Oral Presentation ANZOS-Breakthrough Discoveries Joint Annual Scientific Meeting 2018

Hunger-sensing AgRP neurons engage the hypothalamic-pituitary-adrenal axis to mediate adaptive responses to stress (#97)

Rachel Clarke 1 , Sarah Lockie 1 , Alexander Reichenbach 1 , Mathieu Mequinon 1 , Sarah Spencer 2 , Stuart Mazzone 1 , Zane Andrews 1
  1. Department of Physiology, Monash University, Melbourne, VIC, Australia
  2. School of Health and Biomedical Sciences, RMIT University, Melbourne, VICTORIA, Australia

Hunger-sensing Agouti-related peptide (AgRP) neurons in the hypothalamic arcuate nucleus are fundamental to survival. They increase food intake during energy deficit and also facilitate adaptive behaviors to cope with hunger by reducing anxiety and increasing motivation, therefore enabling appropriate food seeking behavior. A fundamental question remains; what are the physiological mechanisms through which AgRP neurons regulate adaptive behaviors. We examined the hypothesis that activation of AgRP neurons in the absence of food engages the Hypothalamic Pituitary Adrenal (HPA) axis to mitigate anxiety associated with acute emotional stress. Using hM3Dq DREADDS, prior activation of AgRP neurons 3-hours before acute restraint stress significantly increased plasma corticosterone 15, 30 and 60 minutes and ACTH 30 minutes after stress onset. Anterograde tracing of AgRP neurons using the cre-dependent herpes simplex virus H129 ∆TK-TT confirmed that AgRP neurons target ~30% of CRH neurons in the PVN. In behavioural experiments, prior activation of AgRP neurons reduced anxiety-like behaviour, increased memory recall and promoted food intake after acute stress. Prior activation of AgRP neurons also promoted food-seeking and food consumption in a food-baited novel environment used to evoke acute stress. To determine whether the behaviours were a result of increased circulating corticosterone we pre-treated mice with metyrapone, an inhibitor of corticosterone synthesis and repeated these behavioural experiments. Unexpectedly, inhibiting corticosterone did not influence AgRP-induced behavioural adaptation to stress. Activation of selective AgRP to PVN and AgRP to medial amygdala circuits using retrograde transport of DREADDs from terminal regions induced a significant feeding response. However activation of these circuits in isolation did not influence adaptive behaviour in response to acute stress. Our results suggest AgRP neurons promote an adaptive response to stress independent from increases in plasma corticosterone, however the specific circuits responsible remain to be determined and may require multiple AgRP circuits acting in unison.