LaPalombara, Z. | Search bioRxiv

bioRxiv2022

Hyperactivity of indirect pathway-projecting spiny projection neurons drives compulsive behavior

Compulsive behaviors are a hallmark symptom of obsessive compulsive disorder (OCD). Striatal hyperactivity has been linked to compulsive behavior generation in correlative studies in humans and causal studies in rodents. However, the contribution of the two distinct striatal output populations to the generation and treatment of compulsive behavior is unknown. These populations of direct and indirect pathway-projecting spiny projection neurons (SPNs) have classically been thought to promote or suppress actions, respectively, leading to a long-held hypothesis that increased output of direct relative to indirect pathway promotes compulsive behavior. Contrary to this hypothesis, here we find that indirect pathway hyperactivity drives compulsive grooming in the Sapap3-knockout mouse model of OCD-relevant behavior. Furthermore, we show that suppression of indirect pathway activity using optogenetics or treatment with the first-line OCD pharmacotherapy fluoxetine is associated with reduced compulsive behavior. Together, these findings highlight the striatal indirect pathway as a potential new treatment target for compulsive behavior.

neuroscience↗

bioRxiv2021

Corticostriatal dynamics underlying components of binge-like eating in mice

Binge eating (BE) is a maladaptive repetitive feeding behavior present across nearly all eating disorder diagnoses. Despite the substantial negative impact of BE on psychological and physiological health, its underlying neural mechanisms are largely unknown. Other repetitive behavior disorders (e.g., obsessive compulsive disorder) show dysfunction within corticostriatal circuitry. Additionally, previous pre-clinical and clinical work has highlighted an imbalance between goal-directed and habitual responding in BE. The aim of the current study was to longitudinally examine in vivo neural activity within corticostriatal regions associated with habitual behavior- the infralimbic cortex (IL) and dorsolateral striatum (DLS)- in a robust pre-clinical model for BE. Female C57BL/6 mice (N=32) were randomized to receive: 1) intermittent (daily, 2-hour) binge-like access to palatable food (BE mice), or 2) continuous, non-intermittent (24-hour) access to palatable food (non-BE mice). In vivo calcium imaging was performed via fiber photometry at baseline and after chronic (4 weeks) engagement in the model for BE. Feeding behaviors (feeding bout onset/offset) during the recordings were captured using lickometers which generated TTL outputs for precise alignment of behavior to neural data. IL showed no specific changes in neural activity related to BE. However, BE animals showed decreased DLS activity at feeding onset and offset at the chronic timepoint when compared to baseline. Additionally, BE mice had significantly lower DLS activity at feeding onset and offset at the chronic timepoint compared to non-BE mice. These results point to a role for DLS hypofunction in chronic BE, highlighting a potential target for future treatment intervention. Significance StatementBinge eating is a chronic and repetitive eating behavior that is associated with poor physiological and psychosocial outcomes. Despite the negative impact of binge eating, little is known about the neurobiological mechanisms contributing to the chronic course and persistence of the behavior. To investigate potential neural mechanisms underlying binge eating, we are using approaches developed to monitor neural activity in rodents. This study is the first to identify longitudinal changes in neural activity within regions of the prefrontal cortex and dorsal striatum during binge-like eating behavior in mice. Findings from this work could inform targeted biological treatments for binge eating.

neuroscience↗