The neurophysiological effects of glucagon-like peptide-1 receptor agonists on neuronal activity in the lateral septum

Abstract

The lateral septum (LS) has received a growing interest due to its multifaceted roles in aggression, food intake, stress, anxiety, reward and addiction, contextual memory, and locomotion. Some of the same behaviours are modulated by glucagon-like peptide-1 receptor (GLP1-R) agonists. Numerous studies have shown that the LS is one of the regions with high level of GLP-1R expression. Despite this and the overlap in modulating the same functions, the LS GLP-1R system has received limited attention. Thus, this thesis used a variety of electrophysiological tools to investigate the neurophysiological effects of GLP-1R agonists in the LS. The first two results chapters established the diverse effects of GLP-1R agonists on LS neuronal firing rate. Downstream modulation of the activity of protein kinase A (PKA), ATP-sensitive potassium (KATP) channel and hyperpolarisation-activated cyclic nucleotide–gated (HCN) channel, is suggested to play a role in achieving such effects. Glutamate and GABA signalling are also suggested to play a part in modulating the diverse neurophysiological effects. The third results chapter showed differences in the neuronal firing properties between the subregions of LS and that the extracellular action potential half-width of the LS neurons may predict the inhibition of neuronal firing rate in response to GLP-1R agonists. The fourth results chapter showed that the LS neurons across the subregions have an almost homogenous sub-threshold properties but are divergent in their morphology. Most of such sub-threshold properties remain unchanged in response to GLP-1R agonists. The last results chapter showed that systemic administration of GLP-1R agonist was associated with decreased mean beta peak frequency in the LS, in vivo. Collectively, this thesis establishes that the LS GLP-1R system is functional ex vivo and in vivo. Notably, it couples these findings with existing literature to implicate the LS GLP-1R system in various roles such as anxiety and goal-directed behaviour.