GLP-1 action in the mouse bed nucleus of the stria terminalis

Diana L Williams,Nicole A Lilly,Ian J Edwards,Pallas Yao,James E Richards,Stefan Trapp

doi:10.1016/j.neuropharm.2017.12.007

Abstract

Glucagon-like peptide-1 (GLP-1) injected into the brain reduces food intake. Similarly, activation of preproglucagon (PPG) cells in the hindbrain which synthesize GLP-1, reduces food intake. However, it is far from clear whether this happens because of satiety, nausea, reduced reward, or even stress. Here we explore the role of the bed nucleus of the stria terminalis (BNST), an area involved in feeding control as well as stress responses, in GLP-1 responses.Using cre-expressing mice we visualized projections of NTS PPG neurons and GLP-1R-expressing BNST cells with AAV-driven Channelrhodopsin-YFP expression. The BNST displayed many varicose YFP+ PPG axons in the ventral and less in the dorsal regions. Mice which express RFP in GLP-1R neurons had RFP+ cells throughout the BNST with the highest density in the dorsal part, suggesting that PPG neuron-derived GLP-1 acts in the BNST. Indeed, injection of GLP-1 into the BNST reduced chow intake during the dark phase, whereas injection of the GLP-1 receptor antagonist Ex9 increased feeding. BNST-specific GLP-1-induced food suppression was less effective in mice on high fat (HF, 60%) diet, and Ex9 had no effect. Restraint stress-induced hypophagia was attenuated by BNST Ex9 treatment, further supporting a role for endogenous brain GLP-1. Finally, whole-cell patch clamp recordings of RFP+ BNST neurons demonstrated that GLP-1 elicited either a depolarizing or hyperpolarizing reversible response that was of opposite polarity to that under dopamine.Our data support a physiological role for BNST GLP-1R in feeding, and suggest complex cellular responses to GLP-1 in this nucleus.

Highlights

We demonstrate that the bed nucleus of the stria terminalis (BNST), an area known to be involved in feeding and stress responses, receives substantial innervation from nucleus of the solitary tract (NTS) PPG neurons, and that GLP-1 receptors (GLP-1R) expressing neurons of the BNST project widely to other brain areas
Densest innervation with PPG axons was identified in the hypothalamic nuclei of paraventricular nucleus (PVN), dorsomedial hypothalamus (DMH), arcuate nucleus (ARC) and periventricular nucleus (Pe) as previously reported (Llewellyn-Smith et al, 2011)
Substantial numbers of PPG axons were identified in mesolimbic areas of the forebrain that were not analyzed in detail previously

Summary

Introduction

(PPG) neurons of the nucleus of the solitary tract (NTS) are widely considered to play an important role in the control of food intake, body weight, and responses to stress (Gaykema et al, 2017; Holt and Trapp, 2016; Maniscalco et al, 2015; Trapp and Cork, 2015) These neurons project throughout the brain to many regions in which GLP-1 receptors (GLP-1R) are expressed (Cork et al, 2015; Llewellyn-Smith et al, 2011). A variety of behavioral effects of GLP-1R activation can be elicited by selectively targeting some of these locations (Alhadeff et al, 2012, 2014; Dossat et al, 2013; Richard et al, 2014; Shirazi et al, 2013; Williams, 2014). Increased feeding was not recapitulated by knockdown of GLP-1R in SIM1-expressing neurons of the paraventricular nucleus (PVN) or POMC neurons of the arcuate nucleus (ARC), the loss of GLP-1Rs in PVN neurons does attenuate a variety of physiological and behavioral responses to both acute and chronic stress (Ghosal et al, 2017)

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