Aug 2026· Neuropharmacology· Vol 300, pp.
111157
· 0 citations· 85 references
Medicine
TL;DR
It is demonstrated that morphine exposure selectively activates GSDMD-mediated pyroptotic signaling in the dorsal hippocampus (dHip), identifying neuronal pyroptosis as a previously unrecognized mechanism associated with morphine-associated reward memory and position GSDMD as a potential therapeutic target that warrants further investigation for mitigating opioid-induced maladaptive plasticity.
Abstract
Opioid addiction involves maladaptive neuroplasticity within hippocampal circuits, yet the underlying molecular mechanisms remain incompletely understood. Here, we systematically investigated whether pyroptosis, a pro-inflammatory form of programmed cell death, contributes to morphine-induced neuroadaptations and reward memory formation. Using a combination of behavioral, molecular, pharmacological, and cellular approaches in a mouse model of conditioned place preference (CPP), we demonstrate that morphine exposure selectively activates GSDMD-mediated pyroptotic signaling in the dorsal hippocampus (dHip). Morphine-treated mice exhibited significantly elevated expression of pyroptosis-related proteins (GSDMD, GSDMD-N, Caspase-1, and IL-1β) specifically in the dHip, as well as enhanced immunofluorescence intensity within CA3 neuronal populations. Pharmacological inhibition of GSDMD pore formation with dimethyl fumarate (DMF) not only attenuated morphine-induced CPP but also reversed the upregulation of pyroptotic markers in dHip neurons. Complementary in vitro experiments in HT-22 hippocampal neuronal cells confirmed that morphine directly induces dose-dependent upregulation of pyroptosis-related genes and proteins, effects that were abrogated by DMF co-treatment. These findings identify neuronal pyroptosis as a previously unrecognized mechanism associated with morphine-associated reward memory and position GSDMD as a potential therapeutic target that warrants further investigation for mitigating opioid-induced maladaptive plasticity.
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
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.
Huanqing Yang, V. Kovářová, Alena O. Godunova et al.· Neurobiology of Stress· 0 citations
Parkinson's disease (PD) is frequently associated with cognitive impairments, especially deficits in working memory and hippocampus-dependent memory. However, the contribution of dorsal hippocampus (dHipp) Ca2+/calmodulin-dependent protein kinase Ⅱ α (CaMKⅡα)-positive neurons to these deficits remains unclear. In this study, we investigated the impacts of chemogenetic modulation of dHipp CaMKⅡα-positive neurons on cognitive function, hippocampal theta rhythm, and monoamine levels in both sham-operated and unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. 6-OHDA lesions of the medial forebrain bundle impaired spatial working memory and hippocampus-dependent memory, reduced the peak theta frequency in the dHipp, and decreased dopamine levels in the striatum, medial prefrontal cortex (mPFC), dHipp and ventral hippocampus (vHipp). In sham-operated rats, chemogenetic manipulation of dHipp CaMKⅡα-positive neurons did not alter memory performance or theta rhythm. Aside from an increase in dopamine levels in the mPFC following activation, chemogenetic manipulation had no effect on monoamines. In contrast, in the 6-OHDA-lesioned rats, activation of dHipp CaMKⅡα-positive neurons improved spatial working memory and hippocampus-dependent memory, increased the peak theta frequency in the dHipp, and elevated dopamine levels in the mPFC, dHipp and vHipp, whereas inhibition exacerbated cognitive deficits, reduced the peak theta frequency in the dHipp, and decreased the level of noradrenaline in the above brain regions. These findings suggest that activation or inhibition of dHipp CaMKⅡα-positive neurons exerts opposing effects on cognitive function specifically in parkinsonian rats, which may be associated with alterations in hippocampal theta oscillations and monoaminergic transmission. Targeting dHipp CaMKⅡα-positive neurons may offer a promising therapeutic strategy for cognitive symptoms in PD.
BACKGROUND
Stress triggers a complex network of neuroendocrine, immune, and behavioral responses aimed at maintaining homeostasis. Nesfatin-1, a hypothalamic peptide initially identified for its anorexigenic effects, has also been increasingly implicated in stress-related processes.
METHODS
This study investigated whether acute inflammatory stress induced by lipopolysaccharide (LPS) activates Nesfatin-1 neurons in the supraoptic nucleus (SON) and examined the modulatory role of glutamatergic receptor antagonists. Female and male Sprague-Dawley rats were assigned to control, LPS, MK-801 + LPS, and CNQX + LPS groups. Neuronal activation was assessed using dual immunohistochemical staining for c-Fos and Nesfatin-1, followed by quantitative analysis of co-localized neurons in the SON.
RESULTS
LPS administration significantly increased the proportion of c-Fos-positive Nesfatin-1 neurons in both female and male rats compared to controls (p = 0.001). Pretreatment with MK-801 and CNQX attenuated this activation (p < 0.01), indicating the involvement of both NMDA and non-NMDA glutamatergic pathways.
CONCLUSION
Acute inflammatory stress activates Nesfatin-1 neurons in the SON, and this response is modulated by glutamatergic signaling. These findings provide new immunohistochemical evidence linking glutamatergic transmission to stress-induced Nesfatin-1 activation, with potential implications for the neurobiological interaction between inflammation, energy homeostasis, and stress-related processes.
G. Ekizceli, Kiymet Zulal Uygul, İ. M. Kafa et al.· Tissue & Cell· 0 citations
Acetylcholine (ACh) signaling regulates oligodendrocyte lineage progression via muscarinic ACh receptors (mAChRs), yet its role in cocaine-induced myelin-associated and relapse-like changes remains unexplored. Here, we examined whether hippocampal cholinergic and oligodendroglial alterations were associated with cocaine-related outcomes and pharmacologically sensitive to M3-preferential antagonism. Adult male C57BL/6J mice were subjected to cocaine-conditioned place preference (CPP), extinction, and cocaine-primed reinstatement, and treated with benztropine (BZT), the M1-selective mAChR antagonist VU0255035, or the M3-preferential mAChR antagonist solifenacin (SOL). Cocaine conditioning increased dorsal hippocampal ACh levels and reduced the expression of selected myelin-related genes and oligodendroglial transcription factors, including Mbp, Plp, Olig2, and Olig1, predominantly in the dorsal hippocampus. These changes were accompanied by reduced myelin basic protein (MBP) immunoreactivity, increased cholinergic terminal apposition to oligodendrocyte-lineage cells, and upregulation of Chrm3 in O4-sorted hippocampal oligodendrocytes. BZT reduced cocaine-primed reinstatement and increased Mbp and Plp expression and MBP immunoreactivity in several hippocampal layers. BZT also normalized cocaine-induced changes in Fosb, ΔFosb, Creb, and Slc6a3 in the dorsal hippocampus, whereas dorsal Bdnf remained different from vehicle-treated controls. SOL reduced reinstatement relative to both cocaine-conditioned and VU0255035-treated mice. SOL also increased open-arm time and entry ratio in the elevated plus maze test relative to cocaine-conditioned mice. In CD140a-sorted oligodendrocyte precursor cell-derived cultures, SOL increased MBP-positive oligodendrocyte volume relative to cocaine alone; however, the lack of a SOL-VU0255035 difference precluded conclusions about subtype specificity. These findings provide evidence consistent with a contribution of M3-sensitive muscarinic mechanisms to cocaine-associated oligodendroglial and behavioral alterations.
J. Yamada, Shoichiro Maeda, Ayumi Okamura et al.· Neuropharmacology· 0 citations
Summary Abnormal excitatory synaptic function plays a critical role in major depressive disorder. In this study, we investigated the role of the A3 adenosine receptor (A3AR), previously implicated in affective disorders, in excitatory synapse formation within prefrontal cortical circuits. Using a corticosterone-induced mouse model of depression, we found that the adenosine receptor activator 3′-deoxyadenosine (3′dA) produced antidepressant-like effects and selectively increased A3AR expression, whereas fluoxetine did not. 3′dA also restored the synaptic organizers neuroligin-2 (NLGN2) and neurexin-2 and elevated BDNF, excitatory synaptic markers (synapsin-1, PSD-95, and GluR1), and dendritic spine density in the PFC. Notably, enhanced NLGN2 immunoreactivity co-localized with astrocytes exclusively in 3′dA-treated mice but not in fluoxetine-treated mice. Pharmacological blockade of A3AR with MRS-1191 prevented the 3′dA-induced behavioral and molecular changes in this corticosterone-induced depressive-like mouse model. Together, our findings identify A3AR as a key regulator of NLGN2 expression and excitatory synapse formation and suggest a potential target for antidepressant therapies.
Bai Li, Meng Zeng, Jiahui Liu et al.· iScience· 0 citations
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