Vishnu Pradeep Murty - US grants

DESCRIPTION (provided by applicant): To behave adaptively, individuals must learn associations between reward outcomes and features of the environment, and use these associations to inform behavior in novel situations. Previous research in animal models has demonstrated that the neural systems engaged during associative learning can influence such generalization behaviors, such that adaptive generalization requires engagement of the hippocampus. However, the majority of research in human subjects has investigated striatal-guided reward learning and generalization, often during multi-trial, probabilistic feedback learning. In everyday life, reward values are often acquired after only a single experience or episode; the neural mechanisms guiding such single-trial reward feedback learning are undefined. The current proposal advances the claim that single-trial reward feedback learning and generalization may be characterized by the interactions between reinforcement learning and episodic memory systems. We will test this claim by combining behavioral methods, computational modeling, and high-resolution neuroimaging. We will characterize the neural systems engaged during the acquisition of single-trial reward feedback associations using hi-resolution fMRI (Aim 1). Further, we will characterize how associative learning via single-trial reward feedback contributes to generalization behavior using reinforcement-learning modeling (Aim 2) and model-based fMRI (Aim 3). We predict that (1) single-trial reward-feedback learning will engage interactions between the striatum and hippocampus during associative learning, and (2) the interaction between these systems will promote adaptive generalization of reward associations. The knowledge obtained from this proposal will advance our understanding of the neurobiology of reward learning and provide evidence for the mechanisms underlying healthy and impaired reward-related behaviors such as drug addiction.

Project Summary/Abstract The objective of this Career Development Award is to support new mentored training in cognitive neuroscience studies of dopamine-related function in healthy adolescents and first-episode psychosis, as the candidate begins an independent research program. Psychosis is a devastating illness that afflicts ~3% of the world?s population, and has sever economic and social/emotional consequences for both patients and their caregivers. Prior research has implicated deficits in dopamine systems in both the etiology and pathology of the disorder, and thus remediation of this system has been a prominent target for intervention. Although these deficits have been well documented, open questions remains as to how and why these deficits emerge. Prominent models of psychosis have implicated aberrant development of neural systems regulating the activation of dopamine systems. However, very little research has investigated how these regulatory systems develop in normative populations; let alone how deviations from normative development may be implicated in psychosis. Thus, a full understanding of psychosis necessitates a characterization of dopamine-related networks in healthy adolescence and deviations from these trajectories in psychosis. These findings will provide insight into determinants of risk for conversion from a developmental perspective and in turn the timing of interventions. The proposed award will build upon the candidate?s prior training in cognitive neuroscience, to extend this knowledge into the domain of normative development in adolescents and aberrant development in psychosis within dopamine-related networks. Aim 1 will investigate the normative development of neural systems regulating engagement of the ventral tegmental area and substantia nigra, the core of the mesolimbic dopamine system, using multimodal neuroimaging. These developmental neuroimaging markers will then be associated with direct and indirect measures of dopamine to assess how they relate to dopaminergic function. Aim 2 will evaluate how individuals with first-episode psychosis deviate from the normative trajectories characterized in Aim 1, and further probe how these deviations relate to anti-psychotic medication status. Finally, Aim 3 will have first-episode patients return for a 2-year follow-up to characterize how the clinical course of psychosis relates to early markers of dopamine-related dysfunction. Mentored training will compliment the candidate?s expertise in neuroimaging of dopamine-related circuits in healthy adults. Paralleling the proposed research, training will focus on the candidate gaining expertise in conducting neuroimaging studies in adolescent (Aim 1) and psychosis populations (Aim 2,3). Further, the candidate will gain expertise in the translation of animal models of behavior in adolescent and psychosis population, with a focus on understanding the nature of homology across multiple species (Aims 1-3). Finally, the candidate will gain expertise in experimental techniques associated with studying neurodevelopment (e.g., longitudinal data analysis; Aims 1-3), psychosis (e.g., adjustment for antipsychotic medication, characterizing clinical phenomenology; Aims 2-3), and translational neuroscience (e.g., integration of direct/indirect measures of dopamine; Aim 3). The candidate has recruited a mentoring team with expertise in all of the above domains led by mentor Dr. Bea Luna, an expert in adolescent development, and co-mentor Deanna Barch, an expert in neuroimaging in psychosis populations. Further, the candidate will take advantage of the known strengths of the schizophrenia and adolescent research communities, as well as the emphasis on cross-species translation at the University of Pittsburgh. The proposed research will offer novel insight into dopamine dysfunction in psychosis through the lens of adolescent neurodevelopment. Further, the training will lay the foundation for an independent research program assaying the neurodevelopmental of neuromodulatory systems in psychosis. !

Project Summary/Abstract Adolescence marks a state of increased engagement of dopamine systems, a neurobiological state associated with increased reward-motivated behaviors. While increased dopamine signaling during this time period predominately supports adaptive developmental processes, such as exploration and reward learning, it can also propel risk taking behaviors associated with substance use and abuse. Prominent animal models have shown that engagement of dopamine systems and increased reward sensitivtycan increase plasticity and consolidation in hippocampal learning systems, resulting in enhanced memory for rewarding events. Critically, these enhancements in memory underlie the reinstatement of prior drug-related contexts and propel drug use. While a large rodent literature has focused on reward?s influence on hippocampal-dependent plasticity, relatively little work has characterized these processes in human adults or adolescents. We propose to study the influence of reward on memory consolidation and episodic memory throughout adolescence into early adulthood. We will study 90 14- to 25- year-old healthy subjects using multiple neuroimaging modalities. All participants will complete a reward memory paradigm, which will allow for the quantification of the influence of reward on episodic memory, i.e. a behavioral marker of hippocampal consolidation. Memory enhancements for reward will be associated with neural markers related to memory consolidation. In Aim 1, we will characterize associations between reward-mediated memory enhancements and neural markers of consolidation in healthy adults, allowing us to translate and extend animal models into a human neuroscience framework. In Aim 2, we will characterize these relationships throughout adolescence to better understand how adolescents heighted sensitivity to reward influences long-term memory representations throughout development. This work will provide a deeper understanding of how hippocampal plasticity is influenced by reward throughout adolescence, and bolster a foundation to better understand the vulnerability to substance abuse in this population.

Memories are not exact records of past events; rather our emotional states can distort memories leading to accurate recall of the most intense parts of an event and misremembering of more mundane details. For example, imagine while eating brunch at a busy intersection you witness a horrific car accident. While you may have great memory for the anguish in the passenger’s face, you may not have great memory for how the car accident transpired (e.g., was the driver texting while driving?). Understanding how emotion distorts memories is of critical importance because as a society we use personal accounts of prior events to inform communication in both legal and media contexts. This project increases our understanding of how individuals form memories for complex emotional events by defining the features of learning that contribute to distortions in memory. The project leverages rodent and animal models of how emotional arousal influences brain structures underlying memory and extends them by employing more real-life, threatening events. There is accumulating evidence that emotional events heighten threat-related arousal, such as increases in sweating and heart rate, which can impair the function of regions known to construct episodic memories, such as the hippocampus. However, most laboratory based studies use static word lists or pictures as experimental stimuli, which preclude the ability to understand how threat changes individuals’ ability to construct accurate memory-based narratives of real-world situations. Threat may bias memory formation towards the most emotional parts of events while also encouraging the ignoring of mundane details (like where or when the event happened) which makes it difficult to accurately reflect on how events unfolded. A series of behavioral, psychophysiological, and neuroimaging experiments, using highly arousing naturalistic stimuli, address arousal’s role in fragmented memory by placing individuals in more complex, threatening environments than previous research. Understanding the intersection of emotion, arousal, and memory cohesion has broad implications for improving methods to make sure when individuals convey their interpretations of past events to broader audiences—such as an individual sharing their interpretation of a traumatic event to a news outlet or a courtroom—we can accurately determine which parts of their memories are more or less fallible. Alongside the research project are plans for the mentorship of a diverse body of undergraduate and graduate trainees, public outreach through theatre events and digital media, and a plan to develop collaborations with experts in eye-witness testimony, digital media, and memory research.

This project translates models of arousal-mediated biases in episodic memory into the domain of naturalistic, ecologically-relevant stimuli in humans. Research in both rodents and humans shows that emotional memory is supported by a cascade of events which are triggered by threat detection in the amygdala, which then increases physiological arousal and noradrenergic tone in concert with facilitating medial temporal lobe-dependent encoding. These neuromodulatory signals are specifically thought to bias memory encoding towards cortical medial temporal lobe-based memory representations over hippocampal-dependent representations, which in turn results in greater memory for the most salient features of an emotional event at the expense of more mundane details. Critically, intact hippocampal function is necessary to form cohesive memories that maintain their temporal order, contextual details, and a continuous narrative. It follows that, due to amygdala involvement, memories of emotionally arousing events would lack typical markers of hippocampal-dependent memory such as a cohesive temporal narrative. However, prior research has precluded testing such hypotheses based on the use of more simplistic stimuli that are static and lack narrative structures (i.e., word lists, pictures). Emerging work in the cognitive neuroscience of memory has provided behavioral, computational, and neuroimaging techniques to assay memory processes that unfold over time by utilizing more complex memoranda that include a narrative structure. In the first set of studies, participants attend a highly arousing haunted house during the collection of physiological data and then complete free recall tests characterizing the cohesive structure of their memories. In a second series of studies, the investigators leverage neuroimaging methods during the encoding and free recall of horror and neutral movies clips to better understand the relationship between amygdala-medial temporal lobe interactions, physiological arousal, and memory distortion. In the final series of studies, the investigators manipulate individuals’ agency while playing a horror-themed video game, testing a novel hypothesis that agency may protect individuals from arousal-based memory distortions by providing them control over the event, a form of intrinsic emotion regulation. Thus, these studies expand our knowledge on emotional memory by moving beyond simple laboratory-based stimuli into more naturalistic memoranda (i.e., staged events, movie viewing, videogame play). Together, this project tests a model by which physiological arousal disrupts hippocampal-dependent encoding resulting in fragmented, distorted representations of past events which are less communicable to the public. Understanding the behavioral and neural mechanisms that drive memory distortions for complex, aversive events provides a foundation of knowledge to more accurately assess the veracity of individuals’ memories for traumatic events, and provides targets of remediation to reduce distortions in memory. Thus, the findings from this project inform practices of incorporating first-person narratives in service of societal well-being in legal and media contexts.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.