Transcript Adult male Wistar rats 1M sucrose, 0.5% NaCl, water

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
ACUTE STRESS
Heart rate
Blood pressure
Respiratory rate
Muscle tension
Plasma glucose
Gastrointestinal actvity
HPA
Sympato-medullar activity
Sympato-adrenal
CHRONIC or UNRESOLVED
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
Magnocellular part
Hypophyseotropic
•Medial parvocellular dorsal
•Periventricular
Parvocellular part
Autonom projection
•Medial parvocellular ventral
•Dorsal parvocellular
•Lateral parvocellular
Brain stem & spinal cord
PVN
AVP
OXY
CRH
BAT
HEART
SKIN
SUDOMOTOR
CRH & AVP
HPA AXIS ACTIVATION
AVP & OXY
OSMOREGULATION
CARDIOVASCULAR REGULATION
ADRENAL
MEDULLA
VASCULAR
TONE
Afferent connections of the hypothalamic PVN
“Blood borne”
Nociceptive
Visual
Somatosensory
Visceral
Corticosterone
Acustic
Challenge-induced Activation of PVN Neurons
c-Fos-ir 90 min after stress*
Kovács et al, 2005
Colocalization of neuropeptides in the hypothalamic PVN
PARVOCELLULAR
MAGNOCELLULAR
VASOPRESSIN
OXYTOCIN
CRH
?
Dynorphin
CRH
Vasopressin
Oxytocin
Angiotensin II
CCK
Angiotensin II
CRH
Enkephalin
Enkephalin
CCK
Vasopressin
Dopamine
TRH
Galanin
VIP/PHI
Enkephalin
Neurotensin
Galanin
VIP/PHI
Somatostatin
Dynorphin
Enkephaline
Functional plasticity in the PVN - adrenalectomy
Control
Adrenalectomy
ADX + DEX/PVN
Vasopressin potentiates CRH action at the corticotropes
Rivier et al, 1984
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 ANSspinal 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
Laugero et al, Endocrinology, 2001
+ sucrose
+ / - sucrose
adaptation
1. wk
2. wk
3.wk
4.wk
5. wk
6. wk
ADX / SHAM
Record body weight,
fluid and food
consumption
Blood sampling
perfusion
CRH mRNA in situ
AVP mRNA in situ
Adult male Wistar rats
1M 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
How to study complex autonomic circuits ?
Trans synaptic tracing using
pseudorabies virus
(PRV)
Trans-synaptic spread)
PRV: pseudorabies virus, Bartha strain
“self-amplifying transsynaptic tracer”.
Virus-infected neurons in the PVN following inoculation into the kidney
Virus-infected neurons in the dorsal parvocellular subdivision
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
1. Spinal cord,
intermediolateral cell column
Comparison of autonomic innervation of WAT and BAT
Double-virus infection
WAT
BAT
PRV injections
Ba-Dup-Lac (red)- iWAT
Ba-Dup-Green- BAT
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
CORTEX
LIMBIC CORTEX
PVN
Medial
parvo
Magno
PITUITARY
PP
Amygdala
Auton.
related
OXY, VP, CRH
DYN, ENK
CRH, VP
AP
BNST
Parabrachial
A5
PREGANGLIONIC
NEURONS
VP, OXY
ACTH
IML
DVC
ADRENAL
CORTEX
MEDULLA
ENDOCRINE
AUTONOMIC
BEHAVIORAL