Chronic and acute molecular programs enabling working memory

Abstract Working memory is a form of short-term memory that is required for most daily activities, from reading, to driving, to conversing. As such, deficits in working memory are highly disabling and are prominent in learning disability, ADHD, and in Schizophrenia where it is the most important predictor of long-term prognosis. Currently, no treatments exist to improve working memory. Pioneering studies in humans and animal models established a central role for the prefrontal cortex in enabling working memory. Emerging work from our lab and others demonstrate important complimentary roles of thalamus in shaping thalamo-cortical synchrony underlying working memory. An important next step is to understand the molecular programs in thalamus that sustain such long-range thalamo-cortical neural activity on the time-scale of seconds to tens of seconds during working memory. This will provide new mechanisms for how memory is enabled on short time-scales, and also offer therapeutic targets for reversing working memory deficits. Towards this, we recently identified a novel orphan receptor that functions in thalamus as a potent modifier of short-term memory. In this proposal, we will delineate the chronic (steady-state) transcriptional and gene-regulatory programs downstream of Gpr12 that promote and maintain working memory. We will also identify acute (activity-dependent) recruitment of Gpr12 downstream signaling during working memory behavior. Finally, we will link Gpr12 molecular function with its role in maintaining sustained and synchronized thalamo-cortical activity during working memory. The overarching goal of this work is to provide new insight into molecular programs in thalamus that shape thalamo-cortical activity underlying working memory. Such discoveries will inform how our brains enable us to maintain task-relevant information on short time-scales. More broadly, this study will help work towards novel therapeutic strategies for reversing working memory deficits associated with schizophrenia, and related mental illnesses.