0218 OPTOGENETIC MANIPULATION OF PARVALBUMIN CONTAINING GABAERGIC NEURONS IN THE THALAMIC RETICULAR NUCLEUS ALTERS DECLARATIVE AND NON-DECLARATIVE MEMORIES IN MICE

Abstract

Schizophrenia (Sz) patients exhibit sleep and sleep spindle abnormalities along with cognitive impairments. However, a causal link between spindles and cognitive deficits in Sz has not yet been shown. Cortical parvalbumin (PV) containing GABAergic neurons have reduced activity in Sz. Thalamic reticular nucleus (TRN) neurons involved in spindle generation are also GABAergic and most contain PV. Thus, reduced activity of TRN PV neurons may account for spindle abnormalities and associated cognitive deficits. Here we tested whether optogenetic inhibition of TRN PV neurons during sleep following learning alters memory performance in three tasks: novel object recognition (NOR) and object place recognition (OPR) tasks to measure declarative memory; and the rotarod motor learning task to measure non-declarative/procedural memory.AAV-CAG-FLEX-ArchT-GFP was bilaterally injected into the TRN of PV-Cre mice. Inhibition of TRN PV neurons was performed via laser illumination (532 nm, 1-min on, 4-min off) during the 4-hr retention interval of NOR and OPR; the time period between the acquisition and recall phases of the tasks. Separately, we trained mice in the rotarod motor task in which laser (or sham-laser) was applied for the first 7hrs after Day-1 training. Motor skill was tested again on Day-2 to assess animal’s performance improvement. EEG/EMG recordings were performed during the retention intervals of all tasks.Recognition memory was significantly impaired following inhibition of TRN PV neurons during the memory retention interval (NOR: N=10, p<0.01, OPR: N=10, p<0.01). Procedural memory, computed as percent improvement from Day-1 to Day-2 of the rotarod task, was also impaired in the TRN inhibition group (N=7) compared to control (N=5, p<0.05). However, correlations between spindle density and behavioral performance were inconsistent among tasks.These findings demonstrate that optical inhibition of TRN PV neurons following learning affects memory performance. Further investigation of the precise physiological mechanisms that cause behavioral impairments is necessary.VA Merit 1I01BX001356, VA Merit 1I01BX002774, VA CDA 1IK2BX002130, T32HL007901, MH039683, HL095491. JTM received partial salary compensation and funding from Merck MISP, but has no conflict of interest with this work.