ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2013
Dysfunctional astrocytic and synaptic regulation of hypothalamic glutamatergic transmission in a mouse model of early-life adversity: relevance to neurosteroids and programming of the stress response.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 94 papers, 2 of them syntheses that pooled it.
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Who cites it
94 citing papers in PubMed, 2 syntheses or guidelines pooled it, 159 citations in OpenAlex.
- Higher Circulating Cortisol in the Follicular vs. Luteal Phase of the Menstrual Cycle: A Meta-Analysis.Frontiers in endocrinology · 2020Pooled it
- Effects of the Social Environment and Stress on Glucocorticoid Receptor Gene Methylation: A Systematic Review.Biological psychiatry · 2016Pooled it
- Prenatal Origins of Stress Regulation: Maternal Psychological Distress and Inflammation During Pregnancy Prospectively Predict Infant Behavioral Reactivity and Regulation.Developmental psychobiology · 2026Article
- Corticotropin releasing hormone-expressing inputs to the thalamic paraventricular nucleus: pathways from mother to memory?Neurobiology of stress · 2026Article
- Reconfiguration of brain-wide neural activity after early life adversity.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Reconfiguration of brain-wide neural activity after early life adversity.bioRxiv : the preprint server for biology · 2025Article
- Early life stress modulates behavioral sensitivity to alcohol and promotes escalation of alcohol drinking.bioRxiv : the preprint server for biology · 2025Article
- The link between early-life adversity and later alcohol use disorder: A role for microglia?Neurobiology of stress · 2025Article
- Early-life stress induces persistent astrocyte dysfunction associated with fear generalisation.eLife · 2025Article
- Sex-specific and developmental effects of early life adversity on stress reactivity are rescued by postnatal knockdown of 5-HTNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- Unraveling sex differences in maternal and paternal care impacts on social behaviors and neurobiological responses to early-life adversity.Frontiers in neuroendocrinology · 2025Review
- Neurosteroids: a lifelong impact on brain health.Frontiers in behavioral neuroscience · 2025Review
- Enduring memory consequences of early-life stress / adversity: Structural, synaptic, molecular and epigenetic mechanisms.Neurobiology of stress · 2024Review
- Molecular and functional mapping of the neuroendocrine hypothalamus: a new era begins.Journal of endocrinological investigation · 2024Review
- Enduring Neurobiological Consequences of Early-Life Stress: Insights from Rodent Behavioral Paradigms.Biomedicines · 2024Review
- The impact of pubertal stress and adult hormone exposure on the transcriptome of the developing hypothalamus.bioRxiv : the preprint server for biology · 2024Article
- Sex differences in offspring risk and resilience following 11β-hydroxylase antagonism in a rodent model of maternal immune activation.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Article
- Early resource scarcity causes cortical astrocyte enlargement and sex-specific changes in the orbitofrontal cortex transcriptome in adult rats.Neurobiology of stress · 2024Article
- Across ages and places: Unpredictability of maternal sensory signals and child internalizing behaviors.Journal of affective disorders · 2024Article
- The impact of pubertal stress and adult hormone exposure on the transcriptome of the developing hypothalamus.Stress (Amsterdam, Netherlands) · 2024Article
34 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Adverse early-life experiences, such as poor maternal care, program an abnormal stress response that may involve an altered balance between excitatory and inhibitory signals. Here, we explored how early-life stress (ELS) affects excitatory and inhibitory transmission in corticotrophin-releasing factor (CRF)-expressing dorsal-medial (mpd) neurons of the neonatal mouse hypothalamus. We report that ELS associates with enhanced excitatory glutamatergic transmission that is manifested as an increased frequency of synaptic events and increased extrasynaptic conductance, with the latter associated with dysfunctional astrocytic regulation of glutamate levels. The neurosteroid 5α-pregnan-3α-ol-20-one (5α3α-THPROG) is an endogenous, positive modulator of GABAA receptors (GABAARs) that is abundant during brain development and rises rapidly during acute stress, thereby enhancing inhibition to curtail stress-induced activation of the hypothalamic-pituitary-adrenocortical axis. In control mpd neurons, 5α3α-THPROG potently suppressed neuronal discharge, but this action was greatly compromised by prior ELS exposure. This neurosteroid insensitivity did not primarily result from perturbations of GABAergic inhibition, but rather arose functionally from the increased excitatory drive onto mpd neurons. Previous reports indicated that mice (dams) lacking the GABAAR δ subunit (δ(0/0)) exhibit altered maternal behavior. Intriguingly, δ(0/0) offspring showed some hallmarks of abnormal maternal care that were further exacerbated by ELS. Moreover, in common with ELS, mpd neurons of δ(0/0) pups exhibited increased synaptic and extrasynaptic glutamatergic transmission and consequently a blunted neurosteroid suppression of neuronal firing. This study reveals that increased synaptic and tonic glutamatergic transmission may be a common maladaptation to ELS, leading to enhanced excitation of CRF-releasing neurons, and identifies neurosteroids as putative early regulators of the stress neurocircuitry.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.