Choreographing Neural Rythms: Intrinsic and Synaptic Modulations of Temporal and Stereotyped Neural Sequence Generation in the Premotor Cortex of Songbirds

Abstract

Learned sequential behaviors are captivating brain patterns; however, their underlying neural mechanisms are not well understood. Birdsong is a prominent model to study such behavior particularly because juvenile songbirds progressively learn from their tutors and by adulthood are able to sing stereotyped song patterns. We studied the premotor nucleus HVC at a nexus of multiple pathways contributing to song learning and production. The HVC consists of multiple classes of neuronal populations, each that has its own cellular, electrophysiological and functional properties: basal ganglia – projecting (HVCX) neurons, forebrain - projecting (HVCRA) neurons, and interneurons (HVCINT). During singing, a large subset of motor cortex analog-projecting HVCRA neurons emit a single 6-10 ms burst of spikes at the same time during each rendition of song, a large subset of basal ganglia-projecting HVCX neurons fire 1 to 4 bursts that are similarly time locked to vocalizations, while HVCINT neurons fire tonically at average high frequency throughout song with prominent modulations whose timing in relation to song remains unresolved. This opens the opportunity to define models relating explicit HVC circuitry to how these neurons work cooperatively to control learning and singing. Despite the fundamental importance of unveiling the neural mechanisms behind temporal sequence generation in general, and birdsong vocalizations in specific, very little had been done at the experimental and computational levels. In this thesis, we developed conductance-based Hodgkin Huxley models for the three classes of HVC neurons (based on the ion channels previously identified pharmacologically) and connected them in several physiologically realistic networks (based on pharmacologically identified glutaminergic and GABAergic connectivity) via different architecture patterning scenarios with the aim to replicate their in vivo firing patterning behaviors. We are able through these networks to reproduce the in vivo behavior of each class of HVC neurons as shown by the experimental recordings. The different networks unveiled key intrinsic and synaptic processes that modulate the sequential propagation of neural activity (continuous or punctate) in the HVC by highlighting important roles for the T-type Ca2+ current, Ca2+-dependent K+ current, A-type K+ current, hyperpolarization activated inward current, as well as GABA and AMPA synaptic currents in governing important neural mechanisms for sequence propagation, like post-inhibitory rebound bursting in HVCX, mono-synaptic HVCX to HVCRA excitatory connectivity, different classes of interneurons (phasic and tonic), microcircuit architecture patterning in encoding syllables or sub-syllabic segments, among others. The result is an improved characterization of the HVC network responsible for song production in the songbird.