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Functional neuroanatomy and plasticity of the hypothalamic circuits

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. CHRONIC or UNRESOLVED. HPA Sympato-medullar activity

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Functional neuroanatomy and plasticity of the hypothalamic circuits

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  1. 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

  2. CHRONIC or UNRESOLVED HPA Sympato-medullar activity Sympato-adrenal Heart rate Blood pressure Respiratory rate Muscle tension Plasma glucose Gastrointestinal actvity ACUTE STRESS Metabolic X syndrome Mood swings Anxiety Depression Confusion / forgetfulness Burnout Eating disorders Sleeping disorders Social withdrawal / aggression Drug abuse

  3. 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

  4. PARAVENTRICULAR NUCLEUS Parvocellular part Magnocellular part Hypophyseotropic Autonom projection • Medial parvocellular dorsal • Periventricular • Medial parvocellular ventral • Dorsal parvocellular • Lateral parvocellular

  5. PVN Brain stem & spinal cord BAT AVP OXY CRH HEART SKINSUDOMOTOR ADRENAL MEDULLA CRH & AVP HPA AXIS ACTIVATION VASCULAR TONE AVP & OXY OSMOREGULATION CARDIOVASCULAR REGULATION

  6. Nociceptive “Blood borne” Somatosensory Visual Visceral Acustic Corticosterone Afferent connections of the hypothalamic PVN

  7. Challenge-induced Activation of PVN Neurons Kovács et al, 2005 c-Fos-ir 90 min after stress*

  8. Dynorphin CRH Angiotensin II CCK Angiotensin II Enkephalin Enkephalin CCK Dopamine TRH Enkephalin Galanin Neurotensin Galanin VIP/PHI VIP/PHI Colocalization of neuropeptides in the hypothalamic PVN PARVOCELLULAR MAGNOCELLULAR VASOPRESSIN OXYTOCIN CRH ? Oxytocin CRH Vasopressin Somatostatin Dynorphin Enkephaline Vasopressin

  9. Functional plasticity in the PVN - adrenalectomy Control Adrenalectomy ADX + DEX/PVN

  10. Vasopressin potentiates CRH action at the corticotropes Rivier et al, 1984

  11. ETHER STRESS-INDUCED VASOPRESSIN TRANSCRIPTION IN THE PARAVENTRICULAR NUCLEUS

  12. 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...

  13. FUNCTIONAL PLASTICITY OF HYPOTHALAMIC AUTONOMIC-RELATED NEURONS

  14. Laugero et al, Endocrinology, 2001

  15. + sucrose + / - sucrose ADX / SHAM Record body weight, fluid and food consumption Blood sampling perfusion adaptation 1. wk 2. wk 3.wk 4.wk 5. wk 6. wk CRH mRNA in situ AVP mRNA in situ Adult male Wistar rats1M sucrose, 0.5% NaCl, water

  16. Sucrose ingestion results in neuronal activation in neuroendocrine and autonomic-related neurons

  17. 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

  18. How to study complex autonomic circuits ?

  19. Trans synaptic tracing using pseudorabies virus (PRV) Trans-synaptic spread) PRV: pseudorabies virus, Bartha strain “self-amplifying transsynaptic tracer”.

  20. Virus-infected neurons in the PVN following inoculation into the kidney

  21. Virus-infected neurons in the dorsal parvocellular subdivision

  22. PRV-ir neurons after virus inoculation into a peripheral target 5. Insular cortex 4. Hypothalamus, PVN 3. A5 noradrenergic cell group 2. Rostral ventrolateral medulla • Spinal cord, • intermediolateral cell column

  23. Comparison of autonomic innervation of WAT and BAT Double-virus infection WAT BAT

  24. PRV injections Ba-Dup-Lac (red)- iWAT Ba-Dup-Green- BAT

  25. Outline of the brain circuit that provides sympathetic innervation of different target tissues 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. Target organ

  26. PITUITARY AP PP PREGANGLIONIC NEURONS IML DVC CORTEX LIMBIC CORTEX PVN BNST Amygdala Medial parvo Magno Auton. related OXY, VP, CRH DYN, ENK CRH, VP Parabrachial A5 VP, OXY ACTH ADRENAL CORTEX MEDULLA ENDOCRINE AUTONOMIC BEHAVIORAL

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