Modulation of a neuromodulator: Insulin sensing in the basal forebrain

Neuromodulatory systems play pivotal roles in shaping behaviour and cognition. In particular, the cholinergic system has important roles in regulating food consumption, attention, learning and memory. Cholinergic function declines with age which directly impacts cognition. Additionally, insulin, a key player in brain function, is implicated in overlapping roles. Age-related declines in insulin sensitivity have independently been associated with diminished brain health and cognitive abilities.

Notably, our research has pinpointed a central cholinergic hub, that is sensitive to insulin, highlighting a potential nexus for understanding and addressing the challenge of age-related cognitive decline. The overarching goal of this research is to understand the consequences of insulin sensing by the basal forebrain cholinergic nuclei (BFCN) and the underlying mechanisms. To deliver this new knowledge we will complete 2 aims using a multi-disciplinary approach combining behavioural analysis, cellular physiology, and targeted viral knockdown:

Aim 1: Determine the functional consequence of insulin regulation of the BFCN.

We will employ targeted knockdown of insulin receptors in the basal forebrain, specifically focusing on assessing the impact on three key functions linked to established projections from the BFCN: food intake, activity levels, and cognitive performance. By selectively rendering BFCN neurons resistant to insulin, we aim to unveil the repercussions of such resistance on these functions. Our preliminary data indicate that activity levels are affected in both sexes whereas food intake is affected only in males, the consequences on cognition are yet to be addressed.

Aim 2: Determine the cellular and molecular components required for insulin modulation of BFCN projection neurons

The BFCN is composed of different types of projection neurons including, glutamatergic and gabaergic neurons in addition to the cholinergic neurons for which it is named. Using...