terminalis stimulates arginine‬ ‭vasopressin secreting cells in hypothalamus(supraoptic and paraventricular‬ ‭nucleus‬ ‭●‬ ‭Vasopressin acts on kidney for water reabsorption‬ ‭●‬ ‭Oxytocin is a hormone involved in natriuresis to excrete excess NaCl‬ ‭●‬ ‭Study shows both hormones are linked to thirst response as well‬ ‭●‬ ‭Drinking water reduces secretion of both hormones before osmolality resets to‬ ‭base levels‬ Gustatory System Physiology ● Taste buds are groups of taste cells found inside the papillae of the tongue ● Tastants attach to taste hairs → trigger specific taste cells to depolarize, sending afferent signals from Cranial Nerve VII, IX, or X. ● CN signals enter CNS via Nucleus Solitary tract which then go into VPM nucleus in Thalamus ● “Flavor” that we interpret is a combination of many signals alongside tastant afferents, including olfactory and touch afferents. Background ● Previous research has identified that there is a mechanism for sapid stimuli in the gustatory system ● Nuisance variable → often underplayed and not considered important ● Two current theories for the mechanism ○ PNS control by change of receptor cells when presented to low/high concentrations of sucrose ■ Disproven since presence of a water rinse has shown to not reduce the comparison effect ○ CNS control by learning/memory of recent concentration of tastant, allowing for comparison/adjustment to incoming tastant ● Preliminary data shows that simultaneous contrast effects send signals to single gustatory neurons in the NST Hypothesis ● Simultaneous effects of sapid stimuli should occur between both normal and chronic decerebrate rats after intraoral stimulus delivery Methods ● An electric recorder inserted into jaw muscle, allows for quantification of mouth movement ● Two intraoral cannulas inserted into the mouth ● 0.05 vs 0.5M sucrose were infused 40 times a day followed by 28 seconds of recording, some days all one concentration some days alternating Results ● Intact rats showed comparison effects for all categories except Licks/burst ● Decerebrate rats only showed comparison effects in alternating environments except for Bursts Discussion ● Two main takeaways ○ Decerebrate rats proven to respond differentially to stimulus intensity ■ current data shows blunt of phasic response in decerebrate rats ○ Brainstem alone can use short term comparison processes to express simultaneous contrast effects, but cannot anticipate meals or retain long term. ● Background Information & Purpose “Energy Homeostasis” → cumulative energy intake matched to energy expenditure Last few years → identified signaling ● molecules that affect food intake Adiposity Signals: Insulin & Leptin Similarities: Circulate at levels ∝ body fat ; Enter CNS in ∝ plasma level ; Receptors expressed in brain ; Binding to their receptors reduces food intake Differences: Insulin = peptide pancreatic hormone ; leptin = hormone released from adipocytes Adiposity Signals: Which is more important? Leptin > Insulin …for CNS control of energy homeostasis Study: Rat model of uncontrolled, insulin-deficient diabetes ; Injections of leptin → NO diabetic hyperphagia → Leptin more important Leptin Resistance and Obesity Hypothesis: leptin resistance can occur in association with obesity ● Obese individuals have high plasma leptin, so obesity may be related to reduced leptin action in the BRAIN (leptin resistance) Mechanism? 1. Dysfunction of ○ leptin receptors at BBB, preventing transport to brain OR 2. Reduced leptin-receptor signal transduction Neuropeptide Effectors of Adiposity Signals: NPY and Melanocortins Neuropeptide Y (NPY) Stimulates Food Intake ● Injection of NPY into hypothalamus or central ventricles of rats leads to…Increased food intake, decreased energy expenditure, induction of lipogenic enzymes in liver and white adipose tissue → OBESITY Melanocortins Reduce Food Intake via MC3 and MC4 receptors Neuroinflammatory and Autonomic Mechanisms in Diabetes and Hypertension by Han C. et al. Outline Hannah Kaye and Sarah Huh What is the main focus of the article? ● Review article is focused on reviewing all of the previous literature on how neuroinflammation causes the development of diabetes and hypertension through the autonomic nervous system. The Hypothalamus ● Hypothalamus - controls the actions of the neuroendocrine and autonomic nervous system ● Hepatic glucose production, brown adipose tissue activation, blood pressure control – via neuroendocrine, sympathetic, and parasympathetic pathways ● Hypothalamic inflammation is closely linked to development of diabetes and its associations with aging and neurodegenerative diseases → diverse functions of this brain region in maintaining metabolic and homeostatic balance How do the Hypothalamus and Autonomic Nervous System Interact? ● Neurons in the hypothalamus innervate the brainstem and spinal cord which are both known to control sympathetic and parasympathetic actions. ANS innervates important organs in metabolism. Main Results of the Papers Reviewed Autonomic and hypothalamic control of hepatic glucose production: ● Autonomic outflow regulated by hypothalamus (involving parasympathetic and sympathetic innervations of the liver) plays an important role in controlling hepatic glucose output and maintaining glucose homeostasis in the body. Autonomic and hypothalamic modulation of glucose uptake in skeletal muscle: ● Insulin stimulates glucose uptake in skeletal muscle. The hypothalamus has control over muscle glucose uptake through insulin-dependent pathways that employ sympathetic activation. Autonomic and hypothalamic control of glucose utilization in brown fat: ● BAT is primarily regulated by the SNS, mainly through B1 and B2 adrenergic receptors, while B3 adrenergic receptor agonists mainly affect WAT ● Hypothalamic neuronal types (like POMC neurons in arcuate n.) play a role in BAT regulation ● BAT activity is linked to circadian rhythms, cold exposure, and energy metabolism 1) ● ● ● 2) ● ● ● 3) ● ● ● ● ● ● ● ● 4) ● ● ● ● ● ● 5) ● ● ● ● ● Outline What is the background for the experiment of discussion? Recent years it has become apparent that mental disorders among medical trainees and doctors are common and can be very disabling 195 studies from 47 countries ○ 30% of respondents screened positive for a diagnosis of depression and/or anxiety ○ 11% reported suicidal thoughts Only 1 in 7 of the medical students who meet the criteria for depression will seek treatment due to stigmas Why did the authors perform this study? Substantive gaps in current understanding of root causes, drivers, and consequences of ill health in this group Key limitation in literature is over-reliance on survey-based research provided by volunteers (problems such as sampling biases pop up and representativeness) Biological contributors to stress and diminished well-being has rarely been considered If research article, what are the main results (without interpretation) Sample size: n=270 approached, 151 participated (mean age 21.8) No significant impact of sex on results 23.3% (n=35) scored above threshold for sleep disturbances on PSQI 33.8% (n=51) had at least one psychiatric diagnosis based on MINI 33.8% (n=51) scored above threshold for fatigue on SPHERE-SOMA 17% (n=25) reported consumption of alcohol at hazardous levels 27.8% (n=42) reported impaired daily functioning HRV is better for those with better sleep quality, low functional impairment, and no mental diagnosis: HRV = Heart Rate Variability that measures parasympathetic drive How did the authors suggest the results be interpreted in the discussion section? Found strong inter-correlations between measures of psychosocial well-being with somatic symptoms, poor quality sleep, and reduced daily functioning High neuroticism and low conscientiousness: reduced well-being, somatic symptoms, quality of sleep Key role for sleep in well-being and functioning Modifiable health behaviors linked to well-being and sleep ○ Alcohol consumption, caffeine intake, and exercise Various key regulatory systems contribute to health and well-being Highlights necessity for greater research efforts to multifaceted aspects of well-being How are these results helpful to better understand topics discussed during lecture? Bidirectional mind and body Problem when bodies are not in homeostasis: ANS vital in maintaining homeostasis Importance of hypothalamus Complex interplay in biopsychosociology 1) What is the background for the experiment of discussion? ● Recent years it has become apparent that mental disorders among medical trainees and doctors are common and can be very disabling ● 195 studies from 47 countries showed that about 30% of respondents screened positive for a diagnosis of depression and/or anxiety and 11% reported suicidal thoughts ● Only 1 in 7 of the medical students who meet the criteria for depression will seek treatment 2) Why did the authors perform this study? ● Substantive gaps in current understanding of root causes, drivers, and consequences of ill health in this group ● Key limitation in literature is over-reliance on survey-based research provided by volunteers (problems such as sampling biases pop up and representativeness) ● Biological contributors to stress and diminished well-being has rarely been considered 3) If research article, what are the main results (without interpretation) n=270 approached, 151 participated (mean age 21.8) No significant impact of sex on results Health and lifestyle characteristics: ● Substantive portion reported poor sleep and problems with mental and/or physical health and functioning ● 23.3% (n=35) scored above threshold for sleep disturbances on PSQI ● 33.8% (n=51) had at least one psychiatric diagnosis based on MINI ● 33.8% (n=51) scored above threshold for fatigue on SPHERE-SOMA ● 17% (n=25) reported consumption of alcohol at hazardous levels ● 27.8% (n=42) reported impaired daily functioning 4) How did the authors suggest the results be interpreted in the discussion section? ● Found strong inter-correlations between measures of psychosocial well-being with somatic symptoms, poor quality sleep, and reduced daily functioning ● High neuroticism and low conscientiousness: ● Key role for sleep in well-being and functioning, ● More physiologically reactive students are at a greater risk of poor decision making ● Modifiable health behaviors linked to well-being and sleep ● Various key regulatory systems contribute to health and well-being ● Highlights necessity for greater research efforts to multifaceted aspects of well-being 5) Do you agree with the author’s interpretation? Expand on how diet and hydration play a role in well-being: 6) How are these results helpful to better understand topics discussed during lecture? ● Bidirectional mind and body ● Problem when bodies are not in homeostasis: ● ANS vital in maintaining homeostasis ● Importance of hypothalamus ● Complex interplay in biopsychosociology Presentation Outline Angel Gutierrez-Ramos & Serena Huang Background ● ● ● ● ● Vasopressin (antidiuretic hormone): promotes water reabsorption in the renal tubule of kidneys synthesised in the hypothalamus released into the circulation from the posterior pituitary gland Aquaporins: transmembrane channel proteins that create pores to move water across a cell's plasma membrane Vasopressin increases water permeability in the collecting duct (p) Purpose of Study ● Determine vasopressin’s mechanism of action, aquaporin regulation, and localization Results ● ● ● Fluorescence-based enzyme-linked immunosorbent assay (ELISA): highest expression of aquaporin-2 in the outer medullary collecting duct using the level of fluorescence obtained Immunogold Labeling: Within the collecting duct principal cells and inner medullary collecting duct cells, aquaporin-2 was abundant in both the apical plasma membrane and small intracellular vesicles. Effect of Vasopressin Infusion in Rats: Experiment carried out to test whether a 5-day infusion of vasopressin would affect permeability and aquaporin-2 expression ○ Brattleboro vasopressin-deficient rats infused with vasopressin for 5 days ○ Measured protein levels of aquaporin-2 in inner medulla, outer medulla, cortex Interpretation of Results ● Aquaporin-2 was redistributed from intracellular vesicles to the apical plasma membrane in response to vasopressin and was reversed when vasopressin was withdrawn. ● This suggests that the presence and absence of vasopressin drives the movement of aquaporin-2 from within the vesicles to be exocytosed onto the apical plasma membrane. ● water intake restriction in a vasopressin-independent environment is selective for water transport within inner medullary collecting duct tubules. ● Long-term vasopressin infusion demonstrated an increase an aquaporin-2 both non-glycosylated and glycosylated mRNA bands in all layers of the kidney nephron collecting duct Critique of Results ● ● ● No basis for comparison of control in ELISA and western blot experiments Lack of error bars and statistical significance No proven correlation between number of aquaporin/vasopressin expressions to recepor/channel expression Addition to Lecture ● ● Brain’s influence on water reasborption Osmoreceptors in vascular organ of lamina terminals (OVLT) detects plasma hyperosmolarity and inform magnocellular vasopressin-secreting cells in hypothalamic SON and PVN Autonomic and hypothalamic control of B-cell function: ● The autonomic nervous system innervates both the alpha and beta cells of the pancreas. The vagus nerve of the parasympathetic nervous system is depolarized by glucagon-like peptide-1 and activates the pancreas and its functions. The ventral hypothalamus in pancreatic function is critical for glucose-induced pancreatic glucagon secretion. Autonomic and hypothalamic control of blood pressure: ● Brain renin-angiotensin system and leptin are key players in central blood pressure regulation, primarily through sympathetic activation, with the hypothalamus playing a significant role. ● Activation of CVO’s, PVN, and rostral ventrolateral medulla (RVLM) is crucial in angiotensin-induced blood pressure elevation. Obesity-induced hypothalamic inflammation and autonomic dysfunction: ● Obesity and high-fat diets are correlated with hypothalamic inflammation. Increase of endoplasmic reticulum stress in the hypothalamus can cause an upregulation in sympathetic activity which can also increase renal and cardiovascular sympathetic activity. Glucose intolerance by hypothalamic inflammation and autonomic dysfunction: ● Hypothalamic inflammation is associated with diabetic symptoms, induced by short-term ER stress activating the NF-kB pathway ● Specific NF-kB inhibition in the hypothalamus can alleviate glucose intolerance caused by a high-fat diet or ER stress → hypothalamus’s vital role in glucose regulation and its connection to inflammation Insulin resistance and B-cell dysfunction by hypothalamic inflammation: ● Insulin resistance is when the body’s cells do not respond normally to insulin secretion. Excess lipids from a high fat diet showed activation of inflammatory pathways in the hypothalamus and insulin resistance as a consequence. Reactive oxygen species in the hypothalamus also activate inflammatory pathways causing hyperglycemia, hyperinsulinemia, and insulin resistance in mice. Beta cells in the pancreas are partially under autonomic function, so hypothalamic inflammation also causes a loss of insulin secretion. Hypothalamic inflammation links aging to diabetes development: ● Aging is associated with an increased prevalence of obesity, type 2 diabetes, and age-related conditions like Alzheimers and Parkinson’s diseases, with overlapping mechanisms suggesting potential shared treatments ● Animal studies demonstrate connections between diabetes and neurodegenerative disorders, such as Parkinson’s and Huntington’s disease → interplay between metabolic and age-related conditions Hypertensive effect by hypothalamic inflammation and autonomic dysfunction: ● Chronic activation of pro-inflammatory pathways is associated with obesity-induced hypertension. Recent studies have shown a relationship between the renin-angiotensin system and inflammation leading to hypertension. Increased angiotensin can increase cytokines in the hypothalamus which can elevate blood pressure through sympathetic nervous system activation. https://journals.physiology.org/doi/full/10.1152/ajpendo.00012.2016?rfr_dat=cr_pub++0pubmed &url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org Han C, Rice MW, Cai D. Neuroinflammatory and autonomic mechanisms in diabetes and hypertension. Am J Physiol Endocrinol Metab. 2016 Jul 1;311(1):E32-41. doi: 10.1152/ajpendo.00012.2016. Epub 2016 May 10. PMID: 27166279; PMCID: PMC4967151.