On the other hand the AP latency in the SPN offset response showed very little jitter (black histogram; Figure 7D); indeed, the temporal resolution of the SPN offset response is comparable to the onset response in the MNTB (Figure 7E). Thus from a computational viewpoint, the conversion of the inhibitory input to an excitatory offset response improves the temporal resolution of the encoded signal by at least 5-fold. This result provides SAHA HDAC chemical structure insight as to why conversion of the inhibitory MNTB output into an excitatory offset response gives a physiological advantage in terms of temporal accuracy of the offset, and this is confirmed by the modeling (Figures 7F–7H).

The model provides several additional insights into the physiology of offset firing. In the full SPN model, the range of sound durations is represented by a color spectrum from red (long, 100 ms) to blue (short, 10 ms) and the latency of the offset response closely matched in vivo and in vitro stimulus durations (Figures 7Fi and 7G). But removal of the IH conductance (no IH, green; Figure 7Fii) vastly degrades the offset timing, so that latencies increased to over 30 ms (Figure 7G). Lack of IH also increased the input resistance so that the current step now caused a much Selleck LY294002 deeper hyperpolarization,

increasing recovery of other conductances (i.e., ITCa and NaV) from voltage-dependent inactivation, so the injected current (no IH, Vm corrected; Figure 7Fiii) was reduced to match the same steady-state hyperpolarization as in Figure 7Fi (dashed line). Under these conditions ITCa generates a small suprathreshold offset-depolarization and a single AP for only the longest duration (100 ms, green triangle; Figure 7G), Cediranib (AZD2171) confirming that ITCa is not the major trigger of offset firing. This is emphasized in the last model condition, where only ITCa is deleted, and IH alone generated a powerful short-latency single-offset response

AP (Figures 7Fiv and 7G). While IH predominates in triggering the offset response, a plot of AP number against stimulus duration (Figure 7H) emphasizes that ITCa is necessary to maintain the multiple AP firing phenotype. Our results demonstrate a neat ionic mechanism for accurate detection of sound termination. Integration of acoustically driven synaptic inputs with intrinsic conductances converts an inhibition into a well-timed AP offset response by which sound termination and gaps in ongoing sounds are encoded. Sound-evoked inhibition generates large IPSPs in the SPN, which because of the extreme negative ECl can drive IH activation (accelerating the neuronal membrane time constant) and remove steady-state inactivation of ITCa so that on termination of the sound, rapid repolarization triggers a short-latency burst of APs.