Radley, J. J. et al. J. Neurosci. 2006;26:12967-12976 Regional Differentiation of the Medial Prefrontal Cortex in Regulating Adaptive Responses to Acute Emotional Stress Radley, Arias, Sawchenko Salk Institute, La Jolla California Journal of Neuroscience 2006
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Radley, J. J. et al. J. Neurosci. 2006;26:12967-12976
Regional Differentiation of the Medial Prefrontal Cortex in Regulating Adaptive Responses to Acute Emotional Stress. Radley , Arias, Sawchenko Salk Institute, La Jolla California Journal of Neuroscience 2006. Radley, J. J. et al. J. Neurosci. 2006;26:12967-12976. Sawchenko?. Intro. mPFC: - PowerPoint PPT Presentation
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Radley, J. J. et al. J. Neurosci. 2006;26:12967-12976
Regional Differentiation of the Medial Prefrontal Cortex in Regulating Adaptive
Responses to Acute Emotional Stress
Radley, Arias, SawchenkoSalk Institute, La Jolla CaliforniaJournal of Neuroscience 2006
• Influence on HPA axis• Autonomic (sympathoadrenal)
Intro
• HPA (hypothalamic-pituitary-adrenal) axis– Paraventricular nucleus (PVN or PVH)
• CRF neurosecretory neurons – ACTH release from anterior Pituitary– Corticosterone from adrenal cortex
• Projections to CNS cell groups involved in autonomic– Sympathetic preganglionic neurons (ACh release)– Stimulates adrenaline and noradrenalin from adrenal medulla
Intro.
Regional specialization?
• mPFC lesion = inhibitory control of HPA – Lesions mainly dorsal; prelimbic (PL) (as opposed
to infralimbic IL)– Large lesions may alter basal, but not stress
induced HPA response in rats– IL may preferentially modulate autonomic– Suggestions that PL and IL differ in both nature of
influence and underlying circuitry
Schematic of mPFC regions
• Current study compares:– Dorsal vs. ventral (mPFCd vs mPFCv) lesions– Acute restraint stress
• To measure extent of stress induced Fos immunoreactivity– Fast blue crystals into rostral ventrolateral
medulla to be transported by axons of passage to provide maximal labeling of PVH pre-autonomic cell groups projecting to both dorsal vagal complex and preganglionic neurons in spinal cord
– Fast blue fluid in T1-T2 level of spinal cord – Tracer injected during lesion surgery – Dual IR for fos and fast blue
CRF mRNA
• In situ hybridization • Probe built for CRF identification • Allows visualization of mRNA in very small
amounts, localized to individual cells (as little as 10-20 mRNA copies per cell)
Hormone assays
• In-dwelling jugular catheters implanted 2d before stress exposure (12 d following surgery)– Blood samples collected before stress and again
immediately following stress and 30, 60 and 90 mins after
– B and ACTH measured using RIA kit
Lesion placementAcd = dorsal anterior cingulate
Figure 2. Rostrocaudal extent of mPFCd lesion placements
Figure 2. Rostrocaudal extent of mPFCv lesion placements
Figure 6. Acute restraint stress increases activation of preautonomic PVH after mPFCv lesions
VLM
Stress groupBrown = fast blueBlack = fos
Figure 6. Acute restraint stress increases activation of preautonomic PVH after mPFCv lesions
Dual labelling indicates stress-sensitive preautonomic neurons, and they are localized primarily in dorsal, ventral and lateral parvicellular
Also injected tracer into T1-T2 thoracic spinal cord to more specifically label PVH outputs relevant to sympathetic control. Stress + mPFCv lesion in this groupled to 63% more dbl labeled neurons in PVH
Discussion: talk freely amongst yourselves
• Support regional differentiation of mPFC within its capacity to modulate stress-related PVH outputs
• Stress induced HPA activity was greater following mPFCd lesion, suppressed w/ mPFCv
• mPFCv or IL: projects to brainstem cell groups involved in central autonomic control, including NTS (primary central terminus of inputs carried by the vagus and glossopharyngeal nerves)
• PVH innervates both NTS and motor nuclei of vagus and glossopharyngeal nerves
Fight or flight…
• This innervation pattern puts IL in a position to modulate concurrently both cardiac and adrenal medullary activity– “command neurons” for the F or F response
Peri-PVH
• Diencephalic mPFC projections distribute near the PVH, but not within the nucleus proper– Peri-PVH regions are rich in GABA interneurons
• Inhibitory control over HPA response
– mPFC projections are primarily excitatory (glu) • while its effects on HPA is inhibitory
Figure 7. Separate pathways from mPFC may differentially regulate PVH responses to stress
• mPFCd inhibitory mPFCv facilitates HPA• d/v involvment in autonomic output does not
adhere to this scheme
• pPVT (posterior para-vent nuc of thalamus) – Implicated in habituation and facilitation
• Hab: repeated exposure to same stressor = response• Fac: exaggerated response to novel challenge
– pPVT-mPFC connection targets IL preferentially• Implications for chronic stress adaptation
Post Traumatic Stress Disorder
• PTSD patients: functional impairment and shrinkage of mPFC– Correlated with dendritic atrophy and synapse
loss following chronic emotional stress in rodents
• PTSD: HPA axis dysregulation and consistent increases in cardiovascular reactivity
• In the future• Finer grained analysis of mPFC should foster
clarification of functional circuits underlying stress adaptation, and their involvement in affective disorders