The impact of transient developmental HL on corticostriatal eLTP expression during auditory learning.

PROJECT SUMMARY Auditory deprivation during the critical period of development can induce persistent changes along the entire auditory neuraxis, as well as, brain regions downstream of primary auditory cortex. One such brain region, the striatum, forms an excitatory circuit with the auditory cortex that drives decision-making. Recently, I have found that transient developmental HL leads to persistent changes in the excitatory synaptic strength, inhibitory synaptic strength, and cellular firing properties of gerbil auditory corticostriatal neurons. These changes involve receptors that mediate long-term potentiation. Thus the behavioral impairments that remain after recovery from developmental HL could in part be due to changes in the corticostriatal expression of excitatory long-term potentiation (eLTP) during task acquisition. The core hypothesis of this proposal is that auditory associative learning delay in HL subjects is caused by NMDA and GABA receptor mediated disruptions to eLTP expression along the auditory corticostriatal circuit. Aim one will assess how NMDA receptor and GABAA/B receptor function contributes to eLTP expression and auditory learning in the cortex and striatum. This will be accomplished by 1) carrying out whole-cell recording from corticostriatal brain slices in adult gerbils in the presence of NMDA or GABA receptor blockers during the induction of eLTP or 2) by infusing NMDA or GABA blockers directly into the cortex or striatum via micro cannula during auditory discrimination training. Aim two will assess how learning-induced changes to neural and synaptic properties in the cortex and striatum promote eLTP during task acquisition. This will be accomplished by 1) using in vitro whole-cell recordings from ACx L5 or striatum to measure the learning-induced changes to NMDA and GABA receptor function and how they alter the probability of eLTP expression during auditory discrimination learning or 2) by using in vivo electrophysiological recordings from ACx L5 or striatum to measure how changes to neural firing rates and patterns are correlated with increases in in vivo measures of eLTP during auditory discrimination learning. Aim three will ask how developmental HL-induced changes to the set point of synaptic strength or neural firing properties along the corticostriatal circuit affect eLTP expression during auditory learning. This will be accomplished by 1) using in vitro whole-cell recordings from ACx L5 or striatum of adult animals that experienced developmental HL to measure how the HL-induced changes to synaptic strength set points impact the learning-induced changes that drive eLTP expression during auditory discrimination learning or 2) by using in vivo electrophysiological recordings from ACx L5 or striatum of adult animals that experienced developmental HL to measure how HL-induced changes to neural firing properties impact the learning-induced changes that drive LTP during auditory discrimination learning. Together, this proposal will reveal how HL- induced changes to cellular and synaptic properties along the corticostriatal circuit interact with the learning-induced changes to cellular and synaptic properties that promote auditory learning.