ACC Reward Location Information Is Carried by Hippocampal Theta Synchrony and Suppressed in a Type 2 Diabetes Model

The anterior cingulate cortex (ACC) is important for higher order cognitive functions, emotional responses, and monitoring internal states. ACC dysfunction has been implicated in an array of psychiatric and neurodegenerative disorders which have a bidirectional relationship with the metabolic disorder Type 2 diabetes (T2D). T2D is a chronic disease characterized by hyperglycemia, loss of insulin signaling, neuroinflammation, and increased morbidity and mortality chances. To better understand the functional effects of T2D on ACC information processing, we delivered an intermittent, low dose streptozotocin (STZ) protocol to rats (all male due to female insensitivity to STZ) which led to lasting hyperglycemia and recorded single neurons during a delayed alternation task. We observed changes in spatial and reward processing in spite of no differences in overall behavioral accuracy, though we did find hyperglycemic animals spent less time at the reward site. Hyperglycemic animal (n=5) ACC neurons had higher spatial information scores and changes in the allotment of spatial coding assets. Specifically, the hyperglycemic group had greatest spatial information during the reward approach, while in controls (n=3) it was uniformly distributed. We found that state space separation and decoding accuracy were greater in control ensembles at the reward location. Furthermore, control hippocampal theta phase-locked cells had the strongest reward coding and this effect was absent in hyperglycemic animals, leading to a muted reward representation, despite increased reward approach coding. T2D inferred a nuanced and layered effect on ACC activity, leading to reward coding deficits and a differential change in spatial coding properties.<b>Significance Statement</b> Type 2 diabetes (T2D) is a major health challenge in the 21st century and makes patients more prone to psychiatric and neurodegenerative disorders. In this paper, we show that neural information processing in the anterior cingulate cortex (ACC), a central area for goal directed behavior, is altered in multiple ways in a T2D rodent model during a spatial working memory task. Notably, data reveal altered spatial information in ACC cells and muted reward location coding specifically in hippocampal theta modulated ACC neurons and ensembles. The finding of altered reward processing in the ACC that manifested as a shorter post-reinforcement pause, invites profound questions given the importance of lifestyle interventions to treat T2D.