Generalization of Stimulus Value in Reinforcement Learning

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The goal of my research program is to determine how reward learning and motivational processes are encoded in neural activity in the striatum. To accomplish this goal, I am studying different facets of information processing in this brain region, starting with how specific glutamate inputs impact the extent to which animals generalize from past experience. Stimulus generalization is a process where predictive value is ascribed to novel stimuli that are perceptually similar to previously learned stimuli. This results in animals’ actively approaching or avoiding stimuli that they have never previously encountered. The neurobiological mechanisms underlying this phenomenon are of great interest, as there is a wide variability in the extent that humans generalize, and certain neuropsychiatric conditions, such as schizophrenia, generalized anxiety disorder, and post-traumatic stress disorder, are associated with marked abnormalities in this process. The research proposal described here utilizes modern neuroscience techniques to manipulate neural activity at precise moments during reward seeking with the goal of gaining mechanistic insight into the neurobiology of stimulus generalization. The research focuses on information processing in a part of the ventral striatum called the nucleus accumbens. This area integrates midbrain dopaminergic signals with excitatory input from cortical structures. The principal excitatory afferents to the nucleus accumbens come from the ventral hippocampus, basolateral amygdala, and prefrontal cortex, all regions which are thought to regulate distinct aspects of memory. Recent data from human fMRI research have implicated these glutamate inputs to the nucleus accumbens in regulating the extent to which people generalize during simple reward-seeking tasks. These findings are consistent with data from gain of function experiments in rodents, which demonstrate that enhanced activity in each of these pathways is sufficient to reinforce and motivate instrumental behavior. The technical approach I am proposing involves inhibiting discrete glutamate inputs to the nucleus accumbens at specific moments during a discriminative cue learning task. Optogenetic techniques will be used to accomplish this, which utilize genetically-encoded, light-sensitive proteins to inhibit neural activity. The spatial and temporal precision afforded by these techniques allow for pathway-specific inhibition of transmitter release at precise moments during learning and choice behaviour. I have extensive experience with this approach, with integrating optogenetic manipulations with clever behavioural assays. My publication record underscores how I am a well-qualified, highly trained, and committed researcher with a passion for studying the neural circuits underlying motivated behaviour. The overarching goal of the research proposed here is to understand how activity in different glutamate inputs to the nucleus accumbens impacts reward-related learning and choice behaviour. This work will be of wide interest as it touches upon the foundations of motivation, decision making, and reinforcement learning. In addition, the multifaceted nature of this research will provide trainees with extensive technical skills as well as experience collecting, analyzing, and interpreting data. Ultimately, my research program will further our understanding of specific neuropsychiatric conditions. This will hopefully lead to novel treatments and alleviate some of the social stigma attached to these disorders. A better understanding of mental disease from a neural system prospective is absolutely necessary to promote mental health-related rational drug discovery.