Combined exposure to maternal high-fat diet and neonatal lipopolysaccharide disrupts stress-related signaling but normalizes spatial memory in juvenile rats.

Both neonatal infections and exposure to maternal obesity are inflammatory stressors in early life linked to increased rates of psychopathologies related to mood and cognition. Epidemiological studies indicate that neonates born to mothers with obesity have a higher likelihood of developing neonatal infections, however effects on offspring physiology and behavior resulting from the combination of these stressors have yet to be investigated. The aim of this study was to explore immediate and persistent phenotypes resulting from neonatal lipopolysaccharide (nLPS) administration in rat offspring born to dams consuming a high-fat diet (HFD). Neural transcript abundance of genes involved with stress regulation and spatial memory were examined alongside related behaviors. At the juvenile age point, unlike offspring exposed to maternal HFD (mHFD) or nLPS alone, offspring with combined exposure to mHFD + nLPS displayed altered transcript abundances of stress-related genes in the ventral hippocampus (HPC) in a manner conducive to potentiating stress responses. For memory-related phenotypes, juveniles exposed to mHFD + nLPS exhibited normalized spatial memory and levels of memory-related gene expression in the dorsal HPC similar to control diet offspring, while control diet + nLPS, and mHFD offspring exhibited reduced levels of memory-related gene expression and impaired spatial memory. These findings suggest that dual exposure to unique inflammatory stressors in early life can disrupt neural stress regulation but normalize spatial memory processes.

Maternal high-fat diet induces sex-specific changes to glucocorticoid and inflammatory signaling in response to corticosterone and lipopolysaccharide challenge in adult rat offspring.

BACKGROUND: Maternal obesity as a result of high levels of saturated fat (HFD) consumption leads to significant negative health outcomes in both mother and exposed offspring. Offspring exposed to maternal HFD show sex-specific alterations in metabolic, behavioral, and endocrine function, as well as increased levels of basal neuroinflammation that persists into adulthood. There is evidence that psychosocial stress or exogenous administration of corticosterone (CORT) potentiate inflammatory gene expression; however, the response to acute CORT or immune challenge in adult offspring exposed to maternal HFD during perinatal life is unknown. We hypothesize that adult rat offspring exposed to maternal HFD would show enhanced pro-inflammatory gene expression in response to acute administration of CORT and lipopolysaccharide (LPS) compared to control animals, as a result of elevated basal pro-inflammatory gene expression. To test this, we examined the effects of acute CORT and/or LPS exposure on pro and anti-inflammatory neural gene expression in adult offspring (male and female) with perinatal exposure to a HFD or a control house-chow diet (CHD). METHODS: Rat dams consumed HFD or CHD for four weeks prior to mating, during gestation, and throughout lactation. All male and female offspring were weaned on to CHD. In adulthood, offspring were 'challenged' with administration of exogenous CORT and/or LPS, and quantitative PCR was used to measure transcript abundance of glucocorticoid receptors and downstream inflammatory markers in the amygdala, hippocampus, and prefrontal cortex. RESULTS: In response to CORT alone, male HFD offspring showed increased levels of anti-inflammatory transcripts, whereas in response to LPS alone, female HFD offspring showed increased levels of pro-inflammatory transcripts. In addition, male HFD offspring showed greater pro-inflammatory gene expression and female HFD offspring exhibited increased anti-inflammatory gene expression in response to simultaneous CORT and LPS administration. CONCLUSIONS: These findings suggest that exposure to maternal HFD leads to sex-specific changes that may alter inflammatory responses in the brain, possibly as an adaptive response to basal neuroinflammation.

Immune disease dialogue of chemokine-based cell communications as revealed by single-cell RNA sequencing meta-analysis.

Immune-mediated diseases are characterized by aberrant immune responses, posing significant challenges to global health. In both inflammatory and autoimmune diseases, dysregulated immune reactions mediated by tissue-residing immune and non-immune cells precipitate chronic inflammation and tissue damage that is amplified by peripheral immune cell extravasation into the tissue. Chemokine receptors are pivotal in orchestrating immune cell migration, yet deciphering the signaling code across cell types, diseases and tissues remains an open challenge. To delineate disease-specific cell-cell communications involved in immune cell migration, we conducted a meta-analysis of publicly available single-cell RNA sequencing (scRNA-seq) data across diverse immune diseases and tissues. Our comprehensive analysis spanned multiple immune disorders affecting major organs: atopic dermatitis and psoriasis (skin), chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (lung), ulcerative colitis (colon), IgA nephropathy and lupus nephritis (kidney). By interrogating ligand-receptor (L-R) interactions, alterations in cell proportions, and differential gene expression, we unveiled intricate disease-specific and common immune cell chemoattraction and extravasation patterns. Our findings delineate disease-specific L-R networks and shed light on shared immune responses across tissues and diseases. Insights gleaned from this analysis hold promise for the development of targeted therapeutics aimed at modulating immune cell migration to mitigate inflammation and tissue damage. This nuanced understanding of immune cell dynamics at the single-cell resolution opens avenues for precision medicine in immune disease management.

Cell-type-specific epigenetic effects of early life stress on the brain.

Early life stress (ELS) induces long-term phenotypic adaptations that contribute to increased vulnerability to a host of neuropsychiatric disorders. Epigenetic mechanisms, including DNA methylation, histone modifications and non-coding RNA, are a proposed link between environmental stressors, alterations in gene expression, and phenotypes. Epigenetic modifications play a primary role in shaping functional differences between cell types and can be modified by environmental perturbations, especially in early development. Together with contributions from genetic variation, epigenetic mechanisms orchestrate patterns of gene expression within specific cell types that contribute to phenotypic variation between individuals. To date, many studies have provided insights into epigenetic changes resulting from ELS. However, most of these studies have examined heterogenous brain tissue, despite evidence of cell-type-specific epigenetic modifications in phenotypes associated with ELS. In this review, we focus on rodent and human studies that have examined epigenetic modifications induced by ELS in select cell types isolated from the brain or associated with genes that have cell-type-restricted expression in neurons, microglia, astrocytes, and oligodendrocytes. Although significant challenges remain, future studies using these approaches can enable important mechanistic insight into the role of epigenetic variation in the effects of ELS on brain function.

Hippocampus-Anterior Hypothalamic Circuit Modulates Stress-Induced Endocrine and Behavioral Response.

Hippocampal input to the hypothalamus is known to be critically involved in mediating the negative feedback inhibition of stress response. However, the underlying neural circuitry has not been fully elucidated. Using a combination of rabies tracing, pathway-specific optogenetic inhibition, and cell-type specific synaptic silencing, the present study examined the role of hippocampal input to the hypothalamus in modulating neuroendocrine and behavioral responses to stress in mice. Transsynaptic rabies tracing revealed that the ventral hippocampus (vHPC) is monosynaptically connected to inhibitory cells in the anterior hypothalamic nucleus (AHN-GABA cells). Optogenetic inhibition of the vHPC→AHN pathway during a restraint stress resulted in a prolonged and exaggerated release of corticosterone, accompanied by an increase in stress-induced anxiety behaviors. Consistently, tetanus toxin-mediated synaptic inhibition in AHN-GABA cells produced a remarkably similar effect on the corticosterone release profile, corroborating the role of HPC→AHN pathway in mediating the hippocampal control of stress responses. Lastly, we found that chronic inhibition of AHN-GABA cells leads to cognitive impairments in both object and social recognition memory. Together, our data present a novel hypothalamic circuit for the modulation of adaptive stress responses, the dysfunction of which has been implicated in various affective disorders.