2006 — 2015 |
Liu, Robert C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Functional Approach to Communication Sound Processing in Mouse Auditory Cortex
[unreadable] DESCRIPTION (provided by applicant): Project Summary: The long-term goal of this research is to understand how the mammalian auditory cortex processes and learns social communication sounds. A mouse model is proposed for investigating this in a natural communication context between mouse pups and adult female mice. We used advanced quantitative methods to evaluate what information neurons in the auditory cortex can provide about these sounds that will facilitate their detection, discrimination and categorization. 3 specific aims are proposed. First, we will test the hypothesis that animals for whom the sounds are communicative represent the sounds differently from those for whom the sounds are not communicative. Second, we will look at what neural response properties help to improve a neuron's ability to provide information about these communication sounds. Third, we investigate the spatial organization of the auditory cortex for processing these sounds. Researching these questions in a mouse model provides the future opportunity to use genetic methods to dissect the mechanisms involved in communication sound processing. Relevance: This study will improve our understanding of how the brain detects, discriminates and categorizes communication sounds. These tasks are fundamental to how humans perceive and process speech. Thus, this research may eventually help us determine how normal neural processing breaks down in individuals with speech [unreadable] hearing problems. [unreadable] [unreadable] [unreadable]
|
1 |
2012 — 2013 |
Liu, Robert C |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Functional Neural Connectivity During Social Bonding in Voles
DESCRIPTION (provided by applicant): Advances in affiliative neuroendocrinology have revealed that oxytocin acts within a core social behavior neural circuit to facilitate social bondig in mammals. Simply knowing oxytocin's sites of action, however, does not reveal its mode of action during actual conspecific interactions. Our long-term goal is to illuminate how social neurochemicals like oxytocin modulate in vivo the function of neural circuits underlying social reward and social information processing - key elements in establishing social bonds. The objective here is to use chronic electrode implants in specific limbic system sites known to be modulated by oxytocin to determine the normal functional neural connectivity between these circuits during affiliative behaviors in prairie voles. Our central hypothesis is that social interactions synchronize electrophysiological activity across components of the social reward and social information pathways, thus enhancing their functional connectivity. Our rationale is that, once we know how these brain areas normally communicate with one another during social bonding events, we can use pharmacological techniques to test specific hypotheses about the in vivo modulatory function of oxytocin. We will investigate our hypothesis by pursuing two specific aims. First, we will determine functional neural connectivity within components of the social reward pathway during the formation and expression of a social bond in female prairie voles. Second, we will determine functional neural connectivity between components of the social information processing and reward pathways during the formation and expression of a social bond. Our proposal's significance lies in the fact that it initiates an entirely new line of investigation in vole social bonding research that asks about how oxytocin modulates neural activity during bonding. Our use of implanted microelectrodes in awake animals will enable new questions and hypotheses about the mechanisms of social (or even nonsocial) behaviors in the vole model organism. Thus, it holds the potential to change the way we think about how social signals and neuropeptides like oxytocin coordinate the neural resources responsible for social information processing and reward during affiliative interactions. Finally, this research can potentially help guide applications to human health, since intranasal oxytocin is now in clinical trials as a treatment for ameliorating social dysfunctions in several mental health disorders, even though our understanding of how oxytocin works in the brain to promote social cognition is not yet fully elucidated. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because discovering that neural activity in the mammalian social neural network is coordinated during normal social bonding will increase our understanding of how this neural activity may become disrupted in social disorders like autism spectrum disorder, depression, and schizophrenia. Thus, the project is relevant to the part of NIH's mission that pertains to seeking fundamental knowledge about the nature of mental disorders, and the application of that knowledge to enhance health.
|
1 |
2013 — 2014 |
Liu, Robert C Ressler, Kerry J [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Epigenetics of Neuronal Plasticity in Auditory Cortex in a Sensory Memory Model
DESCRIPTION (provided by applicant): A key question in the study of sensory memory formation concerns how and where the long-term engram of a behaviorally relevant stimulus is created and stored, given the dynamic and distributed nature of the underlying neuronal processes. In the case of auditory learning and memory, behavioral and electrophysiological evidence point to a key role played by the auditory cortex, but the molecular mechanisms operating there to enable memory formation and maintenance are unknown. In particular, how are networks of neurons encoding a stimulus-behavior association able to initiate and retain changes in their synaptic connectivity despite turnover in the underlying molecular machinery? We propose to use an auditory fear conditioning paradigm to dis- cover whether the conformational state of DNA in auditory cortical neurons is altered to permit or repress the expression of plasticity-related genes, and whether this is triggered by known experience-dependent plasticity processes to establish persistent auditory memories. Our long-term goal is to reveal the molecular mechanisms that are recruited by specific cell types in the auditory cortex to form stable memories. The objective here is to demonstrate that the BDNF-TrkB cascade, which is critical in regulating adult experience-dependent synaptic plasticity in a large number of brain areas, modifies the epigenetic status of synaptic plasticity-related genes in auditory cortical neurons during fear conditioning, a robust model of auditory learning. Our central hypothesis is that during the consolidation and storage of fear associations to auditory cues, the BDNF-TrkB pathway is upregulated in the auditory cortex leading to the epigenetic regulation of the target plasticity genes. This chain of events results in the stabilization of synapses that encode fear memories. We will test this hypothesis with two specific aims. First, we will determine whether specific genes implicated in the machinery that mediates synaptic plasticity are epigenetically modified in neurons in the auditory cortex after auditory fear conditioning. Second, we will determine whether BDNF-TrkB signaling in the auditory cortex during auditory fear conditioning is necessary for both changes in the epigenetic status/expression of those genes and fear learning. Our proposal's significance lays in the fact that by demonstrating epigenetic modifications in a core sensory cortical area during learning, it initiates a new line a research that merges modern concepts from molecular studies of learning and memory with investigations of sensory cortical contributions to auditory memories. By using a novel methodology to target epigenetic studies to specific cell types, chosen here for proof-of- principle purposes to be neurons rather than glial cells, we are laying the foundation for future studies that will dissociate the contributions of different interneuronal and pyramidal cell types n the molecular maintenance of memories. Finally, gaining these abilities to further decipher the molecular and neural mechanisms of sensory learning and memory will then enable the development of new pharmacological targets to treat disorders involving sensory memory dysfunction, such as post-traumatic stress disorder (PTSD).
|
1 |
2017 — 2021 |
Berman, Gordon Joseph (co-PI) [⬀] Liu, Robert C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Crcns:Predictability as a New Paradigm For Rodent Social Neurobiology
A long-lasting social attachment is built over a course of positive interactions with another individual. Forming such social bonds involves cognitive processes like perceiving salient sensory cues, learning their positive value, and selecting appropriately prosocial behavioral actions. Elucidating the mechanisms of such a complex natural behavior is a Strategic Objective of the NIMH. Our proposal will advance this Objective by contributing new knowledge within the RDoC domains of Social Processes, Positive Valence and Cognitive Systems. Our long-term goal is to enable a more vertical understanding of how molecular mechanisms influence neural circuits underlying moment-by-moment processes that must occur to build enduring social bonds. Our objective here is to use the principles of stereotypy and predictability to elucidate the behavioral and neural dynamics that underlie social bonding in the prairie vole (Microtus ochrogaster), a premier system for uncovering genetic and neuroendocrine mechanisms of social attachments. We will measure social behaviors and striatal, cortical and amygdalar neural activity over long time scales and build predictive models of the social dynamics leading to a bond. Our central hypothesis is that trajectories of stereotyped social behaviors and corresponding neural activity are predictable from a latent internal state of pair-bondedness; and that modeling the dynamics of this latent state will help predict future social interactions between pair-bonded prairie voles. We will quantify the predictability of such interactions in ethologically-relevant social contexts using past social behavior (Aim 1) and behavior-specific dynamic functional connectivity between those key nodes in the social brain neural network (Aim 2). Our research will have a positive impact by validating a novel, quantitative framework for studying the dark matter of social neuroscience, grounded in the idea that there is predictability in the dynamic processes that underlie one's trajectory through a behavioral space of stereotypical social interactions. By establishing predictability as a new paradigm for rodent social neurobiology, our studies will thus advance a comprehensive framework for how to think about social deficits and how to encourage prosocial behavior.
|
1 |
2018 — 2021 |
Liu, Robert C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Resubmission of Functional Approach to Communication Sound Processing in Mouse Auditory Cortex
PROJECT SUMMARY Acoustic communication is critical for normal social interactions in many species, including humans, yet so- cial aspects of communication functions and dysfunctions are often overlooked in studies of how the brain re- sponds to and learns communication sounds. One key brain mechanism concerns the neural plasticity within the auditory cortex to support learning the social meaning of new communication sounds. However, our circuit and cellular level understanding of such plasticity is more often based on studies where a sound's salience is acquired through nonsocial reinforcement procedures, rather than from rewarding social interactions. Hence, there is a gap in our knowledge of the neural principles for communication sound processing and plasticity during more realistic social auditory learning. Our long-term goal is to understand the circuit and cellular mechanisms under- lying the auditory system's encoding of socially-learned sound categories, so that causes underlying deficits in communication processing can be inferred. Our objective here is to uncover whether socially learning a sound category alters higher-order auditory cortical fields' neuronal tuning and tolerance for acoustic variability in that category's sound features. Our central hypothesis is that both Core auditory cortex and secondary auditory cor- tical field A2 are intrinsically tuned to parameters describing complex frequency trajectories of sounds, with neu- rons in a secondary field exhibiting greater tolerance in these parameters. Learning the social meaning of a specific sound category then biases neurons along a feedforward pathway through Core and A2 to become more attuned to the likely parameters of the learned category. We investigate this hypothesis by exploiting a maternal mouse model of ultrasonic communication between pups and adult females. When pup calls become behavior- ally relevant to mothers, neurons in the auditory cortex changes how they respond in ways that were not expected from nonsocial auditory learning paradigms. This proposal addresses the underlying neural mechanisms in two specific aims. First, using extracellular electrophysiology, we will determine how the neural transformation from Core to A2 alters neuronal tuning and tolerance for the acoustic features of the pup call category. Second, using a new socially-reinforced auditory training paradigm, we will determine how calibrated, explicit social experience with a novel sound category modifies the Core to A2 neural transformation. This research's significance lies in its unique ability to bridge the scientific gap between sensory and social/behavioral neuroscience in an animal model in which studies of a high level auditory function (communication) can be conducted from a systems down to a molecular level.
|
1 |
2018 — 2021 |
Liu, Robert C |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Role of Ot in Cortico-Striatal and Amygdalo-Striatal Facilitation of Social Attachment
PROJECT SUMMARY (Project 2, Liu) Oxytocin is important for many aspects of social cognition. However, it is far from understood how oxytocin acts in the brain to have its effects on social perception, learning and the formation of long-term attachments. The monogamous prairie vole (Microtus ochrogaster) is a premier animal model for studying mechanisms of attach- ment, and oxytocin acting in various reward-related brain regions is essential for prairie voles to form pair bonds. Yet exactly how oxytocin facilitates pair bonding by modulating the underlying neural circuitry during social inter- actions to form bonds is unknown, pointing to a gap in our knowledge linking neurochemical to neural circuit mechanisms of attachment. Our long-term goal is to elucidate how oxytocin modulates reward and sensory systems underlying social information processing and learning. We focus here on a key oxytocin receptor-rich node at the interface between these systems, the nucleus accumbens, which receives inputs from other oxytocin receptor-dense areas, the medial prefrontal cortex (Aim 1) and the basolateral amygdala (Aim 2). Our objective here is to determine whether manipulating the oxytocin system to impair or enhance pair bonding affects nucleus accumbens' functional connectivity with its mPFC and BLA inputs. Our central hypothesis is that oxytocin nor- mally acts to improve communication from reward and cue processing areas to local NAc circuits that integrate these channels of information during specific social interactions, helping to reinforce the ability of partner signals to elicit affiliative behavior. We validate this hypothesis using both loss-of-function and gain-of-function experi- mental designs, as well as optogenetics to test causality. The rationale for our proposal is that, once we know how oxytocin affects neural circuitry between brain areas to facilitate the formation of a selective attachment, we can begin to elucidate the molecular mechanisms for plasticity within these circuits.
|
1 |