SOMATO-DENDRITIC MECHANISMS REGULATE THE FIRING BEHAVIORS OF “STUTTERING” NEURONS: A TWO-COMPARTMENT MODELING STUDY ON PREMOTOR RA-PROJECTING HVC NEURONS

Abstract

The high vocal center (HVC) is the avian analogue of the premotor cortex in the songbird brain. It represents a central component of an interconnected circuit of brain nuclei known as ‘the song system’ and constitutes a critical neural site for song learning and production. HVC contains at least three neural populations: neurons that project to the RA (robust nucleus of arcopallium, or HVCRA), neurons that project to Area X (basal ganglia), and interneurons. Recent intracellular whole-cell patch clamp recordings accompanied by neuropharmacological and histological manipulations have shown that HVCRA neurons display a significant variability in their intrinsic firing patterns (Daou et al, in preparation). In particular, Daou et al showed that there exist three classes of HVCRA neurons that are distinguished by their electrophysiological and morphological properties, a diversity that is orchestrated by a cocktail of ion channels that are expressed in these neurons. Despite the fundamental importance of this class of projecting premotor neurons during song learning and production, little is known about the ion channels orchestrating their intrinsic firing properties and their distribution inside the cells (i.e., soma and dendrites). In this work, we developed two-compartment HVCRA conductance-based neuronal models that consist of somatic and dendritic compartments and fit the models to the electrophysiological data we collected in brain slices. Initially, the distribution of ion channels inside the cell membranes of HVCRA followed a similar mammalian distribution of ion channels from neurons that exhibit the same ion channels and similar firing patterns. In the first part of the study, we reproduced the voltage traces exhibited by the three classes of HVCRA neurons in brain slices in response to various current stimuli. Next, we focused on Class III HVCRA neurons, a class of neurons that exhibit a stuttering or pausing firing behavior, reminiscent of the discharges that some classes of neurons in the somatosensory cortex, basolateral amygdala, dentate gyrus, visual cortex, and other areas of the brain exhibit. While some pharmacological manipulations have previously shed light on some of the ionic currents that govern these neurons’ dynamics (not in the HVC), computationally there is yet no coherent mathematical model that provides a clear explanation and analysis of the parameters that orchestrate their intrinsic properties. The models we designed highlighted the importance of low-threshold voltage-gated D-type (ID) and M-type (IM) potassium currents in regulating the firing patterns of class I and class II HVCRA neurons. The models as well highlighted a crucial interplay between somatic IM (M-type) and ISK (calcium-dependent) potassium currents with dendritic ID (D-type) and IA (A-type) potassium currents in shaping the stuttering or pausing behaviors of class III HVCRA neurons. In particular, somatic IM was responsible for dampening their excitability, somatic ISK regulates the number of bursts, while dendritic ID and IA control the inter-burst duration of the “stutters” in spike trains, the number of spikes in the corresponding epochs, and the delay to the onset of spiking in these neurons. Our models provide insight on the distribution and interactions between the distinct ion channels located on the surface membranes of the somatic and dendritic compartments of HVCRA neurons, which we will be testing and verifying histologically. They also provide a solid mathematical framework that could be used to model other neurons in the brain that exhibit this distinctive firing pattern.