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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. CHRONIC or UNRESOLVED. HPA Sympato-medullar activity

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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


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


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


PARAVENTRICULAR NUCLEUS

Parvocellular part

Magnocellular part

Hypophyseotropic

Autonom projection

  • Medial parvocellular dorsal

  • Periventricular

  • Medial parvocellular ventral

  • Dorsal parvocellular

  • Lateral parvocellular


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


Nociceptive

“Blood borne”

Somatosensory

Visual

Visceral

Acustic

Corticosterone

Afferent connections of the hypothalamic PVN


Challenge-induced Activation of PVN Neurons

Kovács et al, 2005

c-Fos-ir 90 min after stress*


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


Functional plasticity in the PVN - adrenalectomy

Control

Adrenalectomy

ADX + DEX/PVN



ETHER STRESS-INDUCED VASOPRESSIN TRANSCRIPTION

IN THE PARAVENTRICULAR NUCLEUS


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...


FUNCTIONAL PLASTICITY OF HYPOTHALAMIC

AUTONOMIC-RELATED NEURONS



+ 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


Sucrose ingestion results in neuronal activation

in neuroendocrine and autonomic-related neurons


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



Trans synaptic tracing using

pseudorabies virus

(PRV)

Trans-synaptic spread)

PRV: pseudorabies virus, Bartha strain

“self-amplifying transsynaptic tracer”.




PRV-ir ne subdivisionurons 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


Comparison of autonomic innervation of WAT and BAT subdivision

Double-virus infection

WAT

BAT


PRV injections subdivision

Ba-Dup-Lac (red)- iWAT

Ba-Dup-Green- BAT


Outline of the brain circuit that provides subdivision

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


PITUITARY subdivision

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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