Salient environmental stimuli can capture attention and drive behavior; this process, vital for guiding adaptive behavior, is called stimulus control. Stimulus control can become maladaptive in disease states, such as cocaine addiction, where cocaine-associated stimuli can wield undue influence and disrupt ongoing preferred behavior (i.e. occupational or social activities) and efforts to remain drug-free. While altered stimulus control is well-understood to contribute to cocaine addiction, the neural mechanisms underlying this process are poorly understood. The locus coeruleus (LC) is a neural structure, which modulates attention, sensation, and behavioral control and is strongly effected by cocaine. Thus, the LC may be at the center of maladaptive stimulus control in cocaine addiction. Stimulus encoding in LC and downstream sensory systems is known to be critical for stimulus- guided behavior although it is not known if cocaine-associated stimuli are encoded in these systems. The research plan proposed in this NRSA will elucidate the role of LC in encoding an auditory cocaine-stumulus and examine whether there is a causal role for LC in mediating control of behavior by this stimulus. We will employ a behavioral paradigm in rats which assesses stimulus control of water-reinforced behavior by an auditory cocaine-stimulus.
Aim 1 will use cellular resolution calcium imaging and electrophysiology to examine neural correlates of stimulus control in the LC and auditory brainstem respectively.
Aim 2 will use a chemogenetic approach to selectively inhibit LC activity during acquisition or expression of conditioned stimulus control by a cocaine-stimulus in order establish a causal role for LC in these processes. Combined, these experiments have the potential to inform therapies aimed at targeting LC to attenuate maladaptive stimulus-driven behavior in cocaine addiction. Furthermore, the proposed fellowship will provide me with a strong foundation for a career as an independent investigator focused on the neurobiological and behavioral underpinnings of addiction. The training environment described in this proposal will incorporate faculty-student mentorships and collaborations aimed at providing me with scientific training across the domains central to this project including LC physiology, calcium imaging techniques, and sensory processing. Additionally, the training plan will provide me with professional training which will prepared me for my future as I establish my own independent research program. As a whole, this Fellowship has significant potential to produce both scientific findings relevant to treatment of addiction and also a scientist well-equipped to become an outstanding member of the addiction research community.
Cocaine use disorder is a disease with significant individual and societal costs and few effective treatment options. Understanding the mechanisms which underlie behavioral control in cocaine addiction and contribute to relapse will inform novel therapeutic strategies which seek to prevent relapse and improve recovery rates.
