PROJECT SUMMARY/ABSTRACT
Noise trauma can lead to loss of parvalbumin-positive inhibitory interneurons in the auditory cortex, which is
associated 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 of
TNFR1 and TNFR2 in cortical PV neurons determines the fate of the PV neurons following noise trauma, with
TNFR1 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 or
scrambled sequences as a control) in the auditory cortex, and exposed or sham-exposed to noise trauma. PV
neurons will be visualized by the Cre reporter tdTomato in auditory cortical sections. Transfected neurons will
be visualized with the viral reporter GFP. Our hypothesis predicts that noise-induced PV neuron loss will be
reduced by TNFR1 knockdown, but enhanced by TNFR2 knockdown for the transfected PV neurons. Cell loss
should not be altered for the populations of un-transfected PV neurons, and PV neurons transfected with the
scrambled sequences.
Specific Aim 2. Examine the effects of TNFR1 or TNFR2 knockdown on noise-induced dysfunction of PV
neuron synapses. Our pilot data indicate that noise trauma leads to a reduced transmitter release probability
at the output synapses of the PV neurons, and accelerated neurotransmitter depletion. We hypothesize that this
synaptic dysfunction depends on the activation of TNFR1 in the surviving PV neurons, and knockdown of TNFR1
will 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 be
exposed or sham-exposed to noise trauma. We will record optically activated inhibitory synaptic current in
Layer2/3 pyramidal neurons in acute auditory cortical slices. Synaptic input-output curve, paired-pulse
modulation and depletion will be examined. Afterward, the slices will be fixed and imaged to quantify PV neuron
loss and viral transfection rate in the surviving PV neurons, which will then be correlated with PV neuron synaptic
dysfunction.We hypothesize that noise exposure disrupts cortical PV neuron function, and PV neuron
dysfunction is a cause of gap detection deficit. We propose to use a mouse model to test this central hypothesis
in the follwing specific aims.