Hypothalamus & Pituitary Goals o Functional and anatomic relationships o Regulation - Hypothalamic releasing & inhibiting factors o Transport

t of hypothalamic neuropeptides o Oxytocin & vasopressin 2 hormones released from posterior pituitary Physiologic target organ responses Cellular mechanisms of action o From each class know hormone: organs, function, problems related deficiency/excess of hormone Hypothalamus o Are of the brain that is forming the lateral walls and floor of III ventricle o Several nuclei are not distinct, very difficult to say that neurons in one nucleus will always perform a specific function Dont need to memorize nuclei Know that based on anatomical demarcation you can group bodies of neurons Might mention a few that you should remember supraoptic or suprachiasmatic nuclei Ultimate Integrator - receives & mediates multiple signals o Receives signals from multiple brain brains and from the periphery o If we have change in blood glucose or pH or plasma osmolarity, hypothalamus can sense it o Inputs Thalamus awareness Limbic system pleasure (sex, drug use) Reticular activating substance arousal (fear or risk potential, sexual) Sensory temperature, light Visceral pain (GI, heart, etc) Hormonal TH, cortisol Substrates glucose Hypothalamic Functions in Regulation o Pituitary function most important function Posterior pituitary Water balance Parturition delivery of baby Lactation Anterior Pituitary Metabolism energy utilization and reserve Growth & development Reproduction Lactation Response to stress o Autonomic processes sympathetic or parasympathetic
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o Behavioral processes o Rhythmic events Mechanisms of Action o DIRECT Peptides made in neurons of hypothalamus and released into the posterior pituitary ADH, OT o INDIRECT Release of peptide at level of median eminence (connecting hypothalamus to pituitary) delivery to anterior pituitary to stimulate production and release of other pituitary hormones Prolactin, GH, TSH, LS, FSH, CRH 2 pathways of hypothalamic Control o Magnocellular neurons (large body neurons) Neurohypophysial axonal transport posterior pituitary (OT, ACP, NP) systemic circulation Endocrine function o Parvocellular neurons Hypophysial axonal transport Median eminence (CRH, TRH, LHRH, GHRH.. Anterior pituitary Hypophysiotropic Hormones Anterior pituitary hormone o TRH (thyrotropin releasing) TSH & PRL o LHRH (luteinizing hormone releasing) LH & FSH o CRH ACTH o GHRH GH o Somatostatin inhibits GH release Somatostatin always inhibits no matter the hormone o Dopamine PRL Oscillating patterns of hormone release o SCN of hypothalamus Knows when you are away or asleep CNS pulse generator Perceives changes Light vs. dark Wake vs. sleep ACTH Cortisol GHRH GH (most at night) o Pulsatility The receptor for any given hormone has time to recover between hormone delivery Sustained levels of hormone will inhibit receptors response will not be appropriate Plays important role in response to hormone Makes diagnosis difficult o Photo-neuro-endocrine System Circadian pattern of hormone release
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 Retina hypothalamic SCN suprachiasmatic nucleus (endogenous circadian oscillator) pineal gland melatonin Melatonin feedback to SCN to maintain oscillatory pattern of hormone release o Patient Care alterations in hypothalamic Night shift workers much higher rate of cardiovascular risk disorders ICU patients in light all the time Aging lose ability to maintain circadian rhythm, lost hormonal effects Travel overseas if frequent, hormone alterations/pattern release will be affected Posterior Pituitary/Neuroectoderm o Brain tissue in floor of III ventricle elongation of hypothalamus o Releases hormones made at level of hypothalamus o Hormones released Oxytocin parturtition & lactation Vasopressin or ADH water balance o Supraoptic & paraventricular nuclei projections Magnocellular to posterior pituitary (MOST) Parvocellular to other brain regions (some) Median eminence, brain stem & spinal cord, limbic & olfactory stress Oxytocin & Vasopressin = peptide hormones o Synthesized and modified (post-transcriptional) o Packages in neurosecretory vesicles that travel down long axon o Further modification occurs as they travel release or production of neurophysinssmall peptides that use to be part of the pre-pro hormone molecule No specific role if an individual has an impairment in processing of this peptide and neurophysins are absent, they never make it to the terminal of the axon Chaperones guide the vesicles to the axon terminal o Arginine Vasopressin (AVP) vasopressin with arginine on it, same as ADH Oxytocin o Targets Lactating breast stimulates milk ejection Term-pregnant uterus contraction CNS establishing maternal behavior o Stimuli Stretch of cervix at end of pregnancy Sucking of lactating breast o Effects Uterine contraction (Smooth muscle) Contraction of myoepithelial cells (lactating breast) o Inhibition Fear, pain, noise, fever o Mechanism of Action Peptide hormone so binds to membrane receptor (GPCRq)
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 Gq PLC IP3 & DAG IP3 Ca2+ release from ER Ca-CM activation MLCK activation Phosphorylation of myosin light chain increases smooth muscle contraction Oxytocin receptor is only one of the multiple receptors in uterine smooth muscle o With elevation in estrogen and progesterone (as seen in pregnancy) changes sensitivity to oxytocin, less hormone needed for effects Increases density of oxytocin receptor Increased gap junctions in smooth muscle cells Increase in prostaglandin synthesis increases contractility of smooth muscle Arginine Vasopressin (AVP) = Antidiuretic Hormone (ADH) o Targets Collectin duct in kidney conserves water Vasculature vasoconstriction o Receptors - GPCRs V1 smooth muscle (Gq) Increases Ca2+ smooth muscle contraction V2 kidney (Gs) Increases cAMP PKA phosphorylation V3 brain o Low circulating basal concentration ~ 1 pg/mL o Mechanism in Collecting Duct AVP in blood collecting duct of kidney binds to V2 AC activated inceases cAMP PKA AQP2 (aquaporin 2) phosphorylated Phosphorylated ADP2 is inserted into the collecting duct membrane Allows water traveling in collecting duct to be reabsorbed by the cell Water is transport into extracellular space via AQP3 or AQP3 Aquaporins 1 - apical & basolateral membrane (ubiquitous) of epithelial cells proximal tubule (90% filtered H2O reabsorbed in the proximal tubule) 2 exclusively expressed in collecting ducts, regulated by ADH 3 & 4 on basolateral membrane of collecting duct, contribute to increasH2O reabsorption, H2O enters epithelial cells via AQP1 on apical membrane and leaves cells via ADP 3 & 4 Water Reabsorption ONLY 10% of filtered H2O reabsorbed in the distal collecting ducts Tight regulation by ADH Increase urine osmolarity 40fold (12000 mOsm/kg) If AVP is responsible for 10% of water reabsorption and we filter out 180 L/day we would make 18 L/day in urine o Mechanism in Vasculature AVP in blood GPCRq PLC sER release of Ca2+ Ca-CM turns on MLCK phosphorylation of MLCK smooth muscle contraction o Control AVP release 2 ways (osmolarity and MABP)
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 Water deprivation/diarrhea/dehydration = increase plasma osmolarity hypothalamic osmoreceptor (shrinks in response to high osmolarity) ADH release kidney Very sensitive system we increase ADH even before we get thirsty so that the threshold for ADH release is much lower than that for water consumption Dropping MAPB baroceptor decrease IX & X afferents SNS tone increases increases AVP release Need at least 5-10% in blood volume Not as sensitive but increases sensitivity of osmolarity effects Increases H2O and BP via H2O reabsorption and vasoconstriction o ADH abnormalities SIADH Syndrome of Inappropriate ADH Secretion Manifestations o Most frequent cause of hyponatremia o Low volume of concentrated urine Etiology drug side effects, tumors, CNS disorders First described in patients with bronchogenic carcinoma (lung) Physiologic stimulus for ADH release The level of secretion of the ADH was deemed inappropriate