Cory T. Miller - US grants

The objective of the proposed project is to understand the range of plasticity in non-human primate vocal behavior and the factors that influence variation. The specific aims will be 1) to assess several possible mechanisms underlying plasticity in the vocal behavior of a non-human primate species, and 2) to experimentally test the underlying mechanisms in non-human primate vocal plasticity. Following research on songbirds and anurans, I will make acoustic recordings and behavioral observations of vocal behavior in several geographically separated populations of a single non-human primate species. By documenting geographic variation in vocal communication, it will be possible to ascertain the role of several possible mechanisms that underlie plasticity in non-human primate vocal behavior. A series of plasticity is a product of specific mechanisms. Specifically, the first series of playback experiments will be used to determine whether non-human primates adapt the acoustic structures of their vocalizations to maximize transmission through the environment. The second set of playback experiments will investigate the plasticity in the alarm call system for adapting to sympatric predators.

DESCRIPTION (provided by applicant): This application seeks to use the natural antiphonal calling behavior of common marmosets to examine the neural mechanisms underlying vocal signal recognition in primates, focusing specifically on the role of prefrontal cortex in this process. Antiphonal calling occurs when one individual recognizes a species-specific long call and responds to that vocalization by producing the same type of vocalization. Because antiphonal calling requires that individuals recognize the initial vocalization, this behavior represents a natural recognition system that can be probed using the neuroethological approach. Specific Aim1 is to characterize the antiphonal calling response of marmosets in order to develop a behavioral assay for the subsequent components of the project. Specific Aim 2 is to use immediate early gene expression to determine the neural substrates underlying antiphonal calling. While auditory cortex is likely involved, which specific region of lateral prefrontal is involved in antiphonal calling is unknown. Specific Aim 3 is to record electrophysiological activity in prefrontal and auditory cortex to determine the functional role of these two cortical areas in call recognition. This project will form the foundation for a long term study of the neuroethology of primate communication and contribute to our understanding of complex sound processing in the primate neocortex.

[unreadable] DESCRIPTION (provided by applicant): The long term goal of the proposed project is to develop antiphonal calling as a model of the primate cortex for studies of the auditory system and human speech. Antiphonal calling is a natural (i.e., untrained) vocal behavior that involves an animal producing their species-specific long distance call in response to hearing the same call produced by an occluded conspecific. As this behavior involves perceiving an acoustic communication signal from a conspecific and generating a planned vocal response, it represents an analog to human speech and can be used to study mechanisms underlying this auditory-vocal interaction. In common marmosets, antiphonal calling involves bouts of reciprocal antiphonal calls that adhere to a species-specific temporal dynamic. Earlier work demonstrates that this behavior can be experimentally induced and manipulated in a captive setting and is readily amenable for neurobiological inquiry. Specific Aim 1 will employ a functional neuroanatomical technique known as behavior-driven immediate early gene (IEG) expression. This technique has been used successfully to determine whether particular areas of the brain play a significant role in a behavior or task. Here the IEG technique will be used to test whether the sensory and motor are mediated by different regions of the frontal cortex during antiphonal calling. Specific Aim 2 is to record electrophysiological activity of individual neurons in the frontal cortex during antiphonal calling. The locations of these recordings will be determined based on the results of Specific Aim 1. The goal is to record from both sensory and motor areas of frontal cortex during this behavior to examine how neurons in the frontal cortex contribute to sensory processing and production of communication signals. GENERAL SUMMARY - Despite the fact that numerous individuals are afflicted with aphasic deficits that result from ablations to cortical networks, there presently is no animal model that can be used to dissect the problem. Frontal cortex is known to play a significant functional role in both the sensory and motor components of human speech and, as such, any model system that targeted this area of the primate brain stands to make significant advances. Here we propose use a natural (i.e., untrained) primate vocal behavior known as antiphonal calling to examine the neural mechanisms in the frontal cortex that mediate both the sensory processing and vocal production of an acoustic communication signal. The proposed project will use a functional neuroanatomical technique and electrophysiological recordings to examine the sensory and motor components of this natural vocal behavior. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Human speech is the primary means by which we communicate with members of our species. Central to this speech is our ability to parse speech from other sounds in the environment and recognize the individual meaningful units, such as words. Because significance of this problem, we evolved specialized perceptual and neural mechanisms for speech recognition. Similarly, many animals communicate with conspecifics using vocalizations and, as such, must have evolved comparable mechanisms for vocal signal recognition. Given the anatomical and physiological similarities between all mammalian brains, studies of the behavioral and neural mechanisms underlying vocal signal recognition are likely to provide key insights into the analogous process in the human brain. This proposal aims to examine the mechanisms underlying vocal signal recognition during a species-specific vocal behavior known as antiphonal calling. Since antiphonal calls are only produced in response to a particular call type, the behavior represents a natural (i.e. untrained) recognition system. This proposal has four aims. Specific Aim 1 is to use synthetic vocalizations to examine the perceptual relevance of particular acoustic features for vocal signal recognition. Specific Aim 2 will record neurophysiological responses of individual neurons in the auditory cortex during vocal signal recognition. Specific Aim 3 will extend these physiological recordings and examine the activity of neurons in the auditory and prefrontal cortex simultaneously during antiphonal calling. Specific Aim 4 will employ pharmacological agents to inhibit specific areas of the cortex and determine the functional relationship between those populations of neurons and vocal signal recognition. Findings from this proposal will have direct relevance to our understanding of the cortical mechanisms underlying speech recognition and can aid in developing treatments for various aphasic disorders. General Summary - Like humans, many animals communicate with each other by vocalizing. By studying how the brains of animals are able to recognize their vocalizations, we will gain important insights into how speech recognition occurs in the human brain. Results from this study are applicable to research on language disorder treatments. [unreadable] [unreadable] [unreadable]

Project Summary Communication is an inherently interactive process involving the exchange of information between individuals. For communication to occur, individuals must both recognize the sound as a social signal (e.g. vocalizations), rather than another sound in the environment, as well as the relevant information encoded within the structure of the signal, such as the caller's identity. Despite the relative ease with which the primate auditory system is able to perform these computations, and evidence of vocal signal processing in primate cortex, relatively is known about the neural mechanisms underlying recognition of these communication signals. The primary aim of this proposal is to investigate the complementary roles of auditory and frontal cortex for vocal signal recognition during natural communication. To investigate this process, we employ a multi-technique approach aimed at elucidating the mechanisms underlying vocal signal recognition throughout the ventral auditory cortical system during marmoset antiphonal conversations. Aim 1 utilizes neuroimaging (fMRI) to identify vocalization responsive populations in the auditory and frontal cortex in awake subjects. The primary aim here is to test whether particular areas of these substrates in the cortical auditory system and will serve as a foundation for subsequent experiments in the proposal. Aim 2 builds on these findings to record the neurophysiological characteristics of neurons in auditory and frontal cortex while freely-moving marmosets engage in their naturally occurring antiphonal conversations. We employ a novel interactive playback paradigm in which subjects directly engage in these vocal interactions with a software-generated `Virtual Marmoset' (VM). Because the vocal behavior and signals of the VM can be experimentally manipulated, we will use this paradigm to test the responses of neurons throughout these substrates for call recognition and social recognition. Aim 3 utilizes optogenetic techniques to explicitly test the functional contributions of auditory cortex for vocal signal recognition. We employ a novel, chronic optogenetic preparation developed in my laboratory for marmosets to selectively photostimulate primary auditory cortex and the rostral belt region during antiphonal conversations. Subjects will engage in the same VM paradigms used in Aim 2 during these experiments to test the respective functional contributions of these substrates on call and social recognition during natural communication.

DESCRIPTION (provided by applicant): A major obstacle to understanding the neural mechanisms underlying behavior is our inability to distinguish between neuronal classes in recordings from behaving animals. Mouse transgenic lines, including CRE lines, have made it possible to use optogenetic techniques to selectively activate different classes to determine their role in behavior. However, it remains a challenge to determine the neuronal identity based on optogenetic stimulation, as the latency of response to direct stimulation can overlap with strong but indirect disynaptic excitation. The proposed research will introduce novel methods for distinguishing direct from indirect stimulation in order to label neuronal identity. It will furthe develop these methods for extracellular recordings made with linear array electrodes and using current source density (CSD) analysis to identify laminar location. These methods will be validated in CRE mice, and then applied to the marmoset (Callithrix jacchus). The marmoset is a particularly interesting primate model because it offers opportunities for dissecting neural circuitry that are comparable to the mouse. It matures quickly and breeds well in captivity, so it is amenable to the kinds of genetic manipulation used in mice and has produced the first primate transgenic lines. It also has a lissencephalic (flat) cortex which aids in laminar recordings. Preliminary data show marmosets can perform visual tasks under head-restraint, making them suitable to awake neurophysiology. Establishing these methods will create opportunities to study cortical circuits at a mechanistic level, enabling the field to understand how aberrations in the cortical circuitry give rise to devastating disorders such as schizophrenia and autism.

Evolution has led to a wide range of neural architectures that allow for specialized behavioral adaptation to a taxon's life history. Comparing these neural organizations across species can help us understand fundamental, cross-cutting principles of circuit structure and dynamics that underlie the functionality of nervous systems across the phylogenetic spectrum and highlight alternative neural strategies for generating a given behavioral function. This workshop on Comparative Principles of Brain Architecture and Function seeks to elucidate common principles of functional brain architecture in a broad comparative context. The workshop brings together investigators working in different animal models using various contemporary molecular, imaging, physiological, behavioral, and theoretical approaches to nervous system structure and function to address lessons learned from canonical animal models, identify obstacles and barriers in studying nervous system circuit operation and function across scales, and discuss strategies forward to overcome these barriers and enable the development of new insights into general principles of functional brain architecture. To accomplish this goal, workshop sessions move across scales of organization from whole nervous systems to specific circuits, in representative species from major clades. Sessions are comprised of a combination of presentations, panel discussions, and open discussions, with a final workshop discussion that lays the groundwork for a Workshop Report to be published in a peer-reviewed journal. Importantly, in alignment with global efforts in advancing our understanding the brain, the workshop includes participants from the US, Japan, and several other nations. Further, to strengthen diversity and training in neuroscience, the workshop is arranged to invite junior and underrepresented scientists to participate in the presentations and discussions, and establish connections in the field of comparative neurobiology nationally and internationally.

The workshop takes place over 2 days immediately following the annual meeting of the Society for Neuroscience, an event attended by over 30,000 neuroscientists from around the globe. The workshop covers topics from whole brain organization to neural circuits and behavior, and genetic as well as theoretical approaches to neural circuit structure and function. The workshop format, which includes sessions and panel discussions, is organized to promote the sharing of ideas between groups using different organisms, methodologies, and conceptual frameworks. Toward the goal of nurturing comparative and interdisciplinary approaches among the next generation of neurobiologists, the workshop also includes a poster session at which student and postdoctoral trainees present and discuss their work. Additionally, many opportunities for small-group and one-on-one discussions are provided. These different elements of the workshop format render the workshop highly conducive to the fostering of new national and international collaborations that cut across experimental models and methods of inquiry. As diversity is the key to the success of the workshop, participants include established as well as early career investigators and trainees from different nations, as well as women and minorities. Their collective insights are instrumental to the workshop's success in leading to the development of new ideas and strategies toward uncovering comparative principles of circuit structure and function.

Project Summary The medial temporal lobe (MTL) plays a critical role in the rapid formation of episodic memories in human and nonhuman primates, while research performed in freely-moving rodents has likewise identified these same structure as being pivotal for spatial navigation. Each of these lines of work reflect powerful research traditions that have significantly contributed to our understanding of medial temporal lobe function, but questions remain about how to reconcile their considerable data sets. One compelling hypothesis is that the same neural mechanisms that support the role of MTL in spatial navigation also support the formation of episodic memories. We propose an innovative set of experiments designed to directly test this hypothesis Our approach involves recording neural activity from the same neurons in the medial temporal lobe of marmoset monkeys in two contexts. One involves head-restrained subjects performing a recognition memory task typical of human experiments while in the other freely-moving subjects navigate spatial environments commonly used in studies of rodents. Our innovative approach will allow us to test ? for the first time - whether the same neurons in primate medial temporal lobe support behaviors performed in tasks representative of these two research traditions. Aim 1 seeks to characterize recognition memory in marmosets using a task that ? like spatial navigation ? relies on incidental memory formation. Experiments in Aim 2 examine the role of the hippocampal CA fields and entorhinal cortex in spatial navigation, including the putative existence of place cells and grid cells, respectively. Aim 3 directly tests the principal question of this proposal by recording from the identical neurons while subjects perform the recognition memory task in Aim 1 and navigate spatial environments similar to studies in Aim 2.

Abstract This application is a request for funds to support the 3rd annual Marmoset Bioscience Symposium (MBS) to be held November 11, two days before the start of the 2021 Society for Neuroscience (SFN) meeting in Chicago, IL. This meeting will be registered as an SFN satellite symposium. The common marmoset (Callithrix jacchus) has experienced unprecedented growth in research across the United States and is rapidly emerging as a likely keystone biomedical model system in the next chapter of scientific discovery. The major goal of the meeting is part of a multiple-pronged approach to establish a U.S.-based consortium aimed at highlighting cutting-edge research in marmosets and promoting marmosets as a key model system. This meeting will provide a networking forum for both established investigators and junior scientists from diverse backgrounds to interact and communicate their research findings. Critical to the success of the marmoset model is fostering the development of junior scientists in the field. This meeting is also aimed at attracting investigators who are currently not using marmosets in their research. The principal objectives of the MBS include: (1) to communicate and disseminate new findings from using marmosets as a model organism in diverse fields and development of new genetic, viral, and analytic tools that will advance research in marmosets; (2) to provide an open forum for discussion of new hypotheses and approaches and discrepancies in the literature and to facilitate the exchange of reagents such as antibodies, protocols, and viral toolbox; (3) to increase interactions and collaborations between basic scientists and translational and clinical groups interested in modeling human disease in the marmoset and (4) to provide an atmosphere in which researchers wishing to use marmosets in their research may interact directly with established investigators. These MBSs are highly relevant to the programmatic mission of multiple NIH ICs. The meetings consist of a Keynote Lecture, Young Investigator talks, invited talks from trainees and young investigators that are selected from submitted abstracts, and poster sessions. These meetings offer a unique combination of features, including (1) breadth of research, (2) cutting-edge questions and technologies, (3) mingling of investigators from all ranks and diverse sub-fields and locales, and (4) intimate size and extended discussion time, allowing for sustained interactions. Three tentative themes are planned: (1) Social behavior, physiology, and neural circuits, (2) Aging and neurodegenerative disease, and (3) Genetic, viral, and analytic tools developed for marmoset research. Finally, participation by women and those from underrepresented groups will be emphasized. Half of the oral presentations will be from these groups and half of the travel awards will be given to women. The leadership of the MBS itself is ~43% female.