What are the genetic, environmental and neurobiological factors that contribute to addiction liability?

We have utilized a unique genetic animal model of individual differences in addiction liability to examine the neurobiological antecedents and consequences of addiction. Dr. Huda Akil's laboratory has been generating selectively-bred rat lines for over 60 generations on the basis of locomotor response to novelty and we have shown that these animals — bred high-responders (bHRs) and bred low-responders (bLRs) — exhibit differences on a constellation of traits relevant to addiction. In addition, these two lines of rats show differences in their dopamine system both under basal conditions and in response to reward cues and drugs of abuse, and there are differences in the epigenetic regulation of gene expression associated with addiction-related behaviors. We are currently using heterogeneous stock (HS) rats provided by Dr. Leah Solberg-Woods at Wake Forest School of Medicine to examine the genetic and neurobiological factors underlying addiction-related behaviors. The HS rats were derived from 8 different founder strains and have been maintained as an outbred population for over 65 generations. The heterogeneity of these rats is highly advantageous for genome wide association studies (GWAS). Thus, we are characterizing these rats on a number of addiction-related traits, in hopes of uncovering genetic factors related to the disorder (see www.ratgenes.org).

What are the neurobiological mechanisms underlying stimulus-reward learning?

Our work over the last several years has centered around an animal model of individual differences in stimulus-reward learning. Following Pavlovian conditioning, whereby a neutral cue (in this case a lever, conditioned stimulus, CS) is paired with a food reward (unconditioned stimulus, US), animals will develop a conditioned response (CR). However, the nature of this CR varies between individuals. All animals learn that the CS is predictive, but some animals will also attribute incentive motivational value (i.e. incentive salience) to the reward cue. Thus, for “sign-trackers” the reward cue becomes attractive and irresistible and they will work for it in the absence of food reward. In contrast, “goal-trackers” treat the cue as a mere predictor and upon its presentation go to the location of reward delivery. This model is extremely valuable in that it allows us to parse the neurobiological mechanisms underlying stimulus-reward learning and motivated behavior. Further, this model will help us understand the processes by which cues associated with reward attain incentive motivational value and gain control over behavior – the same processes that go awry in addicts.

How can we alter these behavioral phenotypes?

We are currently using environmental, pharmacological , chemogenetic and optogenetic approaches to determine whether we can "switch" one phenotype to another. For example, does exposure to stress make a goal-tracker become a sign-tracker? Does altering neuronal communication between certain brain regions alter the propensity to sign-track or goal-track? Are there region-specific neurotransmitter systems (e.g. acetylcholine, dopamine, orexin) that are critical for the acquisition of one behavior, but not the other? Ongoing work is specifically targeting the cortico-thalamic-striatal system to elucidate which nodes of this circuit are critical for encoding the incentive motivational value of reward cues.

How does the “stress system” interact with the dopamine system to regulate stimulus-reward learning and response to the environment?

We also have ongoing studies investigating individual differences in stress responsiveness (e.g. corticosterone levels) and how these differences are related to stimulus-reward learning and neuronal activity. We are particularly interested in the role of glucocorticoid receptors in stimulus-reward learning and interactions between HPA Axis activity and the dopamine system.

Can we translate the sign-tracker/goal-tracker animal model to humans?

We have been working with Ashley Gearhardt (University of Michigan) and Martin Paulus (Laureate Institute for Brain Research) to translate our animal model to humans. As a starting point, we are assessing these tendencies in children. Other collaborators (e.g., Jonathan Morrow, University of Michigan) are doing the same in adults. We hope to soon share data that suggests that we find similar sign- and goal-tracking tendencies in humans. The long-term goal is to be able to exploit the identification of such traits to determine vulnerabilities to psychiatric conditions and to tailor treatments accordingly.

Techniques

Analysis Tools

Clever Sys Inc
Ingenuity Pathway Analysis
NIH Image/Image J

Behavioral Procedures

Locomotor response to novelty
Drug self-administration/reinstatement
Pavlovian conditioning
Impulsive Action (DRL)
Impulsive Choice (delayed discounting, probabilistic choice)
Psychomotor Sensitization

Hormonal Assays

Radioimmunoassay

Microdialysis

Collection of dialysates in freely moving animals

Gene Expression Profiling

Laser capture microdissection combined with gene microarrays

Neurohistochemical Procedures

In situ hybridization
Immunohistochemistry
Retrograde labeling

Neuropharmacology

Systemic injections
Local injections via stereotaxic surgery

“Remote Control” of Neuronal Signaling

Designer Receptors Exclusively Activated
by Designer Drugs (DREADDs)
Optogenetic