2016 — 2020 |
Kuchibhotla, Kishore V |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Neural Circuitry For Flexible Control of Auditory Perception and Behavior @ New York University School of Medicine
? DESCRIPTION (provided by applicant): The mammalian auditory system can be modified by experience and by behavioral context. This is an important feature of the primary auditory cortex (A1), especially in forming representations of sensory signals such as speech, music and other forms of acoustic communication. With time and experience, animals can learn that specific sounds and not others can signal rewards. Moreover, animals can also learn that the same sound in different contexts requires distinct behavioral responses. In humans, for example, the sound of a gunshot heard on the street versus during a movie will likely lead to divergent behavioral responses. Conversely, PTSD patients hear a loud bang and may be unable to make the same differentiation. Such deficits are also implicated in developmental and language disorders including autism. Understanding the mechanisms of perceptual flexibility is thus essential for studies of normal or pathological auditory processing. Classically, sensory information was thought to be processed in a linear manner where each successive brain area extracts more complex features and then transmits this to higher-order areas that confer meaning (feed-forward processing). However, in the auditory cortex, this model is increasingly challenged by neural recordings in behaving animals in which context or behavioral state plays an important role in modulating neuronal activity. What happens during behavioral conditions where the same sound draws attention in one context (active context) but does not require attention in another (passive context)? The preliminary data in this proposal shows that auditory cortical neurons have distinctly different activity patterns in those two contexts. The precise mechanisms that govern this context-dependent activity in auditory cortex remain unknown. Neuromodulatory centers involved in attention may play a critical role in context-switching, given their importance in long-term plasticity and learning. This proposal will test the hypothesis that context- dependence in auditory cortex arises because long-range attentional signals directly act on local circuits. First, experiments will be conducted to test whether synaptic inputs, the building blocks of neuronal activity, are different in auditory cortex in both contexts (Aim 1). Second, experiments will test whether acetylcholine- releasing projections from the nucleus basalis, a brain region involved in attention, are naturally active during the active task and directly alter the synaptic weights in auditory cortex (Aim 2). Third, experiments will test how context-dependent activity emerges over the course of learning by looking at both the attentional signal from the nucleus basalis and the local neuronal population in auditory cortex (Aim 3). An experienced team of mentors and collaborators will provide training critical for the candidate's short- and long-term success, including: in vivo whole-cell recordings, genetic targeting of neuronal subtypes, optogenetic modulation of neural circuits, in vivo imaging of synaptic elements. The proposed training program combines hands-on training, formal mentorship, and consultation with experienced independent researchers, coursework, independent study, seminar attendance, and professional scientific meetings. In the long-term, this support will equip the candidate to lead a laboratory that merges cellular and systems approaches to explore the neural basis of flexible auditory perception.
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2019 |
Kuchibhotla, Kishore V |
R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Impact of Amyloid Deposition On Sensory Processing and Behavioral Encoding in the Auditory Cortex @ Johns Hopkins University
Project summary The work proposed here aims to address a key question in AD: how does amyloid deposition impact the function of sensory cortex involved in linking reward-predictive auditory stimuli with the correct motor actions. In AD, patients exhibit a profound inability to use sensory cues to trigger relevant emotions, memories or action sequences. Sensory regions of the brain have received less attention then higher-order regions involved in cognitive flexibility (e.g. PFC) or regions involved in memory consolidation and recall (e.g. hippocampus). Sensory systems in the brain, however, are critical intermediaries allowing us to perceive the outside world and interact with the external environment. Recent evidence supports the idea that the auditory cortex (AC) serves both as an acoustic ?filter? of the environment3?5 but also as an integrative hub that uses contextual signals to prime downstream circuits for action. In this framework, deficits in sensory processing and behavioral modulation triggered by AD-related pathology directly in the auditory cortex may have profound effects on cognition, limiting the ability to exploit learned stimulus-action associations. In order to address this question appropriately, we need to conduct foundational work looking first at core sensory processing in mice with amyloid pathology and then explore how behavioral modulation of sensory responses are impacted. To that end, we have sequenced this supplement to provide useful data in understanding how amyloid deposition 1) disrupts tonotopic maps, 2) impacts short-term sensory memory formation via stimulus specific adaptation, and finally 3) disrupts context-related modulation of cortical activity in a behaviorally-relevant manner. These studies organize around the idea that inhibitory circuits may be particularly sensitive to amyloid deposition26. The work proposed here builds on the principle findings of the work in the active grant9. During the period of that grant, we have shown how inhibitory networks in the auditory cortex are critical for gating behaviorally relevant information in the response of excitatory neurons in A19. In particular, we showed how cell-type specific modes of inhibition suppress (through direct suppression via PV+ and SOM+ interneurons) or facilitate (through disinhibitory VIP+ interneurons) sub-populations of excitatory neurons. This bidirectional modulation is critical for animals as they move from a passive state, when they do not use that information, to an active state, when they use the sensory stimuli as cues for reward. Here, we aim to use a similar framework to the study of sensorimotor behavior but in the context of AD and amyloid deposition.
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2021 |
Kuchibhotla, Kishore V |
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. |
Neural Circuits For Flexible Audiomotor Learning @ Johns Hopkins University
The mammalian auditory system is remarkably adaptive; salient experiences and behavioral contexts can fundamentally alter the processing of sounds in order to sensitize neural circuits to behaviorally relevant information. How does the central auditory system learn to associate sounds to rewards, and relatedly, how does behavioral context mediate this plasticity? The formation of representations of sensory signals such as speech, music, and other forms of acoustic learning is critical for survival. And, yet, the formation of these representations during real-time learning remains largely unknown. In this proposal, we posit that learning can be dissociated into two distinct learning processes: the initial acquisition and subsequent expression of knowledge. Acquisition involves learning the core discrimination learning that underlie a behavior, and expression entails the use of this acquired discrimination in context. Acquisition and expression have typically been conflated in most laboratory tasks, leaving an important gap in our understanding of learning mechanisms in the central auditory system. Moreover, dissociating between acquisition and expression has important implications for development and language disorders. For example, soothing music can elicit neurotypical behavior in autism patients with otherwise severe symptoms. We aim to identify the separable neural mechanisms that enable sensorimotor acquisition versus contextual expression. Recently, we have shown that we can precisely dissociate acquisition from expression in a sensorimotor reward learning task. Thus, we now have a powerful behavioral approach to isolate acquisition from expression during learning. In this proposal, we will define the precise neural circuitry in the auditory cortex that enables these two aspects of learning. The auditory cortex is known to be a major site of plasticity; associative learning between sounds and rewards induce shifts in the ?tuning? of cortical neurons. The cholinergic basal forebrain, moreover, has been implicated as a potent driver of receptive field plasticity in the central auditory system. These plasticity mechanisms likely reflect fundamental neural changes that are linked to acquisition of task knowledge. A1 is also heavily modulated by brain state and context, suggesting that A1 may also play a role in expression of task knowledge. Here, we propose to combine simultaneous real-time two-photon imaging of neurons in the auditory cortex (Aim 1) and cholinergic axons (Aim 2-3). We will perform causal manipulations of AC (Aim 1), cholinergic activity (Aims 2-3), in vivo whole-cell voltage clamp recordings (Aim 2), and detailed behavioral analysis (Aims 1-3) to determine the neural basis of audiomotor learning.
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