PROJECT SUMMARY/ABSTRACTNoise trauma can lead to loss of parvalbumin-positive inhibitory interneurons in the auditory cortex which isassociated with audiotory processing deficit and tinnitus in rodent models. The mechanisms underlying noise-induced PV neuron loss are unknown. We propose to examine the hypothesis that differential activation ofTNFR1 and TNFR2 in cortical PV neurons determines the fate of the PV neurons following noise trauma withTNFR1 biasing for and TNFR2 biasing against neuronal loss and dysfunction.Specific Aim 1. Determine the effects of TNFR1 or TNFR2 knockdown on noise-induced PV neuron loss.PV-Cre-tdTomato mice will be injected with one of three viral vectors (with TNFR1 shRNA TNFR2 shRNA orscrambled sequences as a control) in the auditory cortex and exposed or sham-exposed to noise trauma. PVneurons will be visualized by the Cre reporter tdTomato in auditory cortical sections. Transfected neurons willbe visualized with the viral reporter GFP. Our hypothesis predicts that noise-induced PV neuron loss will bereduced by TNFR1 knockdown but enhanced by TNFR2 knockdown for the transfected PV neurons. Cell lossshould not be altered for the populations of un-transfected PV neurons and PV neurons transfected with thescrambled sequences.Specific Aim 2. Examine the effects of TNFR1 or TNFR2 knockdown on noise-induced dysfunction of PVneuron synapses. Our pilot data indicate that noise trauma leads to a reduced transmitter release probabilityat the output synapses of the PV neurons and accelerated neurotransmitter depletion. We hypothesize that thissynaptic dysfunction depends on the activation of TNFR1 in the surviving PV neurons and knockdown of TNFR1will prevent the synaptic deficits. In addition knockdown of TNFR2 should exacerbate PV neuron dysfunction.PV-Cre-ChR2-tdTomato mice will be injected with one of the three viral vectors in the auditory cortex and beexposed or sham-exposed to noise trauma. We will record optically activated inhibitory synaptic current inLayer2/3 pyramidal neurons in acute auditory cortical slices. Synaptic input-output curve paired-pulsemodulation and depletion will be examined. Afterward the slices will be fixed and imaged to quantify PV neuronloss and viral transfection rate in the surviving PV neurons which will then be correlated with PV neuron synapticdysfunction.We hypothesize that noise exposure disrupts cortical PV neuron function and PV neurondysfunction is a cause of gap detection deficit. We propose to use a mouse model to test this central hypothesisin the follwing specific aims.