Distinct Patterns of Abnormal Lateral Orbitofrontal Cortex Activity During Compulsive Grooming and Reversal Learning Normalize After Fluoxetine

doi:10.1016/j.biopsych.2021.11.018

Biological Psychiatry

Volume 93, Issue 11, 1 June 2023, Pages 989-999

https://doi.org/10.1016/j.biopsych.2021.11.018 Get rights and content

Abstract

Background

Patients with obsessive-compulsive disorder (OCD) display disrupted performance and abnormal lateral orbitofrontal cortex (LOFC) activity during reversal learning tasks. However, 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.

Methods

Sapap3 knockout (KO) mice were used as a model for OCD-relevant behaviors. Sapap3 KOs and control littermates were injected with a 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 (18 mg/kg, 4 weeks).

Results

Baseline compulsive grooming and reversal learning impairments in KOs improved after fluoxetine treatment. In addition, KOs displayed distinct patterns of abnormal LOFC activity during grooming and reversal learning, both of which normalized after fluoxetine. Finally, reversal learning–associated neurons were distributed randomly among grooming-associated neurons (i.e., overlap is what would be expected by chance).

Conclusions

In OCD, LOFC is disrupted during both compulsive behaviors and reversal learning, but whether these behaviors share common neural underpinnings is unknown. We found that LOFC plays distinct 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.

Section snippets

Animals

All procedures were carried out in accordance with the guidelines for care and use of laboratory animals from the National Institutes of Health and with approval from the University of Pittsburgh Institutional Animal Care and Use Committee. Sapap3 KOs (n = 8; 5 female) and WT (n = 6; 3 female) littermates were maintained on a C57BL/6 background. Further details on housing and light/dark cycle can be found in Supplement 1.

Calcium Imaging Surgery

Mice underwent two surgeries for optical imaging studies (28,29). For the

Analysis of Grooming Behavior

Sapap3 KOs groomed for a larger percentage of time both at baseline and after 4 weeks of fluoxetine treatment (Figure 1C) (genotype: F_1,12 = 8.5, p = .01; drug: F_1,12 = 3.6, p = .08; genotype × drug: F_1,12 = 0.02, p = .88). In contrast, baseline increases in the number of grooming bouts in KOs decreased after fluoxetine treatment (Figure 1D) (genotype: F_1,12 = 13.5, p = .003; drug: F_1,12 = 8.8, p = .01; genotype × drug: F_1,12 = 6.0, p = .03). KOs engaged in longer grooming bouts compared with

Discussion

Patients with OCD display disrupted performance during reversal learning tasks; however, whether these behaviors share common neural underpinnings is unknown. Here, we replicated and extended prior work showing that Sapap3 KO mice display both compulsive behavior and deficits in reversal learning. While we demonstrate that both deficits improve with fluoxetine, the severity of compulsive grooming does not correlate with the extent of reversal learning deficits. In addition, we provide several

Acknowledgments and Disclosures

This work was supported by NIMH (Grant No. R21 MH116330 [to SEA]), Burroughs Wellcome CAMS Award (to SEA), NIMH Biobehavioral Research Awards for Innovative New Scientists (Grant No. R01MH104255 [to SEA]), McKnight Scholar Award (to SEA), MQ Fellows Award (to SEA), and Klingenstein-Simons Fellowship Award in the Neurosciences (to SEA).

We thank Xiaojun Li, Brittany Chamberlain, and Alexander Lammers for help with video scoring; Drs. Jesse Wood, Zoe LaPalombara, and James Hyde for help with data

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¹: EEM, MAG, and SCP contributed equally to this work.

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Archival ReportDistinct Patterns of Abnormal Lateral Orbitofrontal Cortex Activity During Compulsive Grooming and Reversal Learning Normalize After Fluoxetine

Abstract

Background

Methods

Results

Conclusions

Section snippets

Animals

Calcium Imaging Surgery

Analysis of Grooming Behavior

Discussion

Acknowledgments and Disclosures

J Behav Ther Exp Psychiatry

Psychiatry Res

J Affect Disord

Neuropsychologia

Biol Psychiatry

Biol Psychiatry

Curr Biol

Cell Rep

Neuroscience

Neuron

Neural correlates of feedback processing in obsessive–compulsive disorder

J Abnorm Psychol

Reduced orbitofrontal-striatal activity on a reversal learning task in obsessive-compulsive disorder

Arch Gen Psychiatry

Differential frontal–striatal and paralimbic activity during reversal learning in major depressive disorder and obsessive–compulsive disorder

Psychol Med

Reversal learning as a neuropsychological indicator for the neuropathology of obsessive compulsive disorder? A behavioral study

J Neuropsychiatry Clin Neurosci

Cognitive inflexibility in obsessive-compulsive disorder and major depression is associated with distinct neural correlates

PLoS One

Orbitofrontal dysfunction in patients with obsessive-compulsive disorder and their unaffected relatives

Science

Local cerebral glucose metabolic rates in obsessive-compulsive disorder. A comparison with rates in unipolar depression and in normal controls

Arch Gen Psychiatry

Regional cerebral blood flow measured during symptom provocation in obsessive-compulsive disorder using oxygen 15-labeled carbon dioxide and positron emission tomography

Arch Gen Psychiatry

Functional magnetic resonance imaging of symptom provocation in obsessive-compulsive disorder

Arch Gen Psychiatry

Archival Report
Distinct Patterns of Abnormal Lateral Orbitofrontal Cortex Activity During Compulsive Grooming and Reversal Learning Normalize After Fluoxetine