Background: Obsessive–compulsive disorder (OCD) is a mental disease with heterogeneous behavioral phenotypes, including repetitive behaviors, anxiety, and impairments in cognitive functions. The brain regions related to the behavioral heterogeneity, however, are unknown.Methods: We systematically examined the behavioral phenotypes of three OCD mouse models induced by pharmacological reagents [RU24969, 8-hydroxy-DPAT hydrobromide (8-OH-DPAT), and 1-(3-chlorophenyl) piperazine hydrochloride-99% (MCPP)], and compared the activated brain regions in each model, respectively.Results: We found that the mouse models presented distinct OCD-like behavioral traits. RU24969-treated mice exhibited repetitive circling, anxiety, and impairments in recognition memory. 8-OH-DPAT-treated mice exhibited excessive spray-induced grooming as well as impairments in recognition memory. MCPP-treated mice showed only excessive self-grooming. To determine the brain regions related to these distinct behavioral traits, we examined c-fos expression to indicate the neuronal activation in the brain. Our results showed that RU24969-treated mice exhibited increased c-fos expression in the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), prelimbic cortex (PrL), infralimbic cortex (IL), nucleus accumbens (NAc), hypothalamus, bed nucleus of the stria terminalis, lateral division, intermediate part (BSTLD), and interstitial nucleus of the posterior limb of the anterior commissure, lateral part (IPACL), whereas in 8-OH-DPAT-treated mice showed increased c-fos expression in the ACC, PrL, IL, OFC, NAc shell, and hypothalamus. By contrast, MCPP did not induce higher c-fos expression in the cortex than control groups.Conclusion: Our results indicate that different OCD mouse models exhibited distinct behavioral traits, which may be mediated by the activation of different brain regions.

Obsessive-compulsive disorder (OCD) is a severe mental illness characterized by obsessions and compulsions. However, its underlying mechanisms remain to be elucidated. Recent studies have suggested that neuroimmune dysregulation is involved in the pathogenesis of OCD. To investigate the role of microglia in this disorder, we established a pharmacological mouse model by using the serotonin (5-HT) 1A/1B receptor agonist RU24969 to mimic monoamine dysregulation in OCD, and we examined the morphological and functional alterations of microglia in this model. We found that RU24969 treatment led to compulsive circling behavior in mice. Strikingly, we found that the density and mobility of microglia in the prelimbic cortex were much lower in RU24969-treated mice than in control mice. Moreover, the expression of cytokines and chemokines, including BDNF, IL-1β, IL-6, TNFα, CD80, CD86, MHC-I, and MHC-II, also decreased in RU24969-treated mice. Importantly, we found that injection of BDNF or induction of BDNF expression by trehalose completely reversed microglial dysfunction and reduced stereotypic behavior. These results indicate that microglial dysfunction is closely related to stereotypic behaviors in our mouse model of OCD and that BDNF could be an effective treatment for stereotypic behaviors.

Background: Both acute and persistent pain is associated with anxiety in clinical observations, but whether the underlying neural mechanisms differ is poorly understood.Methods: We used formalin or complete Freund’s adjuvant (CFA) to induce acute or persistent pain. Behavioral performance was assessed by the paw withdrawal threshold (PWT), open field (OF), and elevated plus maze (EPM) tests. C-Fos staining was used to identify the activated brain regions. Chemogenetic inhibition was further performed to examine the necessity of brain regions in behaviors. RNA sequencing (RNA-seq) was used to identify the transcriptomic changes.Results: Both acute and persistent pain could lead to anxiety-like behavior in mice. The c-Fos expression indicates that the bed nucleus of the stria terminalis (BNST) is activated only in acute pain, whereas the medial prefrontal cortex (mPFC) is activated only in persistent pain. Chemogenetic manipulation reveals that the activation of the BNST excitatory neurons is required for acute pain-induced anxiety-like behaviors. In contrast, the activation of the prelimbic mPFC excitatory neurons is essential for persistent pain-induced anxiety-like behaviors. RNA-seq reveals that acute and persistent pain induces differential gene expression changes and protein–protein interaction networks in the BNST and prelimbic mPFC. The genes relevant to neuronal functions might underline the differential activation of the BNST and prelimbic mPFC in different pain models, and be involved in acute and persistent pain-related anxiety-like behaviors.Conclusion: Distinct brain regions and gene expression patterns are involved in acute and persistent pain-related anxiety-like behaviors.