Michael A. Long - US grants

DESCRIPTION (provided by applicant): Despite the fundamental significance of temporal order on brain function, little is known about the circuit mechanisms that underlie the ability to generate and learn sequences. In the songbird premotor pathway, information concerning the production of learned vocalizations is encoded in the spatiotemporal activity patterns within a higher-order nucleus, named HVC. In the present proposal, in vivo intracellular recordings will be used to better understand the mechanisms involved in generating precisely timed sequences of activity within HVC. These experiments will address the role of synaptic inhibition and afferent inputs in generating stereotyped neuronal codes. Furthermore, the ontogeny of sequential activity within HVC will be considered in order to address the means by which learned vocalizations are encoded. The present proposal has direct relevance for human speech learning in that songbirds, unlike most animals such as nonhuman primates, are capable of learning vocalizations.

[unreadable] DESCRIPTION (provided by applicant): A principle aim of the NIDCD is the study of the "sensorimotor processing in normal and disordered communication." However, the specific mechanisms which mediate vocal communication are poorly understood. In this proposal, I directly address these issues using the songbird (zebra finch) as a model system. The proposal focuses on HVC, a forebrain structure analogous to motor cortex in humans. A number of methods will be applied to the study of HVC, with the goal of elucidating cellular and synaptic rules that govern the function of that nucleus in order to better understand its function and to ultimately shed light into disorders in human communication. The first specific aim will address the importance of HVC in providing the song system with timing information. In preliminary studies, I have used a thermoelectric device to alter the temperature of HVC in the singing zebra finch, which results in a modification of song duration. Cooling HVC leads to slower singing; heating HVC speeds the song. I will extend these studies into RA (the downstream target of HVC) in order to directly test whether HVC acts as an autonomous clock within the song system. The second specific aim will address the cellular mechanisms that contribute to pattern generation within HVC. The proposed experiments will elucidate the cellular and/or synaptic mechanisms that terminate HVC bursts, leading to sparse, feature-selective neuronal activity within that nucleus. The third specific aim will address the circuit mechanisms that contribute to pattern generation within HVC. Almost nothing is known about the rules that govern HVC synaptic connections. I will record from pairs of HVC cells to study the static and dynamic properties governing HVC synapses. These experiments will allow for a better understanding of the functional principles and topographic organization of HVC. Relevance: Vocal communication is an essential feature of human interaction, but the cellular and synaptic mechanisms that underlie speech production are poorly understood. My experiments will focus on these issues using the zebra finch, a model system capable of producing learned vocalizations with several striking parallels to humans. These studies are likely to be relevant for understanding the mechanisms of cognitive and language deficits such as autism, stuttering, and nonfluent aphasia. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): A principle aim of the field of neuroscience is the study of the mechanisms which enable learned complex behaviors, such as speaking or playing an instrument. However, the processes which underlie the generation of these behavioral sequences are poorly understood, in part because of the limitations of available methods for measuring neuronal activity in behaving animals. Recently, we designed and built a new experimental tool that enables the first ever intracellular recordings in freely behaving small animals engaged in complex behaviors. These recordings provide a wealth of information that is not available with extracellular recordings and allow for the testing of previously unapproachable hypotheses concerning the mechanisms of neural sequence generation in freely behaving animals. To that end, the experiments within this proposal focus on an important motor control nucleus in the zebra finch called HVC (formerly known as the high vocal center), which is analogous to motor areas of the mammalian neocortex. We have previously shown that HVC acts as a 'clock' for the production of learned vocalizations, but we understand little about the mechanisms by which this circuit operates. Experiments described in the first specific aim test the competing hypotheses that neurons within HVC are sequentially activated either through their intrinsic properties or through overt synaptic connections within that nucleus. The second specific aim will identify the relative impact of excitatory and inhibitory synaptic inputs on sequence generation. The third specific aim will directly address an existing controversy concerning the role of sensory feedback on motor patterning within HVC. Through these experiments, we will generate fundamental insights into the processes involved in the production of learned motor sequences in order to inform therapeutic approaches for a range of relevant disorders.

Project Summary/Abstract This project aims to investigate the circuit mechanisms that enable learned complex behaviors, such as playing the violin or hitting a tennis forehand. At present, the processes which underlie the generation of these behavioral sequences by neural networks are poorly understood. Specifically, the contributions of various cell types to this network behavior remain underexplored. Here we consider an important motor control nucleus in the zebra finch called HVC (formerly known as the high vocal center), which produces neural sequences during the performance of the learned courtship song. Our proposal focuses on local circuit interneurons, which represent the sole source of inhibition to this network. Several models have been proposed to explain the role of inhibition in song production, but consensus remains elusive. To test these models, we propose a series of electrophysiological, imaging, and optogenetic studies that will enable us to manipulate and monitor HVC interneurons selectively, often in the context of song production. In Aim 1, we will examine the role of inhibition from a postsynaptic perspective. The primary focus of this aim is to record inhibitory synaptic currents onto HVC projection neurons during song production. In Aim 2, we will examine the role of inhibition from a presynaptic perspective by directly measuring populations of identified interneurons during singing. We will also gauge the impact of individual interneurons on the network using anatomical and electrophysiological methods. In Aim 3, we will use in vivo and in vitro measurements to characterize the genetic subtypes of HVC interneurons and to distinguish their roles within the network.

Project Summary/Abstract This project aims to investigate the circuit mechanisms enabling an ethologically relevant sensorimotor transformation. Specifically, we characterize the neural basis for rapid vocal exchanges in the singing mouse (Scotinomys teguina), a highly vocal neotropical rodent species capable of producing an audible, stereotyped song. Pairs of S. teguina often precisely coordinate the timing of their vocalizations in a process known as countersinging. In preliminary work, we revealed a short-latency pathway from an orofacial region of motor cortex to the muscles involved in vocal production. In this proposal, we will test the hypothesis that neural dynamics in motor cortex, guided by selective acoustic cues, can modify downstream song production circuits to enable rapid vocal communication across individuals. From these studies, we will perform the first characterization of the circuit mechanisms underlying rapid vocal exchanges in a mammalian model system. In Aim 1, we will characterize the acoustic aspects of song that elicit countersinging behavior. We will examine responses to the playback of a range of natural and synthetic sensory stimuli to test perceptual boundaries and factors leading to vocal responsiveness. In Aim 2, we will use several complementary perturbations to address the role of motor cortex on vocal production and countersinging coordination. In Aim 3, we will use population recordings to examine the responses of cortical neural populations during vocal perception and production. We will then characterize the broader neural circuitry leading to countersinging by uncovering both upstream and downstream synaptic partners.

Project Summary/Abstract: Different species often feature distinct communication strategies for the production and perception of acoustic social signals, and a comparative approach to the study of the neural mechanisms underlying acoustic communication can lend insight into general mechanisms of neural function. A more complete understanding of these brain processes is critical for paving the way to novel treatments of the 46 million Americans experiencing a communication disorder, including deficits in speech production and language use resulting from conditions such as stroke-related neural deficits and autism. A major challenge in the study of acoustic communication is the segregation of information between human and nonhuman studies as well as the isolated communities that focus on individual model systems. The Gordon Research Conference on the Neural Mechanisms of Acoustic Communication (NMAC GRC) is a new scientific meeting created to bring together a highly interdisciplinary group of researchers to better understand how the brain encodes and produces acoustic signals. We will leverage the experimental access inherent in laboratory animals to study the cellular mechanisms for acoustic communication from a diversity of organisms, including humans. We anticipate that this conference will help to reveal new principles concerning vocal communication in the hopes of developing a deeper understanding of the disorders that affect these processes. Topics of this inaugural program include vocal development and learning, vocal interactions, auditory specializations, genomics, predictive coding, and cortical mechanisms of vocal production. The 2020 NMAC has three specific aims: 1) To advance acoustic communication research by offering an environment that encourages questions and discussion, challenges current thinking, identifies open questions, and provides opportunities for new collaborations; 2) to create a unique forum for interaction for researchers with different perspectives on acoustic communication; and 3) to promote diversity in acoustic communication research with respect to gender balance, career stage, and representation of underrepresented minorities. Successful completion of these aims will advance acoustic communication research by encouraging new ideas and collaborations, highlighting diversity in the field, and inspiring the next generation of scientists. This should accelerate the pace of discovery and translation to the clinic, consistent with the mission of NIH.

Project Summary/Abstract This project will investigate the neural mechanisms underlying utterance planning in the service of spoken interactions. We hypothesize that planning-related activity within specific cortical sites enables the rapid vocal exchanges necessary for fluent human conversation. To test this hypothesis, we will identify planning regions using electrocorticography (ECoG), a technique with sufficient temporal and spatial precision to localize neural responses in subjects engaged in both controlled interactions and unstructured conversation. In preliminary data, we found that activity within the inferior frontal gyrus (IFG; containing Broca?s region) is often tied to utterance planning. We will characterize ECoG responses by isolating both the linguistic processing and phonological output buffer (i.e., working memory) components of these responses. We will then determine the importance of planning-related activity by examining behavioral effects that result from complementary reversible cortical perturbations. In Aim 1, we will use ECoG to test our hypothesis that specific cortical sites are involved in speech-selective motor planning in both controlled interactions (i.e., a question-answer paradigm) as well as natural, ethologically-relevant conversation. In Aim 2, we will dissect utterance planning into its component parts using two different approaches: (1) a ?command-response? paradigm with increasing relevance to speech (as opposed to other motor acts) to determine the degree to which these responses can be characterized as linguistic processing and (2) a variable delay picture naming task to isolate the phonological output buffering component of the observed planning activity. In Aim 3, we will assess the necessity of planning-related activity for vocal interactions by measuring the behavioral deficits that occur following transient perturbations of planning regions. Direct cortical stimulation will be used to disrupt planning activity with high temporal precision. Mild focal brain surface cooling will be used as a complementary method of modulating the temporal dynamics of planning activity. From our studies, we will investigate the cortical network enabling vocal interactions to better understand the neural mechanisms underlying turn-taking with the broader goal of informing future therapeutic interventions designed to address the clinical conditions affecting human social language use.