Hyperpolarization-activated cation channels confer tonotopic specialization for temporal encoding of sound frequency...

Sensory neurons are endowed with physiological characteristics that facilitate accurate signal extraction from stimuli. The functional importance of such properties is exemplified in auditory neurons where intrinsic excitability is optimized to detect frequency-specific features. In birds, the neurons of nucleus magnocellularis (NM) receive primary auditory inputs that are spatially arranged according to best frequency, or 'tonotopically.' Several physiological properties vary systematically along NM's tonotopic axis. Gradients of voltage-gated channels shape temporal response selectivity enabling precise encoding of sound features. We identified a previously undescribed expression pattern of hyperpolarization-activated cation (HCN) channels in the domestic chick Gallus gallus domesticus of both sexes Electrophysiological and immunohistochemical analyses demonstrated a tonotopic gradient of HCN1 but not HCN2 subunits that underlie I _H currents along NM's tonotopic axis. To measure the effect of I _H on membrane excitability along the tonotopy, we applied depolarizing current ramps prior to and during pharmacological I _H block. We show I _H exerts a strong influence on temporal integration properties of NM membranes. Next, we investigated whether this response modulation facilitates encoding of temporally patterned inputs by injecting depolarizing current pulse trains to simulate synaptic excitatory drive. During I _H block, spike entrainment failed at high input rates suggesting HCN channels contribute strongly to NM's temporal selectivity. Computational modeling extended these results to show a contribution of I _H to high frequency neuron responses in the presence of noise. This work establishes a tonotopic distribution of HCN channels in NM and demonstrates its contributions to temporal response selectivity, particularly at high frequencies.Significance Statement This study is the first to describe a tonotopic gradient of HCN channels in a vertebrate cochlear nucleus. Experimental assays and computational modeling demonstrate that the tonotopic expression pattern of HCN channels enables improved neural encoding of temporally patterned excitatory drive at high synaptic input rates. Temporal response fidelity in this circuit is required for precise sound localization. This work provides compelling evidence suggesting that HCN channel expression is regulated to optimize computational precision in sensory processing.