Coordinated Neurobiological Approaches
In vivo electrophysiology
Optogenetics and Chemogenetics
Individual Vulnerability to Addiction
Why are some individuals more prone to transition to addiction than others? Is information about rewards and associated cues encoded differently in the brains of addiction vulnerable individuals? Is there individual variation in the recruitment of specific brain circuits driving motivated behavior?
In the Calu Lab we study the brain mechanisms underlying individual differences in natural reward learning, motivation, and behavioral flexibility. We use tools to monitor and manipulate real-time neural activity in behaving rats performing reward learning tasks. We examine the possibility that competing brain systems drive individual differences in cognitive strategy, which may underlie individual vulnerability to addiction and other neuropsychiatric diseases.
While many individuals try drugs of abuse, only a subset transition to addiction. Studying individual differences in addiction vulnerability is a critical step towards understanding the neurobiological underpinnings of motivation for drugs and their impact on the brain and behavior.
Nine of eleven of the DSMV criteria for diagnosing individuals with substance use disorder relate to heightened motivation for drugs or behavioral inflexibility, characterized by persistence to seek and take drugs despite negative consequences. The dual nature of this psychological profile inspires our research, which considers both motivation and flexibility prior to drug experience in order to understand addiction vulnerability.
Phenotypic behavioral differences, termed sign-tracking and goal-tracking, differentially predict vulnerability to drug seeking. Sign-trackers show heightened motivation for food- and drug-associated discrete cues compared to goal-trackers. Recent work from our lab replicates and extends our prior finding that sign-tracking rats are inflexible, continuing to respond to previously rewarded cues, even when the value of the reward has been degraded.
Taken together, the “tracking trait” distinction is an ideal model to explore individual differences in both motivation and flexibility prior to drug experience. But what are the brain mechanisms underlying these trait differences?
These behavioral differences lead us to our dissociable amygdala hypothesis of sign- and goal-tracking. We currently test the role of distinct amygdala projections in mediating the individual differences we observe in the motivated and flexible behavior of Sign- and Goal- trackers. We've learned that both sign- and goal-trackers rely similarly on the amygdala to insular cortical pathway to drive motivated behavior. Our preliminary chemogenetic results suggest sign-trackers rely on this pathway to encode the initial appetite incentive value, that is insensitive to outcome value. We also find that amgydala to striatal projections promote sign-tracking, independent of outcome value and that inhibiting this pathway unmasks flexibility. We are currently exploring the role of endocannabinoid signaling in mediating sign- and goal-tracking behaviors and striatal dopamine signaling in collaboration with Dr. Joe Cheer.
How do voluntary drug use and drug dependence interact with brain circuitry to drive drug seeking and drug taking?
A new direction for the lab is to use behavioral economic, choice and relapse models to understand how reward and motivational brain systems are impacted by voluntary opioid drug use and dependence to drive drug seeking and taking. We probe extended amygdala and prefrontal contributions to opioid demand, opioid vs. food choice, and incubation of drug craving.
Food and Drug Addiction: Diet, Reward Processing, and Relapse
Are there shared brain mechanisms underlying comorbidity of PTSD and addiction? How do drugs of abuse interact with reward circuitry to drive individual differences in cue-reactivity?
Post-traumatic Stress Disorder (PTSD) and opiate addiction have detrimental impacts on the quality of life for affected individuals and their families. These disorders also have a high incidence of comorbidity. One common feature of both PTSD and addiction is the heightened reactivity to cues, particularly those associated with traumatic events or with drug use, respectively. A preclinical trait difference model identifies a subpopulation of individuals, termed sign-trackers that show a heightened reactivity to both fear-associated and drug-associated cues that increases with time away from those stimuli. Sign-tracking rats display heightened fear responses during fear incubation procedures and show heighted cue-induced drug seeking during incubation of drug craving procedures. These incubation effects in rodents, which are characterized by time-dependent increases in cue reactivity, resemble the human conditions of delayed onset PTSD and drug addiction, respectively.
Despite the critical role of the extended amygdala in both the expression of fear and the incubation of drug craving, the specific extended amygdala mechanisms mediating the time-dependent increase in reactivity to both fear and opiate cues are understudied. We combine modern neuroscience tools with behavioral approaches to begin shed light on the possible overlapping mechanisms driving maladaptive cue-motivated behaviors in individuals with comorbid PTSD and addiction.
How does the brain encode information about palatable reinforcers to mediate food choice? How does diet alter reward processing, motivation and decision making? What are the brain mechanisms underlying diet-induced blunted motivation and heightened relapse sensitivity?
Excessive consumption of unhealthy palatable foods is a major public health problem contributing to obesity and obesity-related diseases. While many people attempt to control their food intake through dieting, but most relapse to maladaptive eating habits within a short time. The individuals most commonly seeking dietary treatment are overweight or obese women, yet the commonly used rat reinstatement model to study relapse to palatable food seeking during dieting primarily uses normal-weight male rats. This relapse is often triggered by acute exposure to palatable food, food-associated cues, or stress. Recent work in our laboratory has aimed to increase the validity of the relapse to palatable food seeking model by working with overweight female rats. In this study, we pre-exposed female rats to a calorically-dense cafeteria diet to make them overweight before examining motivation for palatable food and relapse to food seeking. We found that history of cafeteria diet makes rats less motivated for otherwise palatable food rewards, but makes them more susceptible to footshock stress-induced reinstatement.
In another line of related research, we have examined the specificity of the pharmacological stressor, yohimbine, on reinstatement behavior. Recently, yohimbine has become the most common stress manipulation in studies on reinstatement of drug and food seeking. However, the wide range of conditions under which yohimbine promotes reward seeking is significantly greater than that of other stressors. We found that yohimbine’s effects on operant responding in reinstatement studies are independent of previous reward history and cue contingency and may not be related to the commonly assumed stress-like effects of yohimbine.
We use Long Evans Rats in rodent models of reward learning, motivation, cognitive flexibility, drug and food relapse
We use fluorescently congugated retrograde tracers to examine neuronal activation in specific brain pathways
We use in vivo electrophysiology to examine real time neural activity in specific brain regions as rats engage in motivated behaviors
We use optogenetic and chemogenetic tools to manipulate specific brain pathways to examine the causal role those circuits play in driving motivated behavior