Sunday, December 22, 2024
12/22/2024
ABSTRACT This project is focused on understanding the mechanisms behind performance deficits that occur with insufficient sleep. In particular, studies in humans have identified cognitive rigidity (compromised situational adaptability in decision making) as a consequence of sleep deprivation (SD). Cognitive rigidity is influenced by a striatopallidal brain circuit that is conserved in subhuman primates and rodents and involves a cell type that expresses dopamine-type 2 (DrD2) and adenosine-type 2a (A2a) receptors. In the current studies, we will employ mouse electrophysiology recordings and real-time striatal event imaging, in addition to a rat cognitive flexibility task that is susceptible to SD. We will apply these techniques to transgenic mouse and rat models in order to interrogate the role of the DrD2/A2a striatopallidal brain circuit in mediating the effects of SD at the biochemical, receptor, regional (brain structure and electrophysiology) levels in addition to probing complex whole organism behavior. In Aim 1, we will determine the extent to which DrD2 cell membrane localization and intracellular cyclic adenosine monophosphate concentration ([cAMP]i) in striatal medium spiny neurons vary as a function of spontaneous and SD-induced sleep/wake cycles. This experiment will address our dynamic interplay hypothesis that striatal DrD2 receptor availability and the inversely-related [cAMP]i function as cellular mediators of sleep pressure in the striatum. In Aim 2, we will examine whether the activity of striatal DrD2/A2a cells is necessary and sufficient to confer the negative impacts of SD on cognitive flexibility. We predict that cell-type specific chemogenetic activation or inactivation of these neurons will mimic or rescue, respectively, the behavioral consequences of SD in a touchscreen operant reversal task. The anticipated results of this project will confirm the mechanistic role of the striatopallidal medium spiny neuron population in the performance decrements that stem from sleep loss. Here, our focus is on dopaminergic signaling, but our long-term objective is to elucidate how signaling mechanisms in the striatum and connected brain areas converge to regulate the cognitive processes that are compromised by SD. Overall, this work will set the stage for future inquiries by confirming cell type-specific SD mitigation targets in striatal circuitry. It will also inform the public and scientific constituencies of potential mechanistic and compensatory approaches to reversing/preventing the deleterious effects of sleep loss.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).