Neuroendocrine Control I PDF

• Lecture 11: Neuroendocrine Control I • The brain-pituitary-gonadal axis • Stress – adrenal axis • C144/244 • F. Gomez-Pinilla, IBP, UCLA c144/244; F. Gomez-Pinilla, UCLA Hypothalamus-pituitary- gland axis c144/244; F. Gomez-Pinilla, UCLA c144/244; F. Gomez-Pinilla, UCLA c144/244; F. Gomez-...

• Lecture 11: Neuroendocrine Control I • The brain-pituitary-gonadal axis • Stress – adrenal axis • C144/244 • F. Gomez-Pinilla, IBP, UCLA c144/244; F. Gomez-Pinilla, UCLA Hypothalamus-pituitary- gland axis c144/244; F. Gomez-Pinilla, UCLA c144/244; F. Gomez-Pinilla, UCLA c144/244; F. Gomez-Pinilla, UCLA Hypothalamus-pituitary-gonad axis • Gonadotropin releasing hormone (GnRH) produced by hypothalamic neurons stimulate production of gonadotropins from ant. pituitary gonadotropes: • Luteinizing hormone (LH) • Follicle-stimulating hormone (FSH) • Activity of the axis varies during lifespan c144/244; F. Gomez-Pinilla, UCLA Hypogonadal (hpg) mice is an animal model to study the Kallmann’s Syndrome - genetic defect in GnRH production, but gonadal function can be restored in both sexes with pusatile GnRH. c144/244; F. Gomez-Pinilla, UCLA c144/244; F. Gomez-Pinilla, UCLA c144/244; F. Gomez-Pinilla, UCLA c144/244; F. Gomez-Pinilla, UCLA Circadian control of reproduction • • • • Season is main factor in controlling reproduction in most mammal Day length determines melatonin production Melatonin production controls seasonal reproduction ablation of SCN disrupts estrus cycle by affecting release of GnRH from hypoth/pituitary • Melatonin affects the function and size of gonads c144/244; F. Gomez-Pinilla, UCLA Photoperiodicity regulates melatonin synthesis c144/244; F. Gomez-Pinilla, UCLA Pulsatile stimulation of pituitary gonadotropes is crucial to maintain normal LH/FSH secretion: • Exposure of pituitary to continuous GnRH leads to downregulation of GnRH receptors • Importance of a physiological frequency of GnRH pulses that varies across age and circumstances • narrow window of acceptable frequencies to stimulate GnRH without downregulation c144/244; F. Gomez-Pinilla, UCLA c144/244; F. Gomez-Pinilla, UCLA Feedback control of GnRH release • Hypothalamic level; feedback regulation decreases pulse frequency of GnRH and LH • Effects can be direct on GnRH neurons or indirect via brain regions that project onto GnRH neurons using (GABA, catecholamines) or endorphins (opiates). • Pituitary, Feedback (-) by estradiol and testosterone decrease LH pulses by reducing sensitivity to GnRH • Inhibin is a glycoprotein produced by gonads that acts at the pituitary to suppress FSH release • Ovarectomy (OVX) decreases synaptic input on GnRH neurons c144/244; F. Gomez-Pinilla, UCLA Brain control of GnRH release • • • • GnRH neurons receive connections from various brain regions within and outside the hypothalamus GnRH neurons receive cues regarding nutrition status, exercise, thermogenesis, stress, social cues to coordinate reproduction timing Just a small subset of GnRH neurons is necessary for normal function of the axis. You can delete most of neurons and still have normal pulsatile secretion of GnRH. The system is redundant, presumably to preserve reproduction and protect species from going extinct. Although most GnRH neurosecretory cells project to the median eminence -- at least 20% of GnRH neurons send axons to other hypothalamic regions, perhaps playing a role as a neurotransmitter or in reproductive behaviors. c144/244; F. Gomez-Pinilla, UCLA Factors causing alterations in ovarian function • Menopause: depletion of ovarian follicles -- loss of estrogen production releases feedback (-) on hypoth (high LH/FSH). Tissue damage (osteoporosis, cardiovascular disease) • Circadian, diurnal rhythms - testosterone (night), LH (day) • Environmental polymodal hypothalamic input, such as: • Seasonal, environmental adaptation signaled by day length • Nutritional factors, undernutrition can disrupt ovarian cycle or spermatogenesis. • Extraneous exercise can disrupt ovarian cycle • Chronic stress acting at hypothalamic and pituitary levels can suppress pulsatile release of GnRH and LH c144/244; F. Gomez-Pinilla, UCLA Stress and loss of homeostasis Hans Selye (1907-1982) Coined a word from Physics STRESS to describe the non-specific response of body to any demand Neural Control of Physiological Systems (C144/244) •STRESS: Adaptive response to noxious stimuli, e.g., disease, fever, psychological Fight or Flight Reaction • • • • • • • Short latency response Heart acceleration Increase in blood pressure Dilation of blood vessels in skeletal muscle Constriction of blood vessels in GI tract and skin Pupil dilation Sweating Factors affecting stress response • • • • • • • Food deprivation Sleep deprivation Emotions Exercise Heat or Fever Cold or hypothermia Anesthetics Neural Control of Physiological Systems (C144/244) Hypothalamus-pituitary-adrenal axis • • Medial parvicellular part of PVN releases corticotropin-releasing hormone to portal vessels to stimulate release of adrenocorticotropic hormone (ACTH) from anterior lobe cells. ACTH stimulates the adrenal cortex to secrete glucocorticoids Corticotropes in anterior Pituitary express receptors for CRH and AVP, and release ACTH ACTH reaches the adrenal cortex and stimulates synthesis and release of glucocorticoids Adrenal gland Releases Stress Mediators Adrenal cortex: Glucocorticoids such as cortisol in humans (corticosterone in rodents, glucose metabolism) Mineralocorticoids such as aldosterone (renin-angiotensin system) regulate sodium and potassium balance. Adrenal medulla (innervated by SNS): innermost part of adrenal gland, releases catecholamines to blood (epinephrine and norepinephrine) and can potentiate the stress response. Glucocorticoid (cortisol/corticosterone) functions • • • • • • • Acts in coordination with the ANS to mobilize energy and prepare the body for defense Cardiovascular system (elevates heart rate and blood pressure) Mobilize energy: Enhances breakdown of glycogen (glycogenolysis), allows glycogen utilization in liver, lungs, and adrenal medulla. Enhances synthesis of glucose from precursors (gluconeogenesis) Decreases uptake of glucose by secondary tissues Modulate immune function by regulating cytokine production and inflammatory response Interact with hormones of other systems: thyroid, growth, reproduction Neural Control of Physiological Systems (C144/244) Feedback inhibition of the CRH axis by corticosteroids • Can occur at multiple levels to turn off stress response: – Hypothalamic (inhibits CRH) – pituitary (inhibits ACTH) – Adrenal (local inhibition) – fast regulation by ACTH secretion (minutes to shut off stress axis) feedback regulation of stress • • • Negative feedback of glucocorticoids on the axis: Adrenal ablation (ADX) increases CRH and AVP in mpPVN Hippocampal lesion increases levels of glucocorticoids • Glucocorticoids activates neurons with steroid receptors (GR, MR) in PVN neurons. GR are throughout the brain -- what are the implications for the action/regulation of stress? • Mineralocorticoid receptor (MR) and glucocorticoid (GR) recognize cortisol, and are highly expressed in the hippocampus (Sapolsky, McEwen). Neural Control of Physiological Systems (C144/244) Receptors mediating stress are almost everywhere -IMPLICATIONS?? • • • CRH receptors found in brain (primarily cerebellum, cerebral cortex, olfactory bulb, striatum, spinal cord, hippocampus, hypothalamus, thalamus, pons) and outside the brain (adrenal gland, placenta, ovaries, immune tissues) Glucocorticoid receptors (GR) are widespread in the CNS, most abundant in hippocampus and hypothalamus, in addition to cerebral cortex, amygdala, septum, thalamus, midbrain, raphe nuclei, cerebellum, brain stem. ACTH receptor derives proopiomelanocortin (POMC). It is primarily expressed in the adrenal cortex. This conversion is an important site for stress regulation such as beta-endorphin. Neural Control of Physiological Systems (C144/244) Rhythmic activity of brain-pituitary adrenal axis 7 am ACTH 7 pm 12 glucocorticoids CRH most sensitive to stress Timing Context Stress hormones exhibit both pulsatile and circadian cycles Glucocorticoids levels are highest by awakening and lowest by end of the day (different patterns depending on if nocturnal or not). The system is more sensitive to stress during resting CRH expression in PVN is regulated by the suprachiamatic nucleus (SCN) and food intake. Stress interacts with learning and memory Most of our learning is emotional!! • • • • • • • Abundance of GR and MR in hippocampus Learning is motivated by stressful or aversive stimuli such as attention and arousal. ACTH injection before or shortly after a learning situation enhances memory Acute stress (inescapable) interferes with instrumental learning. Gain of control reverses effect and may enhance learning Reduced learning capacity in aging has been associated to chronic stress (too much glucocorticoids)? “Stress system is an active monitoring system that constantly compares current events to past experiences, interprets their relevance for survival, determines ability to cope with new events, and recruits physiological mechanisms as needed” Stress not just an alarm system!! 11/15/2010 Neural Control of Physiological Systems (C144/244) Too much or too little glucocorticoids can damage the brain • • • • • • Chronic excess of glucocorticoid can damage hippocampal CA3 cells; however: Lack of glucocorticoids may damage hippocampal dentate gyrus cells. Circulating corticosteroids affect fetal development. Early development of the brain-pituitary adrenal axis. Prenatal stress produces physical and behavioral alterations Neonatal stress (maternal separation) affects adult behavior and brain plasticity. Adrenal dysregulation by reduction of MR and GR in hippocampus in aging reduces feedback. High levels of glucocorticoids due to reduced feedback can deteriorate hippocampal neurons -- spatial memory problems Neural Control of Physiological Systems (C144/244) Health consequences of disruptions in stress homeostasis Hyper-activation • Alzheimer’s: loss of neurons involved in feedback as well as adrenal dysfunction • Mental Illness: anxiety and depression • Inflammation • Susceptibility to infection, tumors, autoimmune disease • Insulin-resistant diabetes (commonly associated with hypercortisolism) • Hypo-activation (under-activity): increased susceptibility to autoimmune disease and inflammation Neural Control of Physiological Systems (C144/244) Addison’s disease: under activity of stress axis. Low glucocorticoids. fatigue, muscle weakness, psychological Cushing’s Disease: oversecretion of cortisol. High level of cortisol suppress release of CRH. immune compromise, increase in appetite, type II diabetes risk, high blood pressure and changes in fat distribution Development of adrenal gland • • • • Adrenal gland develops 20-25 days of age Ant Pituitary activity starts 7-8 weeks CRH 16th week. Diurnal rhythm Not established until 6 months postnatal, although HPA axis matures early • Babies are highly susceptible to stress Neural Control of Physiological Systems (C144/244) Impact of cortisol during pregnancy • • • Cortisol levels are high during pregnancy and (during parturition ) and play an important role in developing of the fetus Steroids easily cross placenta Pregnant women under high stress have higher incidence of babies with physical, developmental and behavioral problems (underweight, eczema, bronchitis, delay in walking or talking) Neural Control of Physiological Systems (C144/244) Stress good or bad? “Stress system is an active monitoring system that determines ability to cope with new events, and recruits physiological mechanisms as needed” • It seems that some stress may be good: helps insulin signaling, and release of glucose to produce energy (ATP) • Experiments in animals have shown that mild postnatal stress makes animal less anxious when they become adult • In general, mild stress is an important stimulus to enhance brain plasticity and health (what does not kill you can make you stronger) Neural Control of Physiological Systems (C144/244)