Christina Gremel is an Assistant Professor of Psychology at the University of California, San Diego. Her lab is interested in the neural bases of decision-making processes, and how these processes are altered in people with neuropathologies like addiction and obsessive-compulsive disorder (OCD). She is especially interested in the role of cortico-basal ganglia circuits in habitual and goal-directed actions, and how an inability to switch between the two can lead to disordered behavior.
Habitual behavior is necessary for us to be able to perform routine actions quickly and efficiently. However, we also need to be able to shift to more goal-directed behavior as circumstances change. An inability to break a habit and to shift our behavior based on updated information can have devastating consequences, and this inability has been shown to underlie neuropsychiatric conditions involved with disordered decision-making, such as addiction and OCD. Thus, a balance between habitual and goal-oriented behavior is critical for healthy action selection. The Gremel lab is studying the molecular mechanisms underlying this balance (or lack thereof), with the ultimate goal of improving treatments for people with these disorders.
In “Endocannabinoid Modulation of Orbitostriatal Circuits Gates Habit Formation” (Gremel et al., 2016), the authors examine the role of the endocannabinoid system on a specific pathway between the orbitofrontal cortex (OFC) and dorsal striatum (DS), both areas involved in the control of goal-directed behavior. More specifically, they examine the role of cannabinoid type 1 (CB1) receptors within the OFC-DS pathway on the ability to shift from goal-directed to habitual action control.
They accomplish this with an instrumental lever-press task in mice that were trained to press a lever for the same reward (either a pellet or sucrose solution) under two different reinforcement schedules: random ratio (RR), which induces goal-directed behavior, and random interval (RI), which induces habitual behavior. Whichever food reward a mouse doesn’t receive during training is used as a control provided in the home cage. To determine if actions are controlled through habitual or goal-directed processes, they perform a two-day “outcome devaluation procedure”. On the valued day, mice prefeed on the home cage food, which is not associated with lever-pressing. On the devalued day, mice prefeed on the food given for lever-pressing, thereby decreasing their motivation for that reward. After prefeeding each day, non-rewarded lever-pressing is measured. A reduction in lever pressing in the devalued condition (rather than valued condition) indicates greater goal-directed control, whereas no reduction indicates habitual control.
To study the role of the endocannabinoid system on the control of goal-directed behavior, the authors examined the effects of deleting CB1 receptors in the OFC-DS pathway. They accomplished this using a combinatorial viral approach in transgenic mice. CB1flox mice and their wild type littermates were injected in the DS with the retrograde herpes simplex virus 1 carrying flipase hEF1a-eYFP-IRES-flp (HSV-1 fp), and in the OFC with AAV8-Ef1a-FD-mCherry-p2A-Cre (AAV fp-Cre), with Cre recombinase dependent on the presence of flipase (Figure 5A). This resulted in CB1 deletion in OFC-DS neurons of the CB1flox mice, but not in the controls.
During the outcome devaluation procedure, the control mice had reduced lever-pressing in the RR, but not RI, context, whereas the CB1flox mice had reduced lever-pressing in both RR and RI contexts (Figure 5G). Additionally, while the CB1flox mice had higher lever pressing in the valued state compared to the devalued state in both RR and RI contexts, the control mice only showed higher valued-state lever-pressing in the RR context (Figure 5H). Finally, calculation of devaluation indices showed that control mice increased their devaluation index between the RI and RR contexts, indicating a shift toward more goal-directed control, whereas the CB1flox mice did not show this shift (Figure 5I).
These results suggest that CB1 receptor-mediated inhibition of OFC-DS activity is critical for habitual action control. In other words, when the OFC-DS pathway is silenced, habit takes over. This is important, because it suggests that therapeutic targeting of the endocannabinoid system may be beneficial in treating people suffering from neuropsychiatric disorders involved with decision-making.
Seraphina Solders is a first-year Ph.D. student currently rotating in Dr. John Ravits’ lab.