Current and future research Prelimbic stimulation in addicted rats decreases compulsive cocaine-seeking behavior. A hallmark of addiction is continued use of drugs despite negative consequences. This compulsive drug-seeking behavior is thought to result, in part, from drug-induced hypofunction in cortical regions, including the PFC. Because the PFC has critical function in exerting control over unwanted behaviors2, dysfunctions in this area may render an addict incapable of resisting the urge to seek drugs. Consistent with this hypothesis, my on-going research has uncovered significant decreases in neuronal activity in the PL in rats with a long history of cocaine self-administration. Moreover, in Addicted rats, photo-stimulation of channelrhodopsin (ChR2)-expressing PL neurons during self-administration sessions significantly reduced cocaine-seeking behaviors, but only after the rats have learned that lever pressing for cocaine is associated with foot shocks. Prior to the pairing of foot shocks with cocaine, photo-stimulation of ChR2-expressing PL neurons has no effect on cocaine-seeking behavior. The PL has been shown to guide goal-directed behaviors and in the absence of any punishment, the goal of the rat is to seek cocaine. Therefore the rat does not need to evaluate the outcome of the decision and activation of the PL has no effect. However, when future cocaine rewards are paired with punishments, a rat is faced with two conflicting goals, to get cocaine or to avoid shocks. In these situations, the rat must evaluate the value of cocaine against foot shocks. My data suggests that in the face of foot shocks, decreased PL activity biases the rats behavior towards continued cocaine seeking (Kourrich et al, under revision for Cell.) My future research program will examine two major PL circuits that may be altered by long-term voluntary consumption of cocaine to allow the execution of addictive behaviors. I will focus on the PL-BLA and the PL-NAc circuit. The PL-BLA and the PL-NAc projections are implicated in promoting goal-directed and drug-seeking behaviors3,7, but their role in regulating compulsive behaviors remains poorly understood. To examine the effects of cocaine-induced neuroadaptations in these two PL output pathways and identify their function in compulsive cocaine seeking, the following experiments will be performed: In vivo and in vitro patch-clamp recording in neurons from Addicted and Non-addicted rats. To identify cocaine-induced changes in the function of PL circuits and the underlying cellular mechanisms, in vivo and in vitro whole-cell patch clamp recordings will be made in Addicted and Non-addicted rats. Of particular interests are adaptations present in Addicted but not Non-addicted rats, which may uniquely permit compulsive cocaine seeking. In vivo patch-clamp recordings will be performed to examine the intrinsic electrophysiological properties of PL neurons in the context of a fully connected network. In addition, because the loss of inhibitory control in Addicted rats may reflect impaired PL responses to punishment, synaptic responses of PL neurons to foot-shocks will also be examined. Lastly, in vivo recordings will be made at various stages of self-administration training. This will provide a longitudinal analysis of cocaine-induced neuroadaptations at various stages of the addiction process. Changes in cocaine-induced network function can be mediated by molecular changes at the cellular and synaptic level. Among the possible neuroadaptations include function and or number of receptors and ion channels as well as release probability of transmitters (i.e. glutamate and GABA). To precisely analyze these parameters in Addicted and Non-addicted rats, in vitro patch-clamp recording in brain slices containing PL, BLA, and NAc will be made. In addition, I will use ChR2 to selectively examine changes in the excitatory strengths of projections from the PL- to BLA or NAc in the two groups. Together, in vivo and in vitro electrophysiological experiments will provide a thorough analysis of cocaine-induced changes at both the circuit and the cellular level. The identification of differences between Addicted and Non-addicted rats may reveal critical adaptations that facilitate compulsive, cocaine-seeking behavior. Optogenetic control of PL circuits to decrease compulsive cocaine seeking. I show that hypofunction of the PL has a critical role in permitting compulsive cocaine-seeking behaviors and that this behavior can be reversed with photo-activation of PL neurons. To understand the function of PL-BLA and PL-NAc circuits in compulsive cocaine seeking, I will use optogenetics to investigate afferent-specific excitatory synaptic function in the BLA or NAc in exerting inhibitory control over cocaine seeking. I will transduce PL projection neurons with adeno-associated virus encoding either ChR2 or halorhodopsin (NpHR) to stimulate or inhibit, respectively, afferent-specific neural activity in the BLA or NAc. Results from in vitro slice experiments will guide in vivo optogenetic experiments. For example, if the strength of a particular PL circuit is significantly reduced in the Addicted rats, ChR2 will be employed to selectively enhance these glutamatergic projections during cocaine seeking. In contrast, if an increase in synaptic strength in one or both of these circuits is observed, NpHR will be used to decrease its activity during cocaine seeking. Real-time modulation of neuronal circuits with optogenetics will establish a causal relationship between PL-circuits and its role in regulating compulsive behavior. Summary The loss of inhibitory control, despite knowing the negative consequences of this behavior, lies at the heart of compulsive drug use and addiction. My research seeks to identify cocaine-induced neuroadaptations, starting from individual synapses to progressing to specific neuronal circuits that contribute to decision-making impairments and allow maladaptive, compulsive cocaine seeking. The integration of rat addiction model with in vivo and in vitro electrophysiology and optogenetic targeting of specific cortical circuits provides the ideal platform to identify neural circuits and cellular mechanisms underlying addictive behaviors.

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National Institute on Drug Abuse
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Seif, Taban; Chang, Shao-Ju; Simms, Jeffrey A et al. (2013) Cortical activation of accumbens hyperpolarization-active NMDARs mediates aversion-resistant alcohol intake. Nat Neurosci 16:1094-100
Chen, Billy T; Yau, Hau-Jie; Hatch, Christina et al. (2013) Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature 496:359-62