Oline, S. | bioRxiv Science

bioRxiv2025

Hyperpolarization-activated cation channels confer tonotopic specialization for temporal encoding of sound frequency in the cochlear nucleus

Sensory neurons are equipped with physiological properties vital for accurate signal processing. The functional importance of such properties is exemplified in auditory circuits where intrinsic excitability is optimized to detect frequency-specific features. In birds, the neurons of nucleus magnocellularis (NM) receive primary auditory input (Rubel and Parks, 1975a; Parks and Rubel, 1978; Jackson et al., 1982) and are arranged tonotopically. NM comprises a superficially homogenous neural population, but several physiological properties vary systematically along its tonotopic frequency axis. In particular, expression of voltage-gated conductances plays a pivotal role in creating selectivity that enables temporal precision. Here, we identify a previously undescribed gradient of hyperpolarization-activated cation channels (IH). Whole cell patch clamp techniques and immunostaining for HCN1, an IH channel subunit, demonstrated an expression gradient corresponding to NMs tonotopic axis. To investigate the function of tonotopic IH expression in NM, we applied a depolarizing ramp injection protocol to measure the impact of pharmacologically blocking IH on neural active properties (Ferragamo and Oertel, 2002; McGinley and Oertel, 2006; Oline et al. 2016). Next, we investigated whether this tonotopic patterning of HCN facilitates encoding of temporally patterned inputs. We injected depolarizing current pulse trains before and during HCN channel block. During pharmacological block, there was a reduction of NM spike entrainment to input pulses suggesting a key contribution of HCN channels to NMs ability to encode its synaptic drive. Results show that there is tonotopic distribution of HCN channels in NM which provides a novel mechanism that enables NM neurons to encode temporally patterned excitatory input. Significance StatementThis study is the first to describe a tonotopic gradient of IH channels in a vertebrate cochlear nucleus. Physiological and computational model assays suggest that the tonotopic expression pattern of HCN channels enables improved neural encoding of high frequency, temporally patterned input. Temporal response fidelity enables precise sound localization computations.

neuroscience↗

bioRxiv2022

Independent inhibitory control mechanisms for aggressive motivation and action

Social behaviors, like other motivated behaviors, frequently consist of a flexible motivated-seeking or approach phase followed by social action. Dysregulated social behavior may arise from changes to motivation, wherein individuals fail to enter a motivated seeking state, or may be in the execution of the social action itself. However, it is unclear how the brain generates and gates this flexible motivation-to-action sequence, and whether aggressive motivation and action are controlled by separate circuit mechanisms. Here, we record populations of neurons in the ventromedial hypothalamus ventrolateral area (VMHvl) of male mice at cellular resolution during "free" aggression and also during an aggression operant task, where the behaviors that precede attack are stereotyped. We find that this population encodes the temporal sequence of aggressive motivation to action and that the temporal selectivity of neurons is invariant to differences in motivated behavior. To test whether motivation and action could be independently regulated, we focused on two key inhibitory inputs to the VMHvl: a source of local inhibition (VMHvl shell) and the primary source of long-range inhibition (the medial preoptic area, MPO). While we find that the VMHvl receives broad monosynaptic inhibitory input from both inputs, optogenetic perturbation of these inputs during recording reveals temporal selectivity during aggressive motivation and action, suggesting specificity of function. Encoding models applied to population calcium recordings of these inhibitory inputs during naturalistic social interactions and during the social operant task further reveal that these inputs have different temporal dynamics during aggression: VMHvl shellvgat+ activity peaks at the start of aggressive interactions, while MPO-VMHvlvgat+ activity peaks at behaviorally aligned endpoints of aggressive interactions. Finally, using closed-loop optogenetic stimulation timed to specific phases of the aggression-operant task, we find a double-dissociation of the effects on aggressive motivation and action: activation of MPO-VMHvlvgat+, even briefly and temporally distant from the initiation of aggression, produces long-lasting motivational deficits, delaying the initiation of aggression and generating behaviors consistent with an unmotivated state. In contrast, activation of VMHvl shellvgat+ produces acute action-related deficits, causing an exit from an attack state. Fitting a Hidden Markov Model (HMM) to behavior further corroborates these findings by showing that MPO-VMHvlvgat+ stimulation prolongs a low motivation state and VMHvl shellvgat+ promotes exit from an attack state. Together, these data demonstrate how separable inhibitory circuits in the hypothalamus can independently gate the motivational and action phases of aggression through a single locus of control.

neuroscience↗