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.
