Biology subjects

Kano, S.-i.

Publications and source records attributed to Kano, S.-i..

5 recordsLinked to original sources

bioRxiv2026

Adolescent social isolation creates a latent vulnerability in maternal care with intergenerational social consequences, rescued by experienced mothers

Early-life adversity (ELA) can produce lasting alterations on brain and behavior, yet its effects on maternal caregiving and intergenerational social outcomes remain poorly understood. Using a mouse model of mild adolescent social isolation, we demonstrated that females exposed to isolation in late adolescence exhibited progressive deficits in pup-directed maternal behaviors, including nursing, licking, nest-building, and pup retrieval, while self-directed behaviors remain intact. Offspring reared by these dams displayed deficits in adult social behavior, including reduced sociability, impaired social novelty recognition, and diminished social odor discrimination, without affecting non-social memory, anxiety-like behavior, or locomotor activity. Chemogenetic activation of the medial cingulate cortex (mCg) to prelimbic cortex (PrL) pathway in offspring of stressed dams rescued social deficits, whereas inhibition of this pathway in control mice recapitulated the impairments. Notably, co-housing stressed dams with experienced parous females during the early postpartum period restored pup-directed maternal behaviors and normalized offspring social outcomes, demonstrating that social experience can buffer the intergenerational consequences of ELA. Circuit analyses identified the mCg[->]PrL projections as a predominantly excitatory pathway critical for social behavior. Electrophysiological recordings revealed hypofunction of this circuit in offspring of stressed dams, which was ameliorated by postpartum co-housing with parous females. Together, these findings define a neural circuit linking adolescent psychosocial adversity to impaired maternal caregiving and intergenerational social dysfunction, and highlight social support from experienced mothers as a potent modulator of maternal and offspring behavioral outcomes. Significance StatementAdverse social experiences before motherhood can compromise maternal caregiving and transmit social vulnerability across generations, yet the underlying mechanisms remain poorly understood. Using a mouse model of subtle adolescent social isolation, we demonstrate that even mild isolation selectively impairs postpartum caregiving behaviors while sparing other behavioral domains, resulting in social deficits in adult offspring. We identify the midcingulate-prelimbic cortex circuit as a critical neural substrate mediating these effects and show that social support from experienced mothers during the early postpartum period restores both maternal behavior and offspring social outcomes. Together, these findings define a neural and social mechanism for the intergenerational effects of adolescent psychosocial adversity.

animal behavior and cognition↗

bioRxiv2023

Adolescent stress impairs postpartum social behavior via anterior insula-prelimbic pathway

Adolescent stress can be a risk factor for abnormal social behavior in the postpartum period, which critically affects the safety of mothers and children. Nonetheless, the underlying mechanisms remain unclear. Using a newly established mouse model with optogenetics and in vivo calcium imaging, we found that adolescent psychosocial stress, combined with pregnancy and delivery, caused hypofunction of the glutamatergic pathway from the anterior insula to prelimbic cortex (AI-PrL pathway), which altered PrL neuronal activity, and in turn led to abnormal social behavior. Specifically, the AI-PrL pathway played a crucial role during recognizing the novelty of other mice by modulating "stable neurons" in PrL, which were constantly activated or inhibited by novel mice. We also observed that glucocorticoid receptor signaling in the AI-PrL pathway had a causal role in stress-induced postpartum changes. Our findings provide novel and functional insights into a cortico-cortical pathway underlying adolescent stress-induced postpartum social behavioral deficits.

neuroscience↗

bioRxiv2021

Prenatal immune stress induces a prolonged blunting of microglia activation that impacts striatal connectivity

Recent studies suggested that microglia, the primary brain immune cells, can affect circuit connectivity and neuronal function1-3. Microglia infiltrate the neuroepithelium early in embryonic development and are maintained in the brain throughout adulthood4,5. Several maternal environmental factors, such as aberrant microbiome, immune activation, and poor nutrition, can influence prenatal brain development6-8. Nevertheless, it is unknown how changes in the prenatal environment instruct the developmental trajectory of infiltrating microglia, which in turn affect brain development and function. Here we show that after maternal immune activation (MIA) microglia from the offspring have a long-lived decrease in immune reactivity (blunting) across the developmental trajectory. The blunted immune response was concomitant with changes in the chromatin accessibility and reduced transcription factor occupancy of the open chromatin. Single cell RNA sequencing revealed that MIA does not induce a distinct subpopulation but rather decreases the contribution to inflammatory microglia states. Prenatal replacement of MIA microglia with physiological infiltration of naive microglia ameliorated the immune blunting and restored a decrease in presynaptic vesicle release probability onto dopamine receptor type-two medium spiny neurons, indicating that aberrantly formed microglia due to an adverse prenatal environment impacts the long-term microglia reactivity and proper striatal circuit development.

neuroscience↗

bioRxiv2021

Early life stress-induced vulnerability to postpartum mental disturbance: prolonged dysregulation of the HPA axis and behavior

Stress during childhood and adolescence increases the risk for postpartum depression (PPD). Patients with depression who have experienced adverse life events tend to be treatment refractory. However, the mechanism by which stress during childhood and adolescence are involved in the pathophysiology of PPD remains unclear. We investigated the longitudinal effects of adolescent stress on the hypothalamic-pituitary-adrenal (HPA) axis and behaviors in the postpartum period through mouse and human studies. We observed that adolescent social isolation caused an aberrantly sustained elevation of glucocorticoids via dysregulation of the HPA axis, leading to long-lasting postpartum behavioral changes in female mice. The postpartum behavioral changes elicited by this adolescent stress were not ameliorated by the medicines currently used for PPD treatment. However, a post-delivery treatment with a glucocorticoid receptor antagonist effectively ameliorated the behavioral changes in mice. We also demonstrated a significant impact of stress during childhood and adolescence on the HPA axis dysregulation and PPD in women. We provide experimental evidence that suggests a mechanism-driven therapeutic strategy (repurposing a GR antagonist) for at least some cases of treatment refractory PPD.

molecular biology↗

bioRxiv2017

Glutathione S-transferases: unexpected roles in astrocyte activation and astrocyte-microglia communication during brain inflammation

Astrocytes and microglia play critical roles in brain inflammation, but their mutual regulation is not fully understood. Here we report unexpected roles for glutathione S-transferases (GSTs), particularly GSTM1, in astrocyte activation and astrocyte-mediated enhancement of microglia activation during brain inflammation. We found that astrocyte-specific silencing of GSTM1 expression in the prefrontal cortex (PFC) attenuated microglia activation in brain inflammation induced by systemic injection of lipopolysaccharides (LPS). Gstm1 silencing in astrocytes also attenuated LPS-induced TNF- production by microglia in co-culture. In astrocytes, GSTM1 was required for the activation of nuclear factor-{kappa}B (NF-{kappa}B) and c-Jun N-terminal kinases (JNK) and the production of pro-inflammatory mediators previously implicated in microglia activation, such as granulocyte-macrophage colony-stimulating factor (GM-CSF/CSF2) and chemokine (C-C motif) ligand 2 (CCL2). Similar results were also obtained with GSTT2 both in vitro and in vivo. Thus, our study identified a critical role for GSTs in priming astrocytes and enhancing microglia activation during brain inflammation.\n\nSignificant StatementAstrocytes and microglia play critical roles in brain inflammation, but it is not fully understood how astrocytes regulate microglia activation. Here we report a novel mechanism by which glutathione S-transferases (GSTs), the enzymes for phase II detoxification of xenobiotic metabolism, in astrocytes control microglia activation during brain inflammation. We found that GSTs, particularly GSTM1, regulate the induction of pro-inflammatory mediators via the activation of NF-{kappa}B and JNK in astrocytes. Our studies provide evidence that GST enzymes are active players in brain inflammation and can be targeted to regulate microglia activation.

immunology↗