The long-term goal of our investigation is to understand how neural circuits in the orbitofrontal cortex support decision-making in the healthy state and how suboptimal choices after chronic drug abuse. Our experiments in this proposal are designed to delineate how OFC representations are mapped to specific neural circuits and how these are impacted by chronic morphine exposure. Our central hypotheses are that distinct projection-neuron types arising from OFC represent different decision-variables and these signals are routed to different subcortical target structures, and that drugs of abuse such as morphine selectively affect defined pathways to impair decision-making. To study this issue, we have developed quantitative psychophysical methods for rodents, adapted from human and primate work, which enables the behavioral readout of different decision variables, such as reward value and perceptual uncertainty in a well-controlled decision task. First, we will record OFC neurons in a reward-biased perceptual decision task that forces animals to make choices in the context of variable reward size and likelihood, and map distinct decision-variables to single neurons. Second, we will determine how these representations map onto specific classes of OFC pyramidal neurons - in particular, OFC projection neurons targeting VS, VTA, and BLA respectively. To achieve this we developed a technique based on a novel use of optogenetics to identify specific projection cell-types during behavior: by targeting ChR2 using retrograde viruses to specific projection neurons we identify these neurons in electrophysiological recordings by their light-responses. Using this approach we can examine what information OFC->NAc, OFC->VTA and OFC->BLA neurons carry. Third, based on information gleaned from recordings about when and how these pathways are activated, we will perform bidirectional manipulations of neuronal activity to reveal their causal roles in impacting choice behavior. Finally, we will determine how morphine self-administration and withdrawal disrupts choice behavior along different OFC output pathways and attempt to rescue this impairment. Upon completion of these aims, we expect to reach an improved understanding of how decision-variables are computed in the OFC. In addition, we will provide new information about how information within OFC is transmitted in a pathway-specific manner from to its subcortical targets. We expect that our approach will contribute to an improved translational understanding how drugs of abuse can cause the sometimes subtle impairments in decision-making that nevertheless have devastating consequences.
This proposal aims at a mechanistic understanding of OFC function during decision making in the healthy state and suboptimal choices after chronic morphine self- administration. Our guiding hypothesis is that there is there a division of labor between different OFC output neurons in terms of the information they carry and behaviors they mediate. By dissecting the contribution of different pathways and examining how they are impacted by chronic morphine exposure we hope our results will contribute to an improved translational understanding how drugs of abuse can cause the sometimes subtle impairments in decision-making that nevertheless have devastating consequences.
| Li, Shu-Jing; Vaughan, Alexander; Sturgill, James Fitzhugh et al. (2018) A Viral Receptor Complementation Strategy to Overcome CAV-2 Tropism for Efficient Retrograde Targeting of Neurons. Neuron 98:905-917.e5 |
| Lak, Armin; Nomoto, Kensaku; Keramati, Mehdi et al. (2017) Midbrain Dopamine Neurons Signal Belief in Choice Accuracy during a Perceptual Decision. Curr Biol 27:821-832 |
