The Anteroventral BST The Anteroventral BST Differentially Regulates HPA Axis Differentially Regulates HPA Axis Responses to Acute and Chronic Responses to Acute and Chronic StressStress

Choi DC, Evanson NK, Furay AR, Ulrich-Lai YMOstrander MM, Herman JP.

IntroductionIntroductionChronic Stress

Decreases body weight and food intake Induces adrenal hypertrophy Involution of thymus Affects neuronal plasticity Elevated expressions of CRH mRNA Elevated expressions of AVP mRNA

(in some stress models) Increased circulating glucocorticoids

The comparison between acute and chronic stress regarding the HPA axis

Acute activation of the HPA axis is an adaptive response

Chronic activation of the HPA axis can be deleterious and has been linked to several different pathologies.

Different brain circuitries are involved in acute and chronic stress responses. Paraventricular thalamus regulate HPA axis

responses to chronic stressors. Chronic stress can produce enhancement

of HPA axis responses to new stressors. Repeated experience with the same

(homotypic) stressor produces habituation of HPA axis responses.

Repeated homotypic stress followed by a novel (heterotypic) stressor induces facilitation.

Forebrain limbic region Forebrain limbic region BST BST PVN PVN

dorsomedial nucleus (dm) &

fusiform nucleus (fu) Located in the anterior

division of the BST Ventral to the anterior

commissure Heavy projections to

the medial parvocellular PVN

Relay stress-excitatory information to the PVN

HypothesisHypothesis

The contribution of the BST to chronic stress?

The BST dm/fu nuclei are necessary for sensitization of HPA axis response after chronic stress?

Chronic variable stress (CVS) paradigm a novel restraint challenge assess CVS-induced adaptations in HPA axis reactivity

Materials and MethodsMaterials and Methods

Subjects: SD rats Bilateral microinjections of ibotenate or

saline into the anterior BST

Four groups: sham non-CVS, sham CVS, lesion non-CVS, lesion CVS Twice-daily exposure to alternating

stressors for 14 days Morning stressor, afternoon stressor and

occational overnight stressor CVS stressors: hypoxia, cold stress, rotation

stress, warm swim, cold swim, overnight social isolation, overnight social crowding

Acute novel restraint stress protocol

day after the cessation of CVS

placement in restraint tubes

blood sampling

20 min restraints tress

Blood sampling

returned to home cage

Blood sampling (40 min from the onset of the restraint stress)

decapitation, collecting blood sample(60min)

MeasurementsMeasurements

RIA measure plasma cort and ACTH level

Lesion verification Nissl staining of cells Neuronal nuclei (NeuN) immunolabeling

In situ hybridization and image analysis Measure AVP, CRH and c-fos mRNA levels in

the PVN Statistical analysis

ResultsResultsLesions of the BST dm/fu nucleiLesions of the BST dm/fu nuclei

Anterior BST lesions were centered ventral to the anterior commissure at approximately AP -0.10mm from bregma.

Body and organ weightsBody and organ weightsBody weightBody weight

Destruction of the BST dm/fu is not sufficient to alter the consequences of chronic stress on body weight.

Body and organ weights Body and organ weights Organ weightsOrgan weights

CVS induces adrenal hypertrophy /hyperplasia No effects of lesion on adrenal weights No effects of lesion on thymus weights Main effects of CVS on raw thymus weight but

not on thymus weight adj. for body weight

Plasma ACTH levelsPlasma ACTH levels

Plasma cort levelsPlasma cort levels

c-fos mRNA expression in the PVN

CRF mRNA expression in the PVN

AVP mRNA expression in the PVN

Discussion

The BSTdm/fu act as activators of the HPA axis response to acute stress, but are also involved in inhibitory regulation of HPA axis reactivity after chronic stress.

Disruption of the BST dm/fu nuclei does not affect the development of steady-state changes in HPA function engendered by chronic stress.

Several possible mechanisms Acute and chronic stress may recruit

different populations of BST dm/fu neurons: CRH, Glu, GABA.

Inputs from brainstem and limbic regions might project to separate pools of neurons in the BST dm/fu.

Interruption of BST dm/fu input to the PVN or PVN-projecting structures may permit a compensatory enhancement of inputs that are sensitive to the effects of chronic stress.