2001 — 2002 |
Shea, Stephen D |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Neuromodulation of Auditory Input
DESCRIPTION (provided by applicant): Songbird vocal learning provides an excellent model system in which to study the relationship of brain and behavior. Electrophysiological data from freely behaving birds suggest that behavioral state is relevant to song maintenance. Auditory feedback, which is necessary for the maintenance of song, is differentially regulated in two functionally and anatomically distinct pathways of the forebrain song system according to behavioral state. Our proposal aims to combine in vivo and in vitro electrophysiological techniques to examine the specific effects of cholinergic input on the transmission of auditory feedback in a forebrain nucleus which is a nexus of auditory and premotor activity. Cholinergic systems have been shown to be related to attention, arousal, and memory in a number of organisms, including humans. This series of experiments will therefore have the potential to illuminate the role of feedback and attentional mechanisms in the performance of complex motor behaviors.
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0.904 |
2016 — 2020 |
Shea, Stephen D |
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. |
Disrupted Auditory Cortical Plasticity and Behavior in a Model of Rett Syndrome @ Cold Spring Harbor Laboratory
? DESCRIPTION (provided by applicant): Impaired perception and production of language, as well as deficits in social behavior generally, are pervasive features among the autism spectrum disorders (ASD). However, the changes to in vivo circuitry that connect disordered molecular and developmental events to altered behavior are largely unknown. Therefore, the goals of this proposal are: 1) To identify inhibitory neuronal circuits that support vocal perception 2) To determine how they are impaired in a rodent model of Rett syndrome 3) To repair the inhibitory circuitry using novel genetic and pharmacological strategies. To achieve these goals, we propose to use a combination of novel behavioral assays, genetic methods, and electrophysiology. With these tools, we can observe plasticity in specific inhibitory circuits, assess the neural and behavioral consequences of perturbing these circuits, and ultimately restore behavioral function by repairing those circuits. In our preliminary data, we describe a simple, robust and ethologically relevant assay of maternal behavior in a model of Rett syndrome (mice carrying only one copy of the gene MeCP2 - `hets'). Our results with this assay reveal a profound deficit of maternal social learning in hets that we hypothesize is related to poor perception of pup vocalizations. Indeed, we link gathering behavior to function and plasticity of the auditory cortex by showing that: 1) MeCP2 expression in the auditory cortex is necessary for proficient maternal behavior. 2) Auditory cortical neurons in hets exhibit impaired plasticity of inhibitory responses to vocal stimuli. 3) Immunohistochemical marker data reflect dysregulated maturation of auditory cortical inhibitory networks in response to maternal experience. Crucially, the hets are characterized by enhanced expression of perineuronal nets (PNNs), structures that closely associate with inhibitory networks and are thought to limit plasticity. 4) A `genetic rescue' manipulation of GABAergic inhibitory function relieves the elevated PNN expression, and remarkably restores normal behavioral performance. 5) Pharmacological inhibition of PNNs selectively in the auditory cortex prior to maternal experience is sufficient to restore maternal learning as well. Our objectives are to identify specific auditory cortical circuits governing vocal perception, to determine the in vivo functional consequences of MeCP2 heterozygosity in these circuits, and to rescue circuit function and behavior with a genetic manipulation of these circuits. By achieving these goals, we will forge crucial links between molecular and circuit pathologies and impaired social communication in the Rett syndrome mouse model, and we will potentially identify candidate circuit targets for therapeutic intervention.
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1 |
2019 — 2020 |
Shea, Stephen D |
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. |
Emotional Modulation of Neural and Behavioral Responses to Social Cues by Locus Coeruleus @ Cold Spring Harbor Laboratory
PROJECT SUMMARY The goal of this proposal is to define the mechanisms by which noradrenaline (NA) from locus coeruleus (LC) attaches emotional significance to social cues and regulates socially-motivated behavior. Appropriate responses to rewarding stimuli are central to survival. Control of reward-driven behavior is most often associated with midbrain dopamine circuits. Yet, there is mounting evidence that the attractive potency (?motivational salience?) of a given cue dynamically depends on a broader set of circuits signaling context and internal state. For example, responses to social rewards depend on their emotional significance. Adult female mice undergo dramatic changes in their response to mating and familial cues after their initial sexual and maternal experiences. These powerfully arousing experiences attach enduring emotional significance to social cues experienced during the encounter and increase their motivational salience. LC is a key structure for broadcasting arousal and emotional significance. Past studies strongly suggest that LC activity signals the emotional content of social cues, but due to the limited temporal resolution of the methods used in those studies, it is unclear whether LC affects motivated behavior by altering neural responses to social stimuli or by promoting specific behaviors. Here we propose to use high temporal resolution methods for recording neural activity, that have never before been performed in LC of animals freely engaging in social behavior. We will answer the question of whether LC spiking occurs predominantly in response to social sensory cues or in advance of behavioral choices. Our central hypothesis is that LC shapes social goal-directed behavior both by modulating the motivational salience of social cues and facilitating behavior responses. We aim to answer three outstanding questions regarding the contribution of LC activity to social behavior: (1) What is the timing of activity LC relative to social behaviors, and does it change with social experience? (2) How do tonic (sustained) activity and phasic (brief) activity contribute to behavior? and (3) How does LC input to downstream targets affect neural activity and behavioral responses. LC has long been indirectly implicated in the regulation of social behavior, but its specific online contribution to social interactions is not known. The significance of these studies lies in their potential to clarify this aspect of LC function and reconcile it with LC?s other roles in cognition, learning and control of arousal state.
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