Aug 2026· Neurobiology of Stress· Vol 44· 0 citations· 41 references
Medicine
TL;DR
These findings suggest that MRs in GABAergic neurons normally function as critical constraints on excitatory synaptic plasticity during high-stress states, underscoring that adaptive stress responses rely on a finely tuned, cell-type-specific balance of corticosteroid signaling within limbic microcircuits.
Abstract
The mineralocorticoid receptor (MR) plays a pivotal role in modulating the neuroendocrine stress response and cognitive function. While recent evidence highlights the importance of MRs in glutamatergic neurons in regulating anxiety-like behavior, the specific contribution of MRs within inhibitory networks remains incompletely understood. To address this gap, we generated a mouse model with targeted ablation of MR in forebrain GABAergic neurons (MRDlx). Comprehensive behavioral profiling revealed a profound, state-dependent cognitive phenotype in male MRDlx mice. Under non-stressful baseline conditions, these mice exhibited impaired object recognition memory, while under aversive learning paradigms, such as the Morris water maze and fear conditioning, they displayed enhanced spatial and contextual memory. Furthermore, male MRDlx mice demonstrated significant behavioral lack of adaptation to 21 days of chronic social defeat stress (CSDS). Notably, these changes were highly sex-influenced, as female MRDlx mice did not exhibit the same baseline cognitive deficits or subsequent stress resistance. Mechanistically, in vitro hippocampal electrophysiological recordings from male mice showed that acute corticosterone (CORT) application, which typically suppresses long-term potentiation (LTP), failed to impair LTP in MRDlx slices, indicating a marked resistance to CORT-induced suppression. Together, our findings suggest that MRs in GABAergic neurons normally function as critical constraints on excitatory synaptic plasticity during high-stress states. Ablating this regulatory mechanism confers robust behavioral and synaptic stress resistance, underscoring that adaptive stress responses rely on a finely tuned, cell-type-specific balance of corticosteroid signaling within limbic microcircuits.
Diabetes is associated with cognitive impairment and alterations in synaptic molecules; however, the factors within the diabetic milieu that drive these central changes remain unclear. Methylglyoxal (MG), a reactive dicarbonyl and major precursor of advanced glycation end products, accumulates under hyperglycemic and metabolically compromised conditions and is a candidate mediator of diabetic phenotypes. Here, we examined whether chronic MG exposure affects metabolism, behavior, and the expression of synaptic genes in the hippocampus and prefrontal cortex. Mice received MG in drinking water for 1 or 3 months, and then metabolic, behavioral, and biochemical analyses were performed. MG mildly impaired glucose clearance and induced insulin resistance, together with reduced adiposity in the 3‐month intervention, indicating a disturbance of glucose and lipid metabolism. MG did not consistently affect anxiety‐like behavior. In the Barnes maze test, MG mildly impaired spatial memory performance. In the hippocampus, MG selectively decreased the expression levels of the excitatory synaptic genes, whereas no gene was altered in the prefrontal cortex. These findings identify learning‐associated excitatory synaptic genes as targets of chronic MG exposure and position MG as a candidate factor linking the diabetic metabolic state to hippocampal synaptic and cognitive alterations.
While brain systems mediating acute stress are essential for survival, chronic early-life stress (ELA) may lead to poor ability to experience pleasure (anhedonia), a core feature of depression. For decades, the stress neuropeptide corticotropin-releasing hormone (CRH) has been a target for treating depression, however the failure of several clinical trials blocking CRH receptor 1 (CRHR1) has left the therapeutic role of CRH signaling a major unresolved mystery. Here, we uncover the signaling plasticity behind this enigma with the use of in vivo G protein-coupled activation-based (GRAB) imaging and viral-genetic and pharmacological mechanistic manipulations. We find CRH signaling via CRHR1 indeed disrupts reward behaviors in naïve mice, but is dysregulated in ‘anhedonic’ mice with a history of ELA. Instead, activation of CRH receptor 2 (CRHR2) reverses anhedonia-like behaviors in adult ELA mice. These findings redefine our understanding of stress-mediated anhedonia and provide a precise, novel therapeutic target for stress-related mental illness.
Matthew T. Birnie, Lara Taniguchi, Lia M. Harvey et al.· bioRxiv· 0 citations
Results suggest that Adgrd1 plays a key role in maintaining hippocampal resilience and regulating motivational behaviors through integrated molecular and circuit-level mechanisms.
Inés Martínez-Soria, Pol Picón-Pagès, A. P. Pérez González et al.· bioRxiv· 0 citations
In conclusion, CORT coordinates via MR the networks underlying how an individual copes with stress, and this action is complemented by the widely distributed lower glucocorticoid receptor (GR) involved in the subsequent management of stress adaptation.
E. R. de Kloet, C. Otte, R. Kumsta et al.· 0 citations
Findings reveal a profound impairment with female GPR158 knockout mice in hippocampal‐dependent cognition and highlight the importance of low‐stress, ethologically testing environments.
Alyson Blount, Shradha V Darira, Emmanuelle B Palmieri et al.· Genes, Brain and Behavior· 0 citations
Introduction Inflammatory processes contribute significantly to the pathophysiology of depression. Although the melanocortin system is well known to regulate inflammation, the specific contribution of melanocortin 1 receptor (MC1R) and its endogenous ligand, α-melanocyte-stimulating hormone (α-MSH), to inflammation-associated depression remains unclear. Methods Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice. Depressive-like behaviors, synaptic functions, and metabolic alterations were evaluated using behavioral tests, patch-clamp recordings, and untargeted metabolomic profiling. To examine the functional involvement of MC1R, adeno-associated virus (AAV)-mediated selective Mc1r overexpression was performed in the medial prefrontal cortex (mPFC). Results LPS administration induced depressive-like behaviors in mice, accompanied by microglial activation and a significant reduction in MC1R expression in the prefrontal cortex (PFC). Treatment with MC1R endogenous ligand α-MSH mimetic Nle4-DPhe7-α-MSH (NDP-MSH) markedly attenuated LPS-induced depressive-like behaviors, enhanced MC1R, postsynaptic density protein 95 (PSD95), glutamate receptor 1 (GluA1) and protein kinase A (PKA) phosphorylation. PKA inhibitor H89-mediated inhibition of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway partially but robustly abolishes the behavioral, anti-inflammatory, and synaptic protective effects of NDP-MSH. Additionally, untargeted metabolomics confirmed that NDP-MSH effectively corrected LPS-induced metabolic dysregulation, a therapeutic effect that was robustly suppressed by H89; this metabolic remodeling was closely associated with purine metabolism, pantothenate, and coenzyme A biosynthesis. Critically, AAV-mediated Mc1r overexpression in the mPFC was sufficient to rescue LPS-induced depressive-like phenotypes. Conclusion This study highlights MC1R-related signaling in the PFC as an important contributor to inflammation-associated depression and suggests that NDP-MSH alleviates inflammation-associated depressive-like behaviors in association with melanocortin signaling involving MC1R and downstream cAMP/PKA activation.
Shanglan Qu, Xin Peng, Jieyu Ji et al.· Frontiers in Pharmacology· 0 citations
