Learning From Animal Models of Obsessive-Compulsive Disorder

Abstract

Obsessive-compulsive disorder (OCD) affects 2%-3% of the population worldwide and can cause significant distress and disability. Substantial challenges remain in the field of OCD research and therapeutics. Approved interventions alleviate symptoms only partially, with 30%-40% of patients being resistant to treatment. Although the etiology of OCD is still unknown, research evidence points toward the involvement of cortico-striato-thalamocortical circuitry. This review focuses on the most recent behavioral, genetics, and neurophysiologic findings from animal models of OCD. Based on evidence from these models and parallels with human studies, we discuss the circuit hyperactivity hypothesis for OCD, a potential circuitry dysfunction of action termination, and the involvement of candidate genes. Adding a more biologically valid framework to OCD will help researchers define and test new hypotheses and facilitate the development of targeted therapies based on disease-specific mechanisms.

Keywords: Animal models; Basal ganglia; CSTC; OCD; Obsessive-compulsive disorder; Striatum; Synapse.

Figure 1. Simplified neuroanatomical model of cortico-striatal circuitry within the human and mouse brain

Motor: Human motor cortex is represented here by premotor and sensorimotor cortical regions that mainly project to posterolateral putamen [11]. Mouse motor cortex is represented here by somatosensory and motor cortex that mainly project to dorso-lateral striatum region [16]. Associative: Human associative cortex, represented here by the dorsolateral PFC and lateral OFC, projects to the caudate and anteromedial portion of the putamen [11]. Mouse associative cortex is represented here by dorsal prelimbic and parietal association cortices that mainly project to dorso-medial striatum region [15]. Limbic: Human limbic cortex, represented here by the paralimbic and limbic cortices (including entorhinal cortexarea28, perirhinal cortex-area35, medial OFC-area11, anterior cingulate cortex-area24) [11], [101], projects to the ventral striatum (ventral region of the caudate nucleus and putamen, including nucleus accumbens - NAcc). Mouse limbic cortex is represented here by OFC and PFC (ventral prelimbic, infralimbic and cingulate cortices), that mainly project to ventromedial striatum region (including NAcc) [15], [16]. Human associative and limbic circuits are implicated in stimuli significance and might generate obsessive thoughts that cause anxiety. Interconnections with motor cortex and basal ganglia circuits then lead to compulsive action execution. Based on the perceived outcome, actions can be reinforced and propagated through this repetitive loop. All regions depicted are representative and are not intended to provide accurate anatomical locations.

Figure 2. Representation of intrastriatal microcircuitry

Cortico- and thalamo-striatal excitatory axons target the dendritic spines of MSNs as well as dendritic shafts and soma of striatal interneurons. FS interneurons receive more cortical contacts and are more responsive to cortical inputs than MSNs [102], [103]; FS interneurons synapse proximally onto both MSN types [104] with a bias towards direct-pathway D1+MSNs [45]; FS interneurons also synapse with other FS cells but not LTS or TANs [45]. LTS interneurons send sparse inhibitory projections onto MSN dendrites [45], [105], [106]. TANs send inputs to dendritic spines, shafts and somata of MSNs [107] and provide powerful excitatory cholinergic input to FS interneurons [108], [109]. D1+MSNs have more elaborate dendritic arbors [110] and their axons project to SNr [37] (not represented); this direct-pathway promotes the execution of intended motor programs [42]. D2+MSNs project to GP [37] (not represented); this indirect-pathway may inhibit the execution of competing motor programs[42]. GPCRs (G protein–coupled receptors) are depicted with their associated G-protein: Gs (pink), Gi (brown), Gq (blue). M- muscarinic ACh receptors; nAChR- ionotropic nicotinic ACh receptor; D- dopamine receptors; A2A- A2A adenosine receptor; ChAT- choline acetyltransferase; Enk- enkephalin; SP- substance P; Dyn- dynorphin; PVparvalbumin; SOM- somatostatin; NPY- neuropeptide Y; NOS- nitric oxide synthase.