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Lack of maternal care and attention during infancy and childhood increases the likelihood of developing a range of neuropsychiatric disorders, such as social deficits, working memory impairment, and anxiety-like behaviors, in adulthood. However, the neuroregulatory signaling through which early-life stress causes behavioral and cognitive abnormalities in the offspring is largely unexplored. Here, we show that in mice, unpredictable maternal separation (MS) during the early postnatal period impairs neuronal development in the medial prefrontal cortex (mPFC) and results in long-lasting behavioral changes. Additionally, MS disrupts excitatory neurotransmission and inhibits the neuronal activity of pyramidal neurons in the mPFC. Differentially expressed gene (DEG) analysis of RNA sequencing (RNA-seq) data of mPFC showed that dopamine D1 receptor (D1R) was significantly downregulated in MS animals. Finally, we show that pharmacological activation of D1R signaling specifically in the mPFC improves neuronal excitability and rescues behavioral and cognitive dysfunction of MS mice, whereas pharmacologically inhibiting of D1R in the mPFC mimics MS-induced behavioral abnormalities in control mice. Together, our results identify D1R signaling in the mPFC, at least in part, as a potential therapeutic target for the behavioral and cognitive abnormalities caused by deprivation of maternal care in early life., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Social experiences during early life are thought to be critical for proper social and emotional development. Conversely, social insults during development causes long-lasting behavioral abnormalities later in life. However, how juvenile social deprivation influences social and emotional behaviors remains poorly understood. Here, we show that juvenile social isolation induces a shift in microbial ecology that negatively impacts social and emotional behaviors in adulthood. These behavioral changes, which occur during this critical period are transferable to antibiotic pre-treated mice by fecal microbiota transplant. In addition, juvenile social isolation decreases the expression of oxytocin receptor (OXTR) in the medial prefrontal cortex (mPFC), and increases the amounts of fecal propionic acid (PA), a short-chain fatty acid derived from gut micobiota. Accordingly, infusion with an OXTR antagonist (OXTR-A, l-368,899) specifically in the mPFC or supplementation of PA both can cause social deficits and anxiety-like behaviors in group housed mice. Collectively, our findings reveal that juvenile social experience regulates prefrontal cortical OXTR expression through gut microbiota-produced PA and that is essential for normal social and emotional behaviors, thus providing a cellular and molecular context to understand the consequences of juvenile social deprivation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The prefrontal cortex (PFC) plays an important role in regulating anxiety-like phenotypes and social behaviors, and impairments in this brain region has been linked to social deficits in mammals. Childhood obesity is associated with an increased risk of neuropsychiatric behavioral abnormalities, including attenuated social preference and increased anxiety-like behaviors in adulthood. However, little data are available on the impact of obesity during adolescence on PFC-dependent behaviors. Herein, we use the mice pups to illuminate whether and how high-fat diet (HFD) feeding in adolescence affects medial prefrontal cortex (mPFC)-dependent behaviors, and what the underlying cellular and molecular mechanism is. We found that juvenile HFD feeding results in the accumulation of senescent astrocytes and microglia in the mPFC of mice. Furthermore, we found a causal link between the accumulation of senescent glial cells and HFD-induced neuropsychiatric behavioral abnormalities. Pharmacological clearance of senescent glial cells in HFD-fed mice enhances neuronal activity and reserves synaptic excitatory/inhibitory balance, thus preserving normal behaviors. Collectively, these results show that senescent glial cells play a significant role in the initiation and progression of juvenile obesity-mediated neuropsychiatric behavioral abnormalities, and suggest that targeting senescent glial cells may provide a therapeutic avenue for the treatment of obesity-related neuropsychiatric disorders in children., (Copyright © 2020 Elsevier B.V. All rights reserved.)

[Display omitted] Ample evidence indicates that maternal immune activation (MIA) during gestation is linked to an increased risk for neurodevelopmental and psychiatric disorders, such as autism spectrum disorder (ASD), anxiety and depression, in offspring. However, the underlying mechanism for such a link remains largely elusive. Here, we performed RNA sequencing (RNA-seq) to examine the transcriptional profiles changes in mice in response to MIA and identified that the expression of Scn1a gene, encoding the pore-forming α-subunit of the brain voltage-gated sodium channel type-1 (Na V 1.1) primarily in fast-spiking inhibitory interneurons, was significantly decreased in the medial prefrontal cortex (mPFC) of juvenile offspring after MIA. Moreover, diminished excitatory drive onto interneurons causes reduction of spontaneous gamma-aminobutyric acid (GABA)ergic neurotransmission in the mPFC of MIA offspring, leading to hyperactivity in this brain region. Remarkably, treatment with low-dose benzodiazepines clonazepam, an agonist of GABA A receptors, completely prevented the behavioral abnormalities, including stereotypies, social deficits, anxiety- and depression-like behavior, via increasing inhibitory neurotransmission as well as decreasing neural activity in the mPFC of MIA offspring. Our results demonstrate that decreased expression of Na V 1.1 in the mPFC leads to abnormalities in maternal inflammation-related behaviors and provides a potential therapeutic strategy for the abnormal behavioral phenotypes observed in the offspring exposed to MIA. [ABSTRACT FROM AUTHOR]

Maternal immune activation (MIA) resulting from viral infections during pregnancy is linked to increased rates of neurodevelopmental disorders in offspring. However, the mechanisms underlying MIA-induced neurobehavioral abnormalities remain unclear. Here, we used a poly (I:C)-induced MIA mouse model to demonstrate the presence of multiple behavioral deficits in male offspring. Through RNA sequencing (RNA-seq), we identified significant upregulation of genes involved in axonogenesis, synaptogenesis, and glutamatergic synaptic neurotransmission in the mPFC of MIA mice. Electrophysiological analyses further revealed an excitatory-inhibitory (E/I) synaptic imbalance in mPFC pyramidal neurons, leading to hyperactivity in this brain region. Cannabidiol (CBD) effectively alleviated the behavioral abnormalities observed in MIA offspring by reducing glutamatergic transmission and enhancing GABAergic neurotransmission of mPFC pyramidal neurons. Activation of GPR55 by lipid lysophosphatidylinositol (LPI), an endogenous GPR55 agonist, specifically in the mPFC of healthy animals led to MIA-associated behavioral phenotypes, which CBD could effectively reverse. Moreover, we found that a GPR55 antagonist can mimic CBD's beneficial effects, indicating that CBD's therapeutic effects are mediated via the LPI-GPR55 signaling pathway. Therefore, we identified mPFC as a primary node of a neural network that mediates MIA-induced behavioral abnormalities in offspring. Our work provides insights into the mechanisms underlying the developmental consequences of MIA and identifies CBD as a promising therapeutic approach to alleviate these effects. [Display omitted] • MIA promotes ASD-like behavior in male offspring. • Impaired E/I balance in the mPFC pyramidal neurons of MIA offspring. • CBD treatment improves social deficits and stereotypies in MIA offspring. • CBD alleviates neurobehavioral abnormalities in MIA mice via inhibiting LPI-GPR55 signaling pathway. [ABSTRACT FROM AUTHOR]