THE PROBLEM
Research in the laboratory of Dr. Kari Johnson seeks to identify neuroadaptations that occur following long-term alcohol exposure. We are particularly interested in how alcohol affects the basal ganglia, a brain system important for reinforcement learning and action selection. Our goal is to understand how alcohol alters basal ganglia physiology and related behaviors so that we can identify new strategies to reverse the effects of alcohol and reduce accompanying problematic behaviors such as excessive alcohol intake.
OUR APPROACH
We use a combination of classic and modern neuroscience techniques to study and manipulate specific synapses in mice. To study alcohol effects on synaptic transmission, we perform ex vivo whole-cell patch clamp recordings in acute brain slices. Stimulation of discrete synaptic terminals using optogenetic techniques enhances the specificity of our analysis. Our behavioral analysis focuses on how distinct basal ganglia circuits contribute to reinforcement learning and how these circuits and behaviors are affected by alcohol. To study the contributions of neural pathways of interest, we use a combination of techniques including optogenetics and chemogenetics. These approaches allow us to determine the effects of increasing or decreasing activity in specific basal ganglia circuit elements during behavior and provide opportunities to evaluate circuit-specific interventions that could reverse the effects of alcohol.
OUR FINDINGS
Previous work by Dr. Johnson and colleagues has identified alcohol-induced disruption of G protein-coupled receptor (GPCR)-mediated plasticity at cortical synapses in the striatum. Building on this finding, the Johnson Lab is now exploring the behavioral implications of disrupting corticostriatal plasticity using techniques including neuron-specific deletion of GPCRs and expression of genetically encoded proteins that selectively disrupt GPCR function in specific types of neurons. We are also exploring the use of both allosteric modulators of endogenous GPCRs and chemogenetic approaches to rescue alcohol-induced disruptions of GPCR function.
In addition to our work on alcohol-induced adaptations in basal ganglia function, the Johnson laboratory studies instrumental learning driven by a variety of reinforcers including palatable food and optogenetic stimulation of neurons. We are particularly interested in how endogenous GPCR activity modulates synaptic transmission to influence reinforcement learning in mice. For example, Dr. Johnson’s recent work established that direct stimulation of thalamic terminals in the striatum using optogenetic techniques is sufficient to reinforce lever-pressing behavior, and lever-pressing for thalamostriatal stimulation is constrained by endogenous metabotropic glutamate receptor activity.