Biology subjects

Ahmari, S. E.

Publications and source records attributed to Ahmari, S. E..

10 recordsLinked to original sources

bioRxiv2026

Discontinuation of GLP-1RA Treatment Reinstates Binge-Like Eating and Drives Body Weight Past Pre-Treatment Levels in Mice

We examined the impact of semaglutide treatment and discontinuation in a pre-clinical model for binge eating. Treatment reduced body weight and palatable food intake in mice with binge-like eating. Discontinuation reinstated binge-like eating and caused body weight to significantly exceed pre-treatment baseline, revealing specific binge-related risk when discontinuing GLP-1RAs.

animal behavior and cognition↗

bioRxiv2024

Striatal indirect pathway mediates hesitation

Determining the best possible action in an uncertain situation is often challenging, and organisms frequently need extra time to deliberate. This pause in behavior in response to uncertainty - also known as hesitation - commonly occurs in many aspects of daily life, yet its neural circuits are poorly understood. Here we present the first experimental paradigm that reliably evokes hesitation in mice. Using cell-type specific electrophysiology and optogenetics, we show that indirect, but not direct, pathway spiny projection neurons specifically in the dorsomedial striatum mediate hesitation. These data indicate that the basal ganglia circuits controlling the pausing involved in cognitive processes like hesitation are distinct from those that control other types of behavioral inhibition, such as cue-induced stopping.

neuroscience↗

bioRxiv2024

Sapap3 knockout mice show threat bias under conflict during platform mediated avoidance task: implications for obsessive compulsive disorder

Obsessive compulsive disorder (OCD) typically involves cycling between symptoms of intrusive aversive thoughts (obsessions) and repetitive rituals aimed at avoiding these aversive outcomes (compulsions), which interferes with patients engagement with other important aspects of their lives. This cycling relationship between obsessions and compulsions highlights a potential role of impaired threat processing and avoidance behavior in OCD symptoms. The most effective behavioral therapy for OCD, exposure with response prevention (ERP), aims to break this cycle. However, it can be difficult for patients to access and engage with, suggesting a need for improved understanding of the neural mechanisms of threat processing and avoidance behavior in OCD to guide development of new and more effective treatments. Platform mediated avoidance (PMA) has proven to be a useful translational paradigm for use in rodents to examine avoidance neurobiology and models relevant to OCD, such as ERP and overtraining-induced persistent avoidance. However, to date this protocol has only been used in rats, and studies in transgenic mouse models relevant to OCD may shed further light on neural mechanisms relevant to disturbances in avoidance and threat processing in the disorder. To address this gap, we tested Sapap3 knockout (KO) mice, a leading preclinical model in OCD research, in the PMA task. Using this paradigm, we examined avoidance acquisition, expression, and extinction, as well as reward seeking under motivational conflict in two separate cohorts conditioned using higher (0.4 mA) or lower (0.24 mA) intensity shock. Surprisingly, the most striking difference observed in Sapap3-KOs vs control mice was heightened suppression of lever pressing for rewards during a tone signaling impending threat, suggesting a shift in action selection under motivational conflict (genotype effect avoidance conditioning: 0.24 mA cohort p=0.011, 0.4 mA cohort p=0.07; avoidance extinction: 0.24 mA p=0.057, 0.4 mA p=0.042). Avoidance responding was also acquired more slowly in Sapap3-KOs trained with a low intensity shock (time x genotype interaction p=0.025) and was extinguished more robustly following ERP (genotype effect p=0.043). In contrast, avoidance was similar between Sapap3 KOs and WT littermate controls trained using higher intensity shock (0.4 mA cohort time effect p<0.0001). Expression of the immediate early gene c-Fos associated with reinstatement of avoidance after ERP showed preliminary evidence for decreased activity of medial orbitofrontal cortex (mOFC) in KOs which may contribute to observed differences in PMA performance (KO vs WT mOFC c-Fos t-test p=0.0456). Together these findings suggest that mOFC dysfunction may contribute to increases in the influence of threats vs rewards over action selection in an animal model with relevance to OCD, and that the Sapap3-KO model presents valuable opportunities for deeper mechanistic investigation of avoidance and threat processing relevant to the human disorder.

neuroscience↗

bioRxiv2022

Examination of Onset Trajectories and Persistence of Binge-Like Eating Behavior in Mice after Intermittent Palatable Food Exposure

Binge eating (BE) is a persistent behavior associated with a chronic course of illness and poor treatment outcomes. While clinical research is unable to capture the full course of BE, pre-clinical approaches offer the opportunity to examine binge-like eating from onset through chronic durations, allowing identification of factors contributing to BE persistence. The current study quantified the trajectories of binge-like eating onset and modeled cycles of abstinence/relapse to develop a translational model for BE persistence. Adult male and female C57Bl6/J mice were randomized to a binge-like palatable food (PF) access schedule (daily 2-hour, 3x/week) or continuous, non-binge like PF access for 12 days (Experiment 1). Persistence of PF consumption in both binge-like PF access groups was then examined across three cycles of forced abstinence and re-exposure to PF (incubation) to model the persistence of BE in clinical populations. Mice with daily 2 hour PF access escalated their intake more than mice in the 3x/week or continuous groups (Experiment 1).This pattern was more pronounced in females. In addition, this pattern of PF intake re-emerged across multiple cycles of behavioral incubation (Experiment 2). These findings provide a model of binge-like eating in mice that can be used in future studies examining both environmental factors and neural mechanisms contributing to BE persistence.

neuroscience↗

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↗

bioRxiv2021

Independent and distinct patterns of abnormal lateral orbitofrontal cortex activity during compulsive grooming and reversal learning normalize after fluoxetine

BackgroundPatients with obsessive-compulsive disorder (OCD) display disrupted performance and abnormal lateral orbitofrontal cortex (LOFC) activity during reversal learning tasks, yet it is unknown whether compulsions and reversal learning deficits share a common neural substrate. To answer this question, we measured neural activity with in vivo calcium imaging in LOFC during compulsive grooming and reversal learning before and after fluoxetine treatment. MethodsSapap3-knockout (KO) mice were used as a model for OCD-relevant behaviors. Sapap3-KOs and control littermates were injected with virus encoding GCaMP6f and implanted with gradient-index lenses to visualize LOFC activity using miniature microscopes. Grooming, reversal learning, and neural activity were measured pre- and post-fluoxetine treatment (18mg/kg, 4 weeks). ResultsBaseline compulsive grooming and reversal learning impairments in KOs improved after fluoxetine treatment. Additionally, KOs display distinct patterns of abnormal LOFC activity during grooming and reversal learning, both of which normalize after fluoxetine. Finally, modulation in response to reversal learning and compulsive behavior are independent, as reversal learning-associated neurons are distributed randomly amongst grooming-associated neurons (i.e. overlap is what would be expected by chance). ConclusionsIn OCD, the LOFC is disrupted during both compulsive behaviors and reversal learning, yet whether these behaviors share common neural underpinnings is unknown. We find that the LOFC plays distinct and independent roles in compulsive grooming and impaired reversal learning and their improvement with fluoxetine. These findings suggest that LOFC plays separate roles in pathophysiology and treatment of different perseverative behaviors in OCD.

neuroscience↗

bioRxiv2020

Transcriptome alterations are enriched for synapse-associated genes in the striatum of subjects with obsessive-compulsive disorder

BackgroundObsessive compulsive disorder (OCD) is a chronic and severe psychiatric disorder for which effective treatment options are limited. Structural and functional neuroimaging studies have consistently implicated the orbitofrontal cortex (OFC) and striatum in the pathophysiology of the disorder. Recent genetic evidence points to involvement of components of the excitatory synapse in the etiology of OCD. However, the transcriptional alterations that could link genetic risk to known structural and functional abnormalities remain mostly unknown. MethodsTo assess potential transcriptional changes in the OFC and two striatal regions (caudate nucleus and nucleus accumbens) of OCD subjects relative to unaffected comparison subjects, we sequenced messenger RNA transcripts from these brain regions. ResultsIn a joint analysis of all three regions, 904 transcripts were differentially expressed between 7 OCD versus 8 unaffected comparison subjects. Region-specific analyses highlight a smaller number of differences, which concentrate in caudate and nucleus accumbens. Pathway analyses of the 904 differentially expressed transcripts showed enrichment for genes involved in synaptic signaling, with these synapse-associated genes displaying lower expression in OCD subjects relative to unaffected comparison subjects. Finally, we estimate that cell type fractions of medium spiny neurons are lower whereas vascular cells and astrocyte fractions are higher in tissue of OCD subjects. ConclusionsTogether, these data provide the first unbiased examination of differentially expressed transcripts in both OFC and striatum of OCD subjects. These transcripts encode synaptic proteins more often than expected by chance, and thus implicate the synapse as a vulnerable molecular compartment for OCD.

neuroscience↗

bioRxiv2020

Dissociable roles of central striatum and anterior lateral motor area in initiating and sustaining naturalistic behavior

Although much is known about how corticostriatal circuits mediate behavioral selection, most previous work has been conducted in highly trained animals engaged in instrumental tasks. Understanding how corticostriatal circuits mediate behavioral selection and initiation in a naturalistic setting is critical to understanding how the brain chooses and executes behavior in unconstrained situations. Central striatum (CS), an understudied region that lies in the middle of the motor-limbic topography, is well-poised to play an important role in these processes since its main cortical inputs (Corbit et al., 2019) have been implicated in behavioral flexibility (lateral orbitofrontal cortex (Kim and Ragozzino, 2005)) and response preparation (anterior lateral motor area, ALM) (Li et al., 2015), However, although CS activity has been associated with conditioned grooming behavior in transgenic mice (Burguiere et al., 2013), the role of CS and its cortical inputs in the selection of spontaneous behaviors has not been explored. We therefore studied the role of CS corticostriatal circuits in behavioral selection in an open field context. Surprisingly, using fiber photometry in this unconstrained environment, we found that population calcium activity in CS was specifically increased at onset of grooming, and not at onset of other spontaneous behaviors such as rearing or locomotion. Supporting a potential selective role for CS in the initiation of grooming, bilateral optogenetic stimulation of CS evoked immediate onset grooming-related movements. However, these movements resembled subcomponents of grooming behavior and not full-fledged grooming bouts, suggesting that additional input(s) are required to appropriately sequence and sustain this complex motor behavior once initiated. Consistent with this idea, optogenetic stimulation of CS inputs from ALM generated sustained grooming responses that evolved on a time-course paralleling CS activation monitored using single-cell calcium imaging. Furthermore, fiber photometry in ALM demonstrated a gradual ramp in calcium activity that peaked at time of grooming termination, supporting a potential role for ALM in encoding length of this spontaneous sequenced behavior. Finally, dual color dual region fiber photometry indicated that CS activation precedes ALM during naturalistic grooming sequences. Taken together, these data support a novel model in which CS activity is sufficient to initiate grooming behavior, but ALM activity is necessary to sustain and encode the length of grooming bouts. Thus, the use of an unconstrained behavioral paradigm has allowed us to uncover surprising roles for CS and ALM in the initiation and maintenance of spontaneous sequenced behaviors.

neuroscience↗

bioRxiv2019

Disruption of prepulse inhibition is associated with severity of compulsive behavior and nucleus accumbens dopamine system changes in Sapap3 knockout mice

Obsessive compulsive disorder (OCD) is associated with disruption of sensorimotor gating, which may contribute to difficulties inhibiting intrusive thoughts and compulsive rituals. Neural mechanisms underlying these disturbances are unclear; however, striatal dopamine is implicated in regulation of sensorimotor gating and OCD pathophysiology. The goal of this study was to examine the relationships between sensorimotor gating, compulsive behavior, and striatal dopamine receptor levels in Sapap3 knockout mice (KOs), a widely used preclinical model system for OCD research. We found a trend for disruption of sensorimotor gating in Sapap3-KOs using the translational measure prepulse inhibition (PPI); however, there was significant heterogeneity in both PPI and compulsive grooming in KOs. Disruption of PPI was significantly correlated with a more severe compulsive phenotype. In addition, PPI disruption and compulsive grooming severity were associated with reduced dopamine D1 and D2/3 receptor density in the nucleus accumbens core (NAcC). Compulsive grooming progressively worsened in Sapap3-KOs tested longitudinally, but PPI disruption was first detected in high-grooming KOs at 7 months of age. Through detailed characterization of individual differences in OCD-relevant behavioral and neurochemical measures, our findings suggest that NAcC dopamine receptor changes may be involved in disruption of sensorimotor gating and compulsive behavior relevant to OCD.

neuroscience↗