Project Grant R01NS131645

REGULATION OF DIURNAL RHYTHMS IN PARVALBUMIN AND PERINEURONAL NET FUNCTION - ABSTRACT MEMORY RETRIEVAL REQUIRES OPTIMAL FUNCTIONING FOR AN ORGANISM'S SURVIVAL AND VARIES WITH THE TIME OF DAY. THE BIOLOGICAL CLOCK BIASES OUTPUT OF BRAIN CIRCUITRY TO COORDINATE BEHAVIORS ACROSS THE LIGHT/DARK CYCLE. GABAERGIC NEURONS ALIGN CIRCUIT ACTIVITY TO GATE DAILY RHYTHMS THROUGH EXPRESSION OF LOCAL CIRCADIAN-ASSOCIATED CLOCK GENES. PARVALBUMIN (PV) GABAERGIC NEURONS POWERFULLY MODIFY CIRCUITS NEEDED FOR MEMORY RETRIEVAL, BUT THE EXTENT TO WHICH PV NEURONS REGULATE DAILY RHYTHMS IN RETRIEVAL IS UNKNOWN. THIS INFORMATION IS IMPORTANT BECAUSE DESYNCHRONY BETWEEN THE 24 HR LIGHT CYCLE AND ENDOGENOUS CIRCADIAN RHYTHMS LEADS TO COGNITIVE DEFICITS IN SHIFT WORKERS, THOSE WITH JET LAG, AGED INDIVIDUALS, AND IN THOSE WITH NEUROLOGICAL DISORDERS IN WHICH CIRCADIAN REGULATION OF THE BIOLOGICAL CLOCK IS IMPAIRED. IN THE MEDIAL PREFRONTAL CORTEX (MPFC), THE FOCUS OF THESE STUDIES, MOST PV NEURONS ARE ENWRAPPED IN STRUCTURES CALLED PERINEURONAL NETS (PNNS), WHICH RESTRICT PLASTICITY IN ADULTHOOD AND ARE VITAL FOR PRECISE FIRING OF PV NEURONS. WE DISCOVERED THAT THE EXPRESSION OF PNNS AND PV EXHIBIT A DIURNAL PATTERN IN THE RAT MPFC, AND PROPOSE THAT THIS DIURNAL PATTERN IS A MAJOR FACTOR DRIVING DIURNAL DIFFERENCES IN MEMORY RETRIEVAL. MOREOVER, WE PROPOSE THAT THE DIURNAL PATTERN IN PNNS IS COORDINATED BY ORTHODENTICLE HOMEOBOX 2 (OTX2), WHICH MAINTAINS PNNS AND EXHIBITS A SIMILAR DIURNAL PATTERN AS PNNS. OTX2 APPEARS TO BIND TO PROMOTER-PROXIMAL REGIONS OF THE CLOCK GENES CLOCK, PER1, AND PER2 AND THUS MAY SERVE AS A MAJOR INTEGRATOR OF ACTIVITY-DEPENDENT RHYTHMS THAT COORDINATE WITH THESE CLOCK PROTEINS. CONSISTENT WITH THIS, WE SHOW THAT PNN REMOVAL DISRUPTS THE DIURNAL RHYTHM OF PER1 PROTEIN LEVELS IN PV NEURONS. TOGETHER, PRIOR WORK AND OUR STUDIES SHOW THAT PNNS INFLUENCE THE CORE CLOCK, WHICH CAN POTENTLY INFLUENCE CIRCUIT FUNCTION DURING MEMORY RETRIEVAL. WE HYPOTHESIZE THAT PNNS SURROUNDING PV NEURONS IN THE MPFC ARE A MAJOR CONTRIBUTOR TO DIURNAL PATTERNS OF MEMORY RETRIEVAL THROUGH REGULATION OF CLOCK GENES. OUR STUDIES WILL DEFINE HOW DIURNAL FLUCTUATIONS IN PNNS AROUND PV NEURONS ALTER CIRCADIAN GENES AND PV NEURON FUNCTION IN THE MPFC, AND WHETHER THESE DIURNAL FLUCTUATIONS UNDERLIE DIURNAL DIFFERENCES IN MEMORY RETRIEVAL. CONVERSELY, WE WILL DETERMINE HOW MANIPULATION OF THE CLOCK GENE BMAL1 ALTERS PNNS, PV NEURON FUNCTION, AND MEMORY RETRIEVAL. WE WILL USE BEHAVIOR, INNOVATIVE MOLECULAR APPROACHES, AND IN VITRO AND IN VIVO ELECTROPHYSIOLOGY TO ADDRESS THE FOLLOWING THREE SPECIFIC AIMS: AIM 1) DETERMINE HOW PNNS IN THE MPFC MODULATE RHYTHMICITY OF PV NEURON CLOCK GENES, PV NEURON FUNCTION, AND MEMORY RETRIEVAL.; AIM 2) DETERMINE WHETHER THE CORE CLOCK IN MPFC PV NEURONS REGULATES RHYTHMICITY OF PNN, PV NEURON FUNCTION, AND MEMORY RETRIEVAL; AND AIM 3) DEFINE DIURNAL CHANGES IN OSCILLATORY COMMUNICATION BETWEEN THE MPFC, BASOLATERAL AMYGDALA, AND HIPPOCAMPUS. UNDERSTANDING HOW ENDOGENOUS DAILY RHYTHMS IN PNNS AND THEIR PV INTERNEURONS CONTRIBUTE TO MEMORY RETRIEVAL IS EXPECTED TO FACILITATE TREATMENT OF COGNITIVE IMPAIRMENTS IN THOSE WITH CIRCADIAN RHYTHM DESYNCHRONY.