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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    858—Animal Behavior and Cognition: Prefrontal and Striatal Systems

    Wednesday, November 13, 2013, 1:00 pm - 5:00 pm

    858.14: Endocannabinoid signaling in orbitofrontal cortex modulates habit formation

    Location: Halls B-H

    *C. M. GREMEL1, G. LUO1, D. LOVINGER1, R. COSTA2;
    1Section on In Vivo Neural Function, NIAAA/NIH, BETHESDA, MD; 2Champalimaud Ctr. for the Unknown, Lisbon, Portugal

    Abstract Body: The ability to shift a volitional action between automatic and goal control is fundamental to executive processing. Disruptions are reflected in diseases such as obsessive-compulsive disorder and addiction where sensory and motivational processing is altered. We previously identified orbitofrontal cortex (OFC) circuits as functionally necessary for the shift between automatic or habitual and goal-directed actions. We found that neural activity in the OFC became more engaged during goal-directed than habitual actions. Optogenetic activation of OFC projections neurons specifically, and selectively during valuation states, increased goal-directed actions. Further, chemicogenetic inhibition of OFC projection neurons via activation of Gi-coupled hM4Di DREADD receptors disrupted goal-directed actions. These findings suggest OFC conveys action value information, and that plasticity of these circuits is necessary for the shift to automatic control. Previous work found that endocannabinonid signaling at the endocannabinoid-type 1 receptor (CB1) is necessary for habit formation, and CB1 receptors are found on excitatory terminals of cortical projection neurons. Given this, we hypothesized that endocannabinoid signaling could be shaping the plasticity of OFC circuits during action learning, with CB1 receptor deletion perturbing the ability of these circuits to shift and thereby altering habitual control over actions. We used a novel variant of an instrumental task where we train the same mouse to perform the same action for the same reward in a goal-directed versus habitual manner to examine mechanisms underlying action shifting. We initially found impaired habit formation and altered action encoding in OFC and dorsal striatal circuits in mice following deletion of CB1 receptors in forebrain alpha-CamKII-expressing projection neurons via tamoxifen induced cre deletion of CB1 in n CB1 loxP/loxP mice. Next we induced CB1 receptor deletion specifically within OFC or in OFC projection neurons by site-specific infusions of cre virus or cre virus expressed under the control of the alpha-camKII promoter in CB1 floxed mice. OFC and OFC projection neuron CB1 receptor deletion impaired habit formation, but left goal-directed actions intact. Currently we are investigating the contribution of different OFC projections based on downstream target brain areas to action shifting and associated in-vivo and ex vivo changes in CB1 mediated plasticity. Our findings suggest the shift from goal-directed to automatic actions is controlled by CB1 receptor modulation of OFC excitatory output, perhaps through modulating pathways conveying action value information.

    Lay Language Summary: We often make the same action, but for different reasons. We constantly shift between habitual and goal-directed actions in our daily lives, with information controlling goal-directed control relayed through a region of the prefrontal cortex known as the orbital cortex. Our research suggests that to form habits, the brain needs a way to decrease this flow of information. We found that endocannabinoids act as a brake on the orbital cortex, thereby allowing for habit formation and expression.
    For optimal everyday function, we need to be able to make routine actions quickly and efficiently, and habits serve this purpose. However, we also encounter changing circumstances, and need the capacity to “break habits” and perform a flexible goal-directed action based on updated consequences. When we can’t, there can be devastating consequences. For example, people suffering from neuropsychiatric disorders such as obsessive-compulsive disorder and addiction have a hard time “breaking habits” and shifting back to goal-directed control. Our results suggest that alterations in the endocannabinoid neuromodulatory system could be blocking the capacity to “break habits” as observed in disorders affecting decision-making.
    To examine mechanisms controlling how the brain “breaks habits”, we trained the same mouse to make the same action in a goal-directed versus habitual manner. Mice were trained to perform a lever-pressing action in two different environments for the same food reward, but under different action requirements that differentially biased the animal toward the development of goal-directed versus habitual actions. Use of this newly developed procedure allowed us to probe the brain mechanisms involved when shifting action strategies.
    We previously found that increasing the output of the orbital cortex via a technique called optogenetic activation increased goal-directed actions. In contrast, decreasing orbital cortex output using a chemogenetic approach disrupted goal-directed actions, and mice used habitual action strategies instead. This suggests that changes in the output of orbital cortex may be necessary to “break habits”. Since endocannabinoids can serve to decrease a neuron’s output in the brain, we hypothesized that endocannabinoids may be controlling the output activity of the orbital cortex. To test this, we removed receptors that are activated by endocannabinoids in either output neurons of the whole prefrontal cortex or specifically in output neurons of the orbital cortex. Mice missing these cannabinoid receptors did not form habits, relying instead upon goal-directed control over actions. We also recorded the neural activity of neurons in involved brain circuits, and found that removing cannabinoid receptors changed how the brain encoded goal-directed and habitual actions.
    The present findings show a way in which habits come to control behavior; by acting as a brake on brain circuits controlling goal-directed actions via an endocannabinoid receptor-mediated decrease in orbital cortex output. Normal endocannabinoid modulation of prefrontal cortex is necessary for the proper balance between efficient and flexible control of actions. Our work directly demonstrates that parallel brain circuits mediating goal-directed versus habitual actions compete for control over behavior. Drugs of abuse and neuropsychiatric disorders affecting decision-making change the balance between habits and goal-directed actions. Based on these findings, possibly we can restore this balance between action strategies by targeting the brain endocannabinoid system; thereby breaking habitual control over behavior and alleviating suffering in disorders involving these decision-making processes.