Cocaine addiction is a detrimental mental health dysfunction that drives aberrant goal- directed behavior. Data from animal models indicate that repeated cocaine exposure induces synaptic plasticity in the neural circuits for reward and motivation. These circuits, particularly the prefrontal inputs to the ventral striatum, are also thought to play important, though ill-defined, roles in decision-making information processing. Research using animal models to study cognition has been making progress in approximating the complexity of human information processing during deliberative decision-making. Work pioneered by the Redish Lab allows us to study, in rats, cognitive mechanisms dissociable in space and time underlying neuroeconomic decision-making strategies in a novel spatial navigation task. Having recently adapted this task from rats into mice, I now (1) have access to various Thomas Lab mouse models of drug addiction equipped with the ability to apply optogenetic interventions optimized for mice, (2) have increased capacity for behavioral testing throughput in mice compared to in rats, and (3) have access to other advanced transgenic lines readily available in mice enabling additional innovative future research approaches. Here, I propose to investigate (Aim 1) the effects of cocaine addiction on complex neuroeconomic decision-making behavior, and (Aim 2) to what extent in vivo optogenetic reversal of cocaine-induced changes in corticostriatal circuitry can ameliorate addiction-related changes in neuroeconomic decision-making behavior. The work proposed here is part of a larger collaboration translating this decision-making approach into healthy human and addiction patient populations coupled with functional magnetic resonance neuroimaging approaches. Of these collaborators, psychiatrist Dr. Kelvin Lim will be serving a role not only as a research mentor to me, but also as a clinical mentor throughout the remainder of my graduate and medical training. Together with my advisors, we will develop a translational research program seeing my thesis work through into the clinic during my proposed time here. The interdisciplinary collaborative research environment at the University of Minnesota is powerful and unique. As an MD/PhD student training across the neurology and psychiatry disciplines, the training plan proposed here will equip me with invaluable technical and career development skills I need in order to become an exceptional physician-scientist in academic medicine.
Addiction is a chronic relapsing disorder, and here we examine in mice the relationship between cocaine-induced synaptic plasticity and aberrant decision-making behavior. We do so by using cellular electrophysiology and genetic insertion of state-of-the-art light-sensitive ion channels into the brain, allowing us to manipulate decision-making and reward circuitry as well as potentially reverse drug- induced mal-adaptations. This approach has substantial promise for advancing our understanding of how drugs of abuse like cocaine exert their addictive effects, how the brain is wired during healthy and dysfunctional decision-making, and how potential future treatments for addiction can be better developed.
| Sweis, Brian M; Redish, A David; Thomas, Mark J (2018) Prolonged abstinence from cocaine or morphine disrupts separable valuations during decision conflict. Nat Commun 9:2521 |
| Sweis, Brian M; Abram, Samantha V; Schmidt, Brandy J et al. (2018) Sensitivity to ""sunk costs"" in mice, rats, and humans. Science 361:178-181 |
| Sweis, Brian M; Larson, Erin B; Redish, A David et al. (2018) Altering gain of the infralimbic-to-accumbens shell circuit alters economically dissociable decision-making algorithms. Proc Natl Acad Sci U S A 115:E6347-E6355 |
| Satrom, Katherine M; Ennis, Kathleen; Sweis, Brian M et al. (2018) Neonatal hyperglycemia induces CXCL10/CXCR3 signaling and microglial activation and impairs long-term synaptogenesis in the hippocampus and alters behavior in rats. J Neuroinflammation 15:82 |
