Accelerating What We Know About OCD: From Genes to Mice to Better Treatments

We’re racing to turn human genetic discovery into a biological model to test new treatments.

The challenge

Obsessive-Compulsive Disorder (OCD) is a serious and debilitating mental health condition that affects approximately 2% of the global population. People with OCD experience persistent, distressing thoughts (obsessions) and feel driven to perform repetitive behaviors (compulsions). These symptoms can severely interfere with daily life, making it difficult to work, maintain relationships, or even leave the house. While medications and therapy can help some individuals, a large portion of people with OCD do not respond to current treatments. This is partly because we still do not fully understand the brain circuits and cell types that give rise to OCD. Without this knowledge, it is difficult to design treatments that target the root of the disorder. However, recent breakthroughs in human genetics¹ have brought us closer than ever to uncovering the biological basis of OCD. That is where our project begins.

Why a mouse model based on human biological mutations is essential

Genetic studies in humans are uncovering new clues about the biological origins of OCD. These studies have identified specific genes that are more common in people with OCD, suggesting that certain brain cells and circuits may be especially important in the development of symptoms. However, studying these genes in people is extremely difficult. This is where mouse models become incredibly valuable². Mice share many of the same brain structures and genetic pathways as humans. By introducing OCD-linked mutations into mice, we can closely examine how it changes brain activity, behavior, and development. This allows us to:

· Identify which brain cells and circuits are affected

· Track how those changes lead to compulsive or anxiety-like behaviors

· Test potential therapies in a high throughput, controlled, measurable way

Currently, available mouse models of OCD have good face validity with behavioral phenotypes that closely resemble symptoms of OCD in people^2,3, however they lack a genetic component associated with human genetic variants^4,5. Our goal is to build new, next-generation transgenic models based on emerging genetic variants identified in human patients. Identifying a genetic mutation in humans that recreates a valid OCD phenotype in a mouse is a critical step toward a biological framework for understanding OCD, one that will help us move beyond symptom reduction and towards new, more effective molecular treatments.

Our hypothesis

Genetic variants associated with OCD in humans will generate a similar phenotype in mice. We assessed the viability and translational promise of the top four candidate variants using criteria including gene expression profiles, prior human genetic association data, known functions in synaptic signaling, and conservation across species. Based on this evaluation, we have selected one high-priority gene, CTNND1, encoding p120 catenin (a cell adhesion molecule), as the most promising candidate from the recent comprehensive report identifying genetic variations¹. OCD is a heterogeneous disorder and different subtypes could correspond to different genetic variations. Importantly, our approach is designed to quickly adapt to new discoveries: this proposal will serve as a blueprint for efficient investigation of other genetic candidates that will be emerging from recent investments in OCD genetics*.

Methods

Overview: We will employ a 2-pronged approach: mice will receive general phenotyping at an off-site core to measure a basic set of behavior and biological changes (e.g. locomotion, metabolism) in addition to more complex behavior and histological analyses performed in the laboratories of the principal investigators.

Does this gene mutation lead to OCD-like behavior in mice?
Which brain cells and circuits are disrupted?

Mice: A genetically modified mouse line that allows for genetic deletion of CTNND1 will be obtained from a public repository (RRID:MMRRC_030112-UCD).

Breeding and Testing: Upon receipt, we will establish a breeding colony under standard housing conditions, generating both heterozygous and homozygous knockout animals along with wild-type littermate controls. Genotyping will confirm Mendelian inheritance and identify offspring for downstream testing. Initial phenotyping will be conducted in partnership with a core facility (Harvard Mouse Behavior Core**), where cohorts will undergo standardized assessments of general health, metabolism, locomotion, and gross neurological function to rule out nonspecific deficits.

Subsequently, animals will undergo a series of more complex behavioral assays that capture validated behavioral dysfunctions in OCD. These disorder-specific assays will be performed in our labs and include: anxiety-like behavior, positive and negative reinforcement, avoidance, compulsive grooming, cognitive flexibility, sequence completion, and probabilistic reversal learning^6-13. At the conclusion of behavioral testing, brains will be harvested and processed for histological and molecular analysis. We will assess post-synaptic density markers (PSD-95, Homer1) and structural abnormalities within relevant OCD circuits (cortico-striatal-thalamo-cortical, midbrain, and amygdala).

Ethics and Data Management: Adult male and female mice will be used for all experiments. Experiment and housing conditions are administered and approved by the Institutional Animal Care and Use Committee(s) at each institution. All experiments will be done blind to genotype to ensure bias in human scoring is eliminated. Upon publication, data and code used for the analyses will be made available.

Planned Statistical Analyses:

We have used G*Power 3.0 to determine the number of animals per group, based on alpha = 0.05, power = 0.80, and effect sizes derived from previous phenotyping datasets. Power analyses were designed to detect 50% differences in mean values with standard deviation estimates from prior behavioral work. For primary analyses, we will use two-way ANOVAs with Genotype (wildtype, heterozygous, homozygous) and Sex as between-subjects factors. Where repeated measures are present (e.g., across sessions), repeated-measures ANOVAs or mixed-effects models will be applied. Post-hoc comparisons will be conducted when significant main effects or interactions are found, with adjustments for multiple comparisons using Tukey’s HSD or Bonferroni correction. All data will be tested for normality and equal variance; non-parametric tests (e.g., Kruskal–Wallis with Dunn's post-hoc) will be employed if assumptions are violated. Analyses will be performed in R or Python, and complete scripts will be archived for reproducibility. Correlations between behavioral outcomes and molecular measures will be explored using Pearson or Spearman tests, depending on distribution characteristics.

Timeline and Milestones

Timeframe	Milestone
Months 1–4	Acquire new genetic mouse line and begin colony breeding
Months 5–8	Offsite behavioral testing (simple behaviors)
Months 5–12	Onsite behavioral testing (complex behaviors)
Months 13–18	Analyze behavior data; Identify disrupted brain circuits

Budget

Item	Cost
Acquisition of new mouse line (purchase, shipping, licensing fees)	$10,000
Mouse colony setup and 1 year of care (housing, feeding, genotyping)	$25,000
Behavioral testing (equipment use, software, technician time)	$20,000
Brain analysis (tissue processing, microscopy, reagents)	$15,000
Personnel support (1 part-time research assistant)	$25,000
Open-access publication fees & public engagement materials	$5,000
Total	$100,000

Project Leads

Robyn St. Laurent, PhD 14+ years experience with preclinical models of psychiatric conditions Postdoctoral Scholar, Stanford University, Department of Psychiatry and Behavioral Sciences

Susanne Ahmari, MD, PhD 20+ years experience with preclinical and clinical OCD research Associate Professor, University of Pittsburgh, Department of Psychiatry, Director, Translational OCD Laboratory

Marc Fuccillo, MD PhD 20+ years experience with preclinical neurodevelopmental models Associate Professor, University of Pennsylvania, Department of Neuroscience

References

1 Strom, N. I. et al. Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder. Nat Genet 57, 1389-1401 (2025). https://doi.org/10.1038/s41588-025-02189-z

2 Chamberlain, B. L. & Ahmari, S. E. Animal Models for OCD Research. Curr Top Behav Neurosci 49, 55-96 (2021). https://doi.org/10.1007/7854_2020_196

3 Welch, J. M. et al. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 448, 894-900 (2007). https://doi.org/10.1038/nature06104

4 Bienvenu, O. J. et al. Sapap3 and pathological grooming in humans: Results from the OCD collaborative genetics study. Am J Med Genet B Neuropsychiatr Genet 150B, 710-720 (2009). https://doi.org/10.1002/ajmg.b.30897

5 Boardman, L. et al. Investigating SAPAP3 variants in the etiology of obsessive-compulsive disorder and trichotillomania in the South African white population. Compr Psychiatry 52, 181-187 (2011). https://doi.org/10.1016/j.comppsych.2010.05.007

6 St Laurent, R. et al. Intercalated amygdala dysfunction drives avoidance extinction deficits in the Sapap3 mouse model of obsessive-compulsive disorder. Biol Psychiatry (2024). https://doi.org/10.1016/j.biopsych.2024.10.021

7 Manning, E. E., Geramita, M. A., Piantadosi, S. C., Pierson, J. L. & Ahmari, S. E. Distinct Patterns of Abnormal Lateral Orbitofrontal Cortex Activity During Compulsive Grooming and Reversal Learning Normalize After Fluoxetine. Biol Psychiatry (2021). https://doi.org/10.1016/j.biopsych.2021.11.018

8 Manning, E. E., Wang, A. Y., Saikali, L. M., Winner, A. S. & Ahmari, S. E. Disruption of prepulse inhibition is associated with compulsive behavior severity and nucleus accumbens dopamine receptor changes in Sapap3 knockout mice. Sci Rep 11, 9442 (2021). https://doi.org/10.1038/s41598-021-88769-5

9 Manning, E. E., Dombrovski, A. Y., Torregrossa, M. M. & Ahmari, S. E. Impaired instrumental reversal learning is associated with increased medial prefrontal cortex activity in Sapap3 knockout mouse model of compulsive behavior. Neuropsychopharmacology 44, 1494-1504 (2019). https://doi.org/10.1038/s41386-018-0307-2

10 Manning, E. E. et al. <em>Sapap3</em> knockout mice show threat bias under conflict during platform mediated avoidance task: implications for obsessive compulsive disorder. bioRxiv, 2024.2002.2012.579940 (2024). https://doi.org/10.1101/2024.02.12.579940

11 Choi, K. et al. Distributed processing for value-based choice by prelimbic circuits targeting anterior-posterior dorsal striatal subregions in male mice. Nat Commun 14, 1920 (2023). https://doi.org/10.1038/s41467-023-36795-4

12 Alabi, O. O., Fortunato, M. P. & Fuccillo, M. V. Behavioral Paradigms to Probe Individual Mouse Differences in Value-Based Decision Making. Front Neurosci 13, 50 (2019). https://doi.org/10.3389/fnins.2019.00050

13 Rothwell, P. E. et al. Input- and Output-Specific Regulation of Serial Order Performance by Corticostriatal Circuits. Neuron 88, 345-356 (2015). https://doi.org/10.1016/j.neuron.2015.09.035

* https://www.ffor.org/three-vectors-detailed

** https://behavior.hms.harvard.edu/

Funding

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Accelerating What We Know About OCD: From Genes to Mice to Better Treatments

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