Synaptic mechanisms for differential severity of social preference deficits in male and female mice induced by diminished activity-dependent BDNF

Social isolation disrupts prefrontal excitatory-inhibitory balance to impair social novelty memory in adult male mice.

Social isolation is a pervasive stressor that disrupts social cognition, yet its neural mechanisms in adulthood remain unclear. Here, we showed that four weeks of social isolation in adult male mice selectively impaired social novelty memory without affecting general sociability, object recognition, working memory, or anxiety- and depression-like behaviors. This deficit was sex-specific, as female mice remained unaffected. Mechanistically, c-Fos mapping and in vivo calcium imaging revealed that social isolation induced a maladaptive shift in prefrontal excitatory-inhibitory (E/I) balance, characterized by both exaggerated activation of medial prefrontal cortex (mPFC) glutamatergic neurons and attenuated recruitment of local GABAergic interneurons specifically during novel social exploration. Causal manipulations showed that chemogenetic or optogenetic activation of mPFC glutamatergic neurons in group-housed males was sufficient to recapitulate the social novelty memory impairment, whereas inhibition of these neurons in isolated mice rescued the deficit. At the cellular level, electrophysiological recordings demonstrated that SI enhanced the intrinsic excitability of mPFC pyramidal neurons and induced a synaptic E/I imbalance, characterized by increased excitatory and decreased inhibitory drive. Together, our findings establish that adult social isolation disrupts social novelty memory processing by shifting the mPFC excitatory-inhibitory balance toward a net hyperexcitable state, revealing a reversible, circuit-specific mechanism for isolation-induced social cognitive deficits.

Effects of early postnatal dopamine transporter (DAT) inhibition on social and cognitive behavior in a rat model of autism.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social behavior and cognition. Increasing evidence suggests that alterations in dopaminergic neurotransmission, including changes in dopamine transporter (DAT) function, may contribute to ASD-related behavioral abnormalities. This study investigated whether selective DAT inhibition during early postnatal development influences behavioral and molecular alterations in a rat model of ASD induced by prenatal exposure to sodium valproate (NaVP). Pregnant Wistar rats received NaVP (600mg/kg, i.p.) on gestational day 12.5. Male offspring were treated with the selective DAT inhibitor CE-123 (10mg/kg, i.p.) once daily from postnatal day (PND) 10 to 23. Behavioral assessments during adolescence (PND25-42) evaluated social interaction, recognition memory, spatial preference, anxiety-like behavior, locomotor activity, and aversive memory. DAT, dopamine D2 receptor, brain-derived neurotrophic factor (BDNF), and interleukin-1β (IL-1β) protein expression were assessed in selected brain regions. Prenatal NaVP exposure impaired social novelty discrimination, declarative, spatial, and aversive memory, reduced locomotor activity, and increased anxiety-like behavior. These behavioral alterations were accompanied by elevated DAT and dopamine D2 receptor expression. Early postnatal CE-123 treatment attenuated several ASD-like behavioral abnormalities, normalized DAT and dopamine D2 receptor expression, increased BDNF levels in the prefrontal cortex (PFC), and increased IL-1β expression, without inducing non-specific locomotor stimulation. Together, these findings demonstrate that early postnatal CE-123 treatment was associated with long-lasting behavioral improvements accompanied by alterations in dopaminergic markers and BDNF expression. Although these findings support a role for dopaminergic regulation and neuroplasticity in the observed behavioral effects, the underlying mechanisms require further investigation.

Altered social behavior and prefrontal dopaminergic signaling in female Dtnbp1 knockout mice.

It is demonstrated that dysbindin-1 deficiency drives distinct, female-specific vulnerabilities in behavioral and molecular alterations relevant to neuropsychiatric conditions, providing insight into the sex-dependent pathophysiology of social and cognitive deficits in preclinical models of schizophrenia.

Age-dependent reorganization of behavioral and striatal function in Cntnap2 knockout mice.

It is demonstrated that ASD-related alterations are not static but evolve across adulthood, revealing a multi-level reorganization of behavioral, synaptic, and structural features.

Social hierarchy shapes behavioral and transcriptional responses to chronic stress and ketamine in male mice

Summary Chronic stress is a major risk factor for psychiatric disorders, yet the mechanisms underlying individual differences in vulnerability and treatment response remain poorly understood. Using the Social Box, a seminatural environment, we performed high-resolution, continuous tracking of group-housed male mice during 11 days, capturing behavior during both active and inactive phases. We found that social hierarchy within a group strongly shapes stress outcomes, with dominant individuals exhibiting amplified behavioral alterations following chronic stress, including rest fragmentation and disrupted social interactions. A single ketamine administration mitigated these effects, restoring baseline behavioral signatures in dominant individuals. Bulk mRNA sequencing was performed in the medial prefrontal cortex and ventral hippocampus. This revealed a hierarchy-dependent transcriptional response with 141 differentially expressed genes in the medial prefrontal cortex of dominant, ketamine-treated mice. Overall, this study provides a framework for examining stress and pharmacological interventions in group-housed mice, enabling high-resolution, longitudinal analyses under semi-naturalistic conditions.

Sex-Dependent Modulation of Emotional and Cognitive Processes by Prefrontal CB1 Receptors