The Role of Acetylcholine and Dopamine in Working Memory

Abstract

Working memory, the ability to remember a stimulus for a brief period of time and to use that memory flexibly to guide ongoing behavior, is a ubiquitous function essential to our cognition. In this thesis, I investigate the temporally-precise role of two major neuromodulatory systems - midbrain dopaminergic (DA) system and basal forebrain cholinergic (ChAT) system- in spatial working memory.

In the first study, the role of ChAT system in working memory is examined. Using delayed non-match to position task (DNMTP) as a behavioral assay to probe rodent spatial working memory, I first quantitatively demonstrate that animals’ locomotion explains more variance in medial septum (MS) ChAT neurons than task events while task events explains more variance in nucleus basalis (NB) ChAT neurons than locomotion, establishing two distinct roles of these ChAT brain regions in subserving DNMTP task. Furthermore, I show that NB ChAT neurons respond to lever press action and reward, and this task event encoding is spatially organized along the medio- lateral axis of the NB. Lastly, I report that these ChAT neurons in the NB are surprisingly integrated within the basal ganglia in a topographical fashion, providing an anatomical substrate to the functional heterogeneity in the NB ChAT neurons.

In the second study, the role of DA system in working memory is investigated using the same working memory task. I first quantitatively show that task events such as lever presentation cue and reward, are encoded with phasic elevated activity, similarly between DA neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). In contrast, SNc and VTA DA neurons are relatively depressed during the delay period. Next, I present a series of causal, optogenetic experiments to test a set of predictions outlined by the “gating” theory and “inverted- U-shape” hypothesis of DA in working memory. We demonstrate that bi-directional manipulation of VTA DA neurons during the sample and delay period impairs the cognitive component of the task supporting the “inverted-U-shape” hypothesis, while SNc DA neurons may be more involved in the motor execution of the task. This is the first evidence providing dissociable causal roles of VTA and SNc DA neurons in working memory.