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Scholarly Works (6 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2022)

Alcohol use disorder (AUD) is characterized by cognitive deficits thought to escalate maladaptive behaviors that increase the vulnerability to relapse. Neurobiological investigations have identified a key role for orbitofrontal cortex (OFC) computations in control of adaptive behavior. OFC-based computations and their underlying circuits have been shown to disrupted in alcohol addiction and other disorders characterized by repetitive behaviors. However, little is known about how these changes manifest in vivo when behaviors are self-initiated and reliant on inferences shaped by action-related information. In this dissertation, I used a mouse neural circuit-dissection approach in conjunction with an unconstrained lever-pressing task to investigate OFC computations made during adaptive behavior and their disruption in alcohol dependence. Chapter 1 explored how alcohol dependence induced changes in OFC neural activity correlates of self-initiated actions and their associated outcomes. Results suggested that chronic alcohol exposure induces long-lasting disruptions to OFC function such that activity associated with volitional actions was enhanced, but OFC activity contributions to outcome-related information was diminished. Chapter 2 investigated how different OFC populations support action-related computations, including computations relating to prior action information. Results identified a novel role for OFC excitatory and inhibitory neurons in the continuous integration of action information for behavioral control. These studies showed that OFC populations differentially encode action-related information in a dynamic manner, and that these cortical representations are significantly altered in alcohol dependence. Overall, this dissertation revealed some of the complexity of OFC’s contributions to adaptive behavior and further support the OFC as a target brain region for the intervention of AUD.

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Cover page: Orbitofrontal Cortex Mediates Action and Outcome Information and is Disrupted in Alcohol Dependence
  • Article
  • Peer Reviewed
UC San Diego Previously Published Works (2022)
Decision-making is a continuous and dynamic process with prior experience reflected in and used by the brain to guide adaptive behavior. However, most neurobiological studies constrain behavior and/or analyses to task-related variables, not accounting for the continuous internal and temporal space in which they occur. We show mice rely on information learned through recent and longer-term experience beyond just prior actions and reward - including checking behavior and the passage of time - to guide self-initiated, self-paced, and self-generated actions. These experiences are represented in secondary motor cortex (M2) activity and its projections into dorsal medial striatum (DMS). M2 integrates this information to bias strategy-level decision-making, and DMS projections reflect specific aspects of this recent experience to guide actions. This suggests diverse aspects of experience drive decision-making and its neural representation, and shows premotor corticostriatal circuits are crucial for using selective aspects of experiential information to guide adaptive behavior.
    Cover page: Information normally considered task-irrelevant drives decision-making and affects premotor circuit recruitment
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2021)
    Alcohol dependence can result in long-lasting deficits to decision-making and action control. Neurobiological investigations have identified orbitofrontal cortex (OFC) as important for outcome-related contributions to goal-directed actions during decision-making. Prior work has shown that alcohol dependence induces long-lasting changes to OFC function that persist into protracted withdrawal and disrupts goal-directed control over actions. However, it is unclear whether these changes in function alter representation of action and outcome-related neural activity in OFC. Here, we used the well-validated chronic intermittent ethanol (CIE) exposure and withdrawal procedure to model alcohol dependence in mice and performed in vivo extracellular recordings during an instrumental task in which lever-press actions made for a food outcome. We found alcohol dependence disrupted goal-directed action control and increased OFC activity associated with lever-pressing but decreased OFC activity during outcome-related epochs. The ability to decode outcome-related information, but not action information, from OFC activity following CIE exposure was reduced. Hence, chronic alcohol exposure induced a long-lasting disruption to OFC function such that activity associated with actions was enhanced, but OFC activity contributions to outcome-related information was diminished. This has important implications for hypotheses regarding compulsive and habitual phenotypes observed in addiction.
      Cover page: Different Effects of Alcohol Exposure on Action and Outcome Related Orbitofrontal Cortex Activity
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2022)
      The ability to use information from ones prior actions is necessary for decision-making. While orbitofrontal cortex (OFC) has been hypothesized as key for inferences made using cue and value-related information, whether OFC populations contribute to the use of information from volitional actions to guide behavior is not clear. Here, we used a self-paced lever-press hold-down task in which mice infer prior lever-press durations to guide subsequent action performance. We show that the activity of genetically identified lateral OFC (lOFC) subpopulations differentially instantiate current and prior action information during ongoing action execution. Transient state-dependent lOFC circuit disruptions of specified subpopulations reduced the encoding of ongoing press durations but did not disrupt the use of prior action information to guide future action performance. In contrast, a chronic functional loss of lOFC circuit activity resulted in increased reliance on recently executed lever-press durations and impaired contingency reversal, suggesting the recruitment of compensatory mechanisms that resulted in repetitive action control. Our results identify a novel role for lOFC in the integration of action information to guide adaptive behavior.
        Cover page: Orbitofrontal cortex populations are differentially recruited to support actions.
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2023)
        Alcohol use disorder (AUD) alters decision-making control over actions, but disruptions to the responsible neural circuit mechanisms are unclear. Premotor corticostriatal circuits are implicated in balancing goal-directed and habitual control over actions and show disruption in disorders with compulsive, inflexible behaviors, including AUD. However, whether there is a causal link between disrupted premotor activity and altered action control is unknown. Here, we find that mice chronically exposed to alcohol (chronic intermittent ethanol [CIE]) showed impaired ability to use recent action information to guide subsequent actions. Prior CIE exposure resulted in aberrant increases in the calcium activity of premotor cortex (M2) neurons that project to the dorsal medial striatum (M2-DMS) during action control. Chemogenetic reduction of this CIE-induced hyperactivity in M2-DMS neurons rescued goal-directed action control. This suggests a direct, causal relationship between chronic alcohol disruption to premotor circuits and decision-making strategy and provides mechanistic support for targeting activity of human premotor regions as a potential treatment in AUD.
          Cover page: Chronic alcohol exposure alters action control via hyperactive premotor corticostriatal activity.
          • Article
          • Peer Reviewed
          UC San Diego Previously Published Works (2021)
          Psychiatric disease often produces symptoms that have divergent effects on neural activity. For example, in drug dependence, dysfunctional value-based decision-making and compulsive-like actions have been linked to hypo- and hyperactivity of orbital frontal cortex (OFC)-basal ganglia circuits, respectively; however, the underlying mechanisms are unknown. Here we show that alcohol-exposed mice have enhanced activity in OFC terminals in dorsal striatum (OFC-DS) associated with actions, but reduced activity of the same terminals during periods of outcome retrieval, corresponding with a loss of outcome control over decision-making. Disrupted OFC-DS terminal activity was due to a dysfunction of dopamine-type 1 receptors on spiny projection neurons (D1R SPNs) that resulted in increased retrograde endocannabinoid signaling at OFC-D1R SPN synapses reducing OFC-DS transmission. Blocking CB1 receptors restored OFC-DS activity in vivo and rescued outcome-based control over decision-making. These findings demonstrate a circuit-, synapse-, and computation-specific mechanism gating OFC activity in alcohol-exposed mice.
            Cover page: Mechanism for differential recruitment of orbitostriatal transmission during actions and outcomes following chronic alcohol exposureCreative Commons 'BY' version 4.0 license
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