Contribution of medial septal modulation to spatial working memory through optogenetic manipulations

Abstract

Working memory (WM) is a critical function needed to interact with our environment and those around us. WM refers to the ability to hold information “online” and actively manipulate that information for successful use in task-relevant behavior. One way to further examine WM, is by modeling WM in rodents by assessing aspects of spatial working memory (SWM). SWM in rodents refers to the ability to maintain goal-relevant information over a temporal delay and successfully recall that information when it is needed. The underlying neural mechanisms involved in SWM are believed to be orchestrated by the septo-hippocampal theta oscillations. Septo-hippocampal theta oscillations are known to synchronize the hippocampal network through a vast expansion of GABAergic inhibitory influence. The intricate local connections and physiology of the medial septum (MSA) and reciprocal inhibitory influences returning from the hippocampus, pace theta oscillations in the hippocampal formation and temporally organize hippocampal and prefrontal cell assemblies. Septo-hippocampal theta oscillations are reported to offer a method of communication between the prefrontal cortex and hippocampus, of which both are critical for SWM. My hypothesis is that the MSA provides a critical modulatory influence on hippocampal-prefrontal theta communication, which is necessary for optimal SWM performance. To investigate the role of MSA during SWM, I first demonstrate that MSA is crucial for SWM maintenance (Aim 1). Next, I paced hippocampal theta oscillations via MSA optogenetic theta stimulation during short and extended delays to determine whether MSA theta stimulation is beneficial to task performance (Aim 2). Lastly, I examined the impact of MSA theta stimulation on hippocampal-prefrontal communication by assessing theta coherence between the two regions (Aim 3). My results demonstrate that MSA activity is crucial for SWM maintenance during a hippocampal-dependent conditional discrimination working memory task. In addition, I found that MSA theta stimulation during SWM maintenance enhances choice accuracy, specifically on trials where the working memory demand was prolonged. This finding may be explained by observations in Aim 3, of MSA theta stimulation altering dorsal hippocampal (dHPC) and medial prefrontal cortex (mPFC) theta power dynamics and enhancing dHPC-mPFC theta synchrony over the extended delay trials. These results highlight a vital role for septo-hippocampal theta in SWM. Moreover, they extend the implications of theta stimulation for therapeutic interventions by providing foundational evidence for its effects in non-pathological models.