From songs to synapses, ion channels and mathematical modeling

Since the scientific study of birdsong began in the late 1950s, songbirds have emerged as impressive neurobiological models for aspects of human verbal communication because they learn to sequence their song elements, analogous, in many ways, to how humans learn to produce spoken sequences with syntactic structure. Thus, determining how spoken language evolved is more likely to become clearer with concerted efforts in researching songbirds. Some of the most fundamental questions in neuroscience are pursued through the study of songbirds. How does the brain generate complex sequential behaviors? How do we learn to speak? How do humans learn various behaviors by observing and imitating others? Where are the "prime movers" that control behavior? Which circuits in the brain control the order in which motor gestures of a learned behavior are generated? Among all these questions, of particular interest to us is the question of sequential behavior. Understanding the neural mechanisms that underlie sequential behavior and imitative learning is the holy grail of the field. The birdsong provided us with a uniquely powerful model for tackling this question in a system where the brain structures responsible for its generation are well known.;We pursued the study of sequential neural activity in songbirds on three levels: behavioral, cellular and network. On the behavioral level, we developed a computational tool for automated, quantitative syllable-level analysis of bird song syntax. This tool aids songbird researchers and fanciers in comparing and quantifying the syntactic structure of songs produced by a bird prior to and after a manipulation such as ablation of brain region or infusion of pharmacological agents, in addition to several other purposes. As we will discuss later, this syntactic structure is highly stereotyped in songbirds and driven by neurons firing in sequential order in particular regions of the songbird's brain.;On the cellular level, the telencephalic nucleus HVC (proper name) within the songbird analogue of the mammalian pre-motor cortex is situated at a critical point in the pattern-generating premotor brain circuitry of oscine songbirds. This nucleus is of extreme importance to the songbird and produces stereotyped instructions through the motor pathway leading to precise, learned vocalization by songbirds. HVC contains three populations of neurons that are interconnected, with specific patterns of excitatory and inhibitory connectivity. Characterizing the neurons in HVC is a very important requirement for decoding the neural code of the birdsong. We performed whole-cell current clamp recordings on HVC neurons within brain slices to examine their intrinsic firing properties and determine which ionic currents are responsible for their characteristic firing patterns. We also developed conductance-based models for the different neurons and calibrated the models using data from our brain slice work. These models were then used to generate predictions about the makeup of the ionic currents that are responsible for the different responses to stimuli. These predictions were then tested and verified in the slice using pharmacological manipulations. Our results are an improved characterization of the HVC neurons responsible for song production in the songbird which are the key ingredients in understanding the HVC network.;We then developed prototype neural architectures of the HVC that can produce the patterns of sequential neural activity exhibited by the three types of HVC neurons during singing. Our networks consist of microcircuits of interconnected neurons which are active during different syllables of the song. The various networks that we consider assign different roles to each of the HVC neurons types in the production of the sequential activity pattern, and show great flexibility in the connectivity patterns among the neuron types. The model networks developed provide key insights into how the different types of HVC neurons can be used for sequence generation.;The significance of the work presented in this dissertation is that it helps elucidate the neural mechanisms behind HVC activity. The in vitro studies we performed in brain slices and the models we developed provide critical pieces to the puzzle of sequential behavior.