functional neuroanatomy and plasticity of the hypothalamic circuits regulating autonomic responses...
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Functional neuroanatomy and plasticity of the hypothalamic circuits
regulating autonomic responses to stress
Krisztina J. KovácsLaboratory of Molecular Neuroendocrinology
Institute of Experimental MedicineBudapest, Hungary
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ACUTE STRESS
Heart rate
Blood pressure
Muscle tension
Respiratory rate
Plasma glucose
Gastrointestinal actvity
HPASympato-medullar activitySympato-adrenal
Metabolic X syndrome
Mood swingsAnxietyDepressionConfusion / forgetfulnessBurnout
Eating disordersSleeping disordersSocial withdrawal / aggressionDrug 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
Hypophyseotropic Autonom projection
•Medial parvocellular dorsal•Periventricular
•Medial parvocellular ventral•Dorsal parvocellular•Lateral parvocellular
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BATBAT
HEARTHEART
SKINSKIN SUDOMOTORSUDOMOTOR
ADRENAL ADRENAL MEDULLAMEDULLA
VASCULAR VASCULAR TONETONE
AVPAVPOXYOXYCRHCRH
CRH & AVPCRH & AVP
AVP & OXYAVP & OXY
PVNPVN Brain stem & spinal cordBrain stem & spinal cord
HPA AXIS ACTIVATION
OSMOREGULATIONOSMOREGULATIONCARDIOVASCULAR REGULATIONCARDIOVASCULAR REGULATION
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Afferent connections of the hypothalamic PVN
“Blood borne”
Acustic
Nociceptive
Visceral
SomatosensoryVisual
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 OXYdorsal vagal complex - predominantly AVP
Express ER-beta, MC4R, IRS-2 etc
Physiological evidences for mediation of sympatoexcitation...
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FUNCTIONAL PLASTICITY OF HYPOTHALAMICAUTONOMIC-RELATED NEURONS
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Laugero et al, Endocrinology, 2001
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+ sucrose
+ / - sucrose
1. wk 2. wk 3.wk 4.wk 5. wk
Record body weight, fluid and foodconsumption
Blood samplingperfusion
ADX / SHAM
adaptation
Adult male Wistar rats1M sucrose, 0.5% NaCl, water
6. wk
CRH mRNA in situAVP 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 BATDouble-virus infection
WAT BAT
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PRV injections
Ba-Dup-Lac (red)- iWAT Ba-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
Magno Auton.related
BNST Amygdala
A5
Parabrachial
PREGANGLIONIC NEURONS
IML DVC
PITUITARY
AP PP
ADRENAL
CORTEX MEDULLA
ACTHVP, OXY
CRH, VP
AUTONOMICENDOCRINE BEHAVIORAL
OXY, VP, CRHDYN, ENK