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Functional neuroanatomy and plasticity of the hypothalamic circuits regulating autonomic responses to stress Krisztina J. Kovács Laboratory of Molecular Neuroendocrinology Institute of Experimental Medicine Budapest, Hungary
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ACUTE STRESS Heart rate Blood pressure Muscle tension Respiratory rate Plasma glucose Gastrointestinal actvity HPA Sympato-medullar activity Sympato-adrenal Metabolic X syndrome Mood swings Anxiety Depression Confusion / forgetfulness Burnout Eating disorders Sleeping disorders Social withdrawal / aggression Drug abuse CHRONIC or UNRESOLVED
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Selye explains STRESS – induced activation of HPA axis Nature, July 4, 1936. A Syndrome produced by Diverse Nocuous Agents “…. a typical response appears, the symptoms of which are independent of the nature of the damaging agent… and represent rather a response to damage as such” H. Selye
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PARAVENTRICULAR NUCLEUS Magnocellular part Parvocellular part HypophyseotropicAutonom projection Medial parvocellular dorsal Periventricular Medial parvocellular ventral Dorsal parvocellular Lateral parvocellular
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BAT HEART SKIN SUDOMOTOR ADRENAL MEDULLA VASCULAR TONE AVPOXYCRH CRH & AVP AVP & OXY PVN Brain stem & spinal cord HPA AXIS ACTIVATION OSMOREGULATION CARDIOVASCULAR REGULATION
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Afferent connections of the hypothalamic PVN “Blood borne” Acustic Nociceptive Visceral Somatosensory Visual Corticosterone
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Challenge-induced Activation of PVN Neurons c-Fos-ir 90 min after stress* Kovács et al, 2005
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MAGNOCELLULAR PARVOCELLULAR CRHVASOPRESSIN Dynorphin Angiotensin II Enkephalin Dopamine Galanin VIP/PHI OXYTOCIN CRH CCK Enkephalin TRH Enkephalin CCK Angiotensin II Neurotensin Galanin VIP/PHI Vasopressin Colocalization of neuropeptides in the hypothalamic PVN ? Oxytocin CRH Vasopressin Somatostatin Dynorphin Enkephaline
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Functional plasticity in the PVN - adrenalectomy Control Adrenalectomy ADX + DEX/PVN
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Vasopressin potentiates CRH action at the corticotropes Rivier et al, 1984
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ETHER STRESS-INDUCED VASOPRESSIN TRANSCRIPTION IN THE PARAVENTRICULAR NUCLEUS
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Autonomic projection neurons in the PVN Approx. 1500 neurons in 3 different parvocellular subdivisions: (dorsal-, ventral aspect of medial parvocellular- and lateral-) Neurochemical specificity of these neurons is less known: (Oxytocin, vasopressin, corticotropin-releasing hormone, somatostatin, dynorphin, enkephalin, dopamine…..) Efferent connections: to medullar and spinal preganglionic cells for both divisions (sympathetic and parasympathetic) of the ANS- spinal cord (intermediolateral cell column) - predominantly OXY dorsal vagal complex - predominantly AVP Express ER-beta, MC4R, IRS-2 etc Physiological evidences for mediation of sympatoexcitation...
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FUNCTIONAL PLASTICITY OF HYPOTHALAMIC AUTONOMIC-RELATED NEURONS
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Laugero et al, Endocrinology, 2001
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+ sucrose + / - sucrose 1. wk 2. wk3.wk4.wk5. wk Record body weight, fluid and food consumption Blood sampling perfusion ADX / SHAM adaptation Adult male Wistar rats 1M sucrose, 0.5% NaCl, water 6. wk CRH mRNA in situ AVP mRNA in situ
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Sucrose ingestion results in neuronal activation in neuroendocrine and autonomic-related neurons
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Hypothalamus coordinates autonomic responses in part through AVP, released in NTS. AVP inhibits afferent synaptic transmission in the NTS: 1. By decreasing glutamate release probability (V1a receptor) 2. By inducing synaptic failures and increased conduction times
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How to study complex autonomic circuits ?
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Trans synaptic tracing using pseudorabies virus (PRV) PRV: pseudorabies virus, Bartha strain “self-amplifying transsynaptic tracer”. Trans-synaptic spread)
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Virus-infected neurons in the PVN following inoculation into the kidney
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Virus-infected neurons in the dorsal parvocellular subdivision
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PRV-ir neurons after virus inoculation into a peripheral target 1.Spinal cord, intermediolateral cell column 2. Rostral ventrolateral medulla 3. A5 noradrenergic cell group 4. Hypothalamus, PVN 5. Insular cortex
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Comparison of autonomic innervation of WAT and BAT Double-virus infection WAT BAT
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PRV injections Ba-Dup-Lac (red)- iWATBa-Dup-Green- BAT
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Outline of the brain circuit that provides sympathetic innervation of different target tissues Target organ Five cell groups in the brain appear to regulate the entire sympathetic outflow: the paraventricular hypothalamic nucleus (PVH), A5 noradrenergic cell group, caudal raphe region, rostral ventrolateral medulla, and ventromedial medulla.
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CORTEX LIMBIC CORTEX PVN Medial parvo MagnoAuton. related BNSTAmygdala A5 Parabrachial PREGANGLIONIC NEURONS IMLDVC PITUITARY APPP ADRENAL CORTEXMEDULLA ACTH VP, OXY CRH, VP AUTONOMICENDOCRINEBEHAVIORAL OXY, VP, CRH DYN, ENK
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