Working memory is an essential cognitive function central to virtually all behaviors. Despite the fact that we know which brain areas and which neuromodulators are involved in working memory, we know very little about which neurons need to be activated when to enable working memory. This gap in our knowledge arose because of the technical difficulty in manipulating and monitoring neural activity in genetically- and anatomically- defined cell-types with sufficiently high temporal resolution. In order to overcome this challenge and elucidate some of the causal neural dynamics for working memory, we propose to combine multiple synergistic approaches, including a rat optogenetic model that we have previously developed to target dopaminergic neurons, in vivo electrophysiological recordings, and fluorescence-based monitoring of neural activity in freely behaving animals (with gCaMP6).
In Aim 1, we will optogenetically inhibit several cortical and striatal circuits eiter during the updating, maintenance, or readout of working memory to determine which aspect of working memory each circuit supports.
In Aims 2, we will monitor neural activity in dopaminergic neurons using gCaMP6 to determine how dopaminergic dynamics correlate with working memory performance.
In Aim 3, we will generate different patterns of dopaminergic stimulation (e.g. tonic vs phasic) to determine the causal relationship between working memory performance and dopaminergic activity dynamics.
In Aim 4, we will integrate dopaminergic stimulation with electrophysiological recordings in dorsal striatum and prelimbic cortex to isolate the downstream changes in neural activity mediated by dopaminergic activity. Together, this work will provide new insights into the neural circuit mechanisms underlying working memory, with implications for both basic science and an understanding of the working memory dysfunction in various psychiatric disorders.
Working memory, our essential ability to maintain and manipulate information over short periods of time, is disrupted in numerous psychiatric diseases, including schizophrenia. Despite the prevalence of working memory deficits, there are no effective therapies, possibly due to the fact that the timeframe of existing drug-based interventions do not match the much faster timeframe of the neural dynamics that mediate working memory. The goal of this proposal is to use new technologies to monitor and manipulate neural activity during working memory with high temporal resolution in order to determine which neurons support which aspect of working memory.
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