0224 Optogenetic Manipulation of Basal Forebrain Parvalbumin Neurons Modulates Vigilant Attention and Rescues Sleep Deprivation Induced Impairments

Introduction Sleep disruption leads to attention impairments, excessive daytime sleepiness, and is a major contributor to accident rates and decreased workplace productivity. The basal forebrain (BF) region has long been associated with promoting cortical arousal and wakefulness. Recently, selective excitation of BF parvalbumin (PV) GABAergic neurons has been shown to produce high frequency cortical activation and brief periods of wakefulness. Here we test the hypothesis that BF PV neurons are involved in vigilant attention using bidirectional optogenetic manipulations in a signaled reaction time task. Methods Brief optogenetic excitation (ChR2) and inhibition (ArchT) of BF PV neurons was applied during a lever release version of the rodent psychomotor vigilance task (rPVT). Mice were trained to hold a lever down to initiate a trial and after a random delay, a 200ms cue light signaled the mouse to quickly release the lever within 1s to receive a sucrose pellet reward. The reaction time between cue light onset and lever release was the primary measure of attentional performance. Sleep deprivation (8h) produced by gentle handling was also investigated. Laser parameters: brief (1s) of continuous (non-pulsatile) laser stimulation was delivered beginning 500ms prior to cue light onset (5mW 473nm blue light for ChR2-mediated excitation; 10mW 530nm green light for ArchT-mediated inhibition). Results BF PV excitation led to faster reactions times (N=6, 14% faster, p<.001), interpreted as an enhancement of attention. Sleep deprivation slowed reaction times (20% slower, p<.01) and BF PV excitation rescued the sleep deprivation induced impairments. BF PV inhibition significantly slowed reaction times (25% slower, p<.02), an effect that resembled the effects of sleep deprivation. Conclusion This is the first demonstration of a role for BF PV neurons in attention and in the attention deficits produced by sleep deprivation. Support T32 HL007901, I01 BX002774, P01 HL095491, R01 MH039683, I01 BX004500, IK2 BX002130, Stonehill College SURE program, I01 BX001356

GABAergic inhibition of neuronal activity in the primate motor and premotor cortex during voluntary movement

1. The functional role of GABAergic inhibition in neuronal activity in the forearm-hand area of the motor cortex and the postarcuate premotor cortex was studied while monkeys pressed and released a lever in response to a visual cue. gamma-Aminobutyric acid (GABA), its agonist muscimol (MUS), and its antagonist bicuculline methiodide (BMI), as well as acetylcholine, noradrenaline, and sodium glutamate, were applied iontophoretically to isolated single neurons whose activity was recorded via glass micropipettes that contained carbon fibers. 2. The activity from single neurons recorded in the motor and premotor cortex showed changes during the press or release of the lever by movement of the contralateral wrist. Discharge of most of the movement-related neurons (greater than 90%) was decreased or completely suppressed by iontophoretically applied GABA or MUS. 3. The activity of the movement-related neurons increased after application of BMI. In 70% of neurons tested, the activity during application of BMI was specifically enhanced at or near the phase of their peaks of activity, with or without a noticeable elevation in background activity. 4. About 10% of the neurons that had been unidirectional (i.e., neurons that showed a change in activity at either the lever-press or lever-release phase) became bidirectional (i.e., they showed changes in activity at both phases) when GABA transmission was blocked by the application of BMI. Bidirectional neurons also showed a reduction in the value of the directionality index. 5. One-half of the silent neurons, which had not shown any activity during either the lever-release or the lever-press phase, became active during the movement phases that followed application of BMI. 6. Most of the cortical neurons in layers II-VI in the motor area were found to be subject to GABAergic inhibition during voluntary movement. 7. We conclude that GABAergic inhibition plays a role in regulating the population of task-related neurons, and the levels of the task-related activity. GABAergic inhibition also improves directionality index in the motor cortex neurons to control the activity of target muscles.