Mechanisms underlying peptidergic modulation of feeding and feeding associated behaviours

Abstract

Of the various neuromodulatory agents found in the central nervous system the class of peptide modulators is of particular interest in the context of innate motivated behaviours wherein they have been shown to modify the synaptic gain and alter intrinsic properties of neurons to initiate or extend stable behavioural states e g sleep arousal roaming dwelling Feeding is an important behaviour where peptides are known to exert modulatory control Although much is known about the neuropeptides and anatomical regions regulating feeding and associated behaviours the underlying molecular mechanisms remain poorly understood This thesis focuses on Cocaine and Amphetamine Regulated Transcript CART and Neuropeptide Y NPY two peptides strongly implicated in regulating feeding and associated modalities Using a combinatorial approach we explore the biochemical changes triggered due to CART and NPY signalling and their consequences on behaviour and neural activity in the Zebrafish Danio rerio nervous system Previous data from our lab used a neural activity marker phosphorylated extracellular signal regulated kinase p ERK to identify CART peptide responsive regions In this study we find a strong correlation between high levels of p ERK in the dorsomedial telencephalon Dm and an associated anorexic behavioural output We thus used pharmacological intervention coupled with behavioural monitoring and neuronal activity imaging in Dm to better understand the molecular mechanisms involved in establishing CART mediated anorexia We found that N methyl D aspartate receptor NMDAR activity is necessary for CART signalling as the CART induced increase in activity of Dm neurons and reduction in feeding drive were both disrupted by blocking NMDAR signalling We then tested if protein kinase A PKA is also involved in mediating this effect Indeed we found that PKA activity was required for CART induced upregulation of neural activity in the Dm and suppression of feeding drive PKA mediated phosphorylation of NR1 subunits is known to alt