Investigating the Effects of Alcohol Dependence on the Neural Circuitry Supporting Decision-Making Behavior

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Project Summary Daily life involves making flexible and adaptive decisions to achieve desired goals. Disorders of decision- making, such as those associated with alcohol use disorder, can surface when the underlying neurobiology of decision-making goes awry. Difficulties in parsing the effects of alcohol dependence on decision-making processes arise from a fundamental lack of structural and functional input-output mapping of the highly complex neural circuits that support decision-making. While neurobiological investigations have identified a key role for orbitofrontal cortex (OFC) computations in decision-making, the specific neural mechanisms underlying these computations and their disruption in alcohol addiction are unknown. Thus, the goal of Christian Cazares’s F99-phase is to apply unbiased and circuit specific techniques in parallel to unveil the long-lasting structural and functional toll that alcohol dependence places on OFC circuitry. Christian’s work submitted for publication used extracellular recording techniques to establish how OFC representations of decision-making actions are significantly altered following induction of alcohol dependence using an instrumental lever pressing task. However, the biological mechanisms for these functional changes remain unknown. Given the vast complexity of the circuit mechanisms that support decision-making, unbiased approaches can pose an advantage for identifying the dependence-induced changes that result in aberrant decision-making behavior. To this end, Christian proposes to utilize an exploratory monosynaptic rabies tracing technique on a well- validated animal model of alcohol dependence to identify changes in whole-brain inputs to the OFC. A greater understanding of how alcohol-dependence results in decision-making deficits also requires the use of in vivo techniques that take into consideration the genetic identity of cells involved. Thus, Christian will utilize miniaturized fluorescence microendoscopes to capture large-scale, spatiotemporal neural activity from genetically identified OFC subpopulations during decision-making. By clustering activity in relation to decision- making behavior, Christian will be able to train and test decoders on each of these neuron clusters to assess the extent to which OFC subpopulations reflect behavioral performance, as well as investigate if alcohol- dependence effects on OFC function are specific to excitatory or inhibitory sub-populations. In the K00-phase, Christian plans to use large-scale datasets in conjunction with information theory to draw relationships between brain activity and behavior that might otherwise have gone unobserved. Capturing these subtle relationships will open avenues for investigating otherwise unobservable information that guides decision-making behavior. By conducting experiments only achievable by an interdisciplinary approach, Christian will not only shed light on the connections between neurobiology and decision-making, but also on how these connections may break down in a psychiatric disease in which decision-making is aberrant.