Aug 2026· Neuropsychopharmacology· 0 citations· 34 references
Medicine
TL;DR
These findings identify ANO2 as a potential modulator of dopamine-related signaling and inhibitory behavioral control, expanding current understanding of calcium-activated chloride channel function in neural circuits relevant to behavioral domains implicated in neuropsychiatric disorders.
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
Nicotine induces pronounced neural and behavioral activation through dopaminergic signaling. However, the underlying molecular mechanisms that regulate nicotine sensitivity remain poorly understood. Here, we investigated the roles of lysosomal sialidase Neu1 and neural glycan polysialic acid (PSA) in nicotine-induced responses in zebrafish, a vertebrate model. Western blot analyses revealed reduced PSA levels and significantly upregulated neu1 expression in the zebrafish brain following acute nicotine exposure. Behavioral assays revealed increased tolerance to nicotine-induced lethality and attenuated nicotine-evoked swimming excitation in neu1-knockout (neu1-KO) zebrafish compared with those in wild-type fish. Nicotine-induced neuronal activation, assessed based on c-Fos expression, was markedly reduced in neu1-KO zebrafish. Gene expression analyses revealed altered dopaminergic signaling, including reduced drd3 expression, in neu1-KO zebrafish. Pharmacological experiments demonstrated that blocking dopamine D2/D3 receptors suppressed nicotine-induced swimming excitation in wild-type zebrafish, whereas treatment with a selective dopamine D3 receptor agonist partially rescued the attenuated nicotine responsiveness observed in neu1-KO zebrafish. Nicotine-induced c-Fos activation occurred predominantly in PSA-positive neurons within the hypothalamus, a brain region implicated in dopaminergic signaling. These findings suggest that Neu1-mediated PSA degradation may modulate dopamine D3 receptor-dependent nicotine sensitivity. We propose a conceptual model wherein nicotine-induced Neu1 activation may contribute to reduced PSA levels and altered dopamine D3 receptor-related signaling, thereby influencing the threshold for nicotine-induced neural and behavioral activation.
Sumomo Tsuji, Haruka Ego, Ryota Shimizu et al.· Fish Physiology & Biochemist...· 0 citations
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.
Huanqing Yang, V. Kovářová, Alena O. Godunova et al.· Neurobiology of Stress· 0 citations
Abstract β-catenin-coding gene CTNNB1 is a top-ranking risk gene for autism and intellectual disability. To better understand how CTNNB1 haploinsufficiency is involved in the pathophysiology of neurodevelopmental disorders, we generated a new mouse model that enables Ctnnb1 deletion in forebrain excitatory neurons starting at embryonic corticogenesis. Behavioural assays of the Ctnnb1 conditional knockout (cKO) mice revealed significant fear memory deficits, despite normal social preference, anxiety, spatial and recognition memory. Pyramidal neurons in prefrontal cortex (PFC) of Ctnnb1 cKO mice exhibited the significantly elevated intrinsic excitability but markedly decreased AMPA receptor-mediated synaptic response, while GABAA or NMDA receptor-mediated synaptic response was unchanged. Gene profiling revealed the significantly reduced mRNA level of Syp (encoding Synaptophysin) and Nlng2 (encoding Neuroligin-2) in PFC of Ctnnb1 cKO mice, while most of other screened genes were unchanged. These results suggest that β-catenin deficiency in forebrain excitatory neurons leads to fear conditioning impairment, which could be contributed by the diminished excitatory synaptic transmission in PFC resulting from disrupted synaptic gene expression.
Luis Gustavo Hernandez Carballo, Rachel Senek, Ksenia Novototskaya-Vlasova et al.· Brain Communications· 0 citations
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.
Dongyu Yu, Xi-xi Yang, Xiaoyun Yang et al.· Neuropharmacology· 0 citations
Chronic stress exposure causes neurobiological and behavioral changes that resemble those reported in psychiatric conditions such as major depressive disorder (MDD). Preclinical stress models and studies using postmortem tissue from MDD patients have shown that DNA Damage-Inducible Transcript 4 (Ddit4) is increased in the prefrontal cortex (PFC). This is important because DDIT4 negatively regulates the mammalian target of rapamycin (mTOR) pathway, which may lead to behavioral deficits through diminished neuroplasticity and PFC function. Our prior studies indicate that coordinated neuron-microglia interactions contribute to synaptic remodeling in the PFC. The present studies aimed to test the hypothesis that increased neuronal Ddit4 expression is sufficient to drive structural remodeling of PFC neurons, in part by provoking microglia activation, and this leads to behavioral and cognitive deficits. To this end, we bilaterally infused AAV5-hSyn1-Ddit4-tdTomato or a control vector into the PFC of male Thy1-GFP and C57BL/6 mice and examined molecular, cellular, and behavioral endpoints. Mice with Ddit4 overexpression (Ddit4-OV) showed no change in passive stress coping yet exhibited a deficit in temporal order memory. Immunohistology analyses showed a decrease in dendritic spine density of Ddit4-OV mice. However, we found no changes in microglia count, microglia size, or nearest neighbor distance. Bulk RNA sequencing of Ddit4-OV PFC revealed increases in transcripts involved with dendrite and synapse function and decreases in transcripts involved with mitochondrial function, implicating mTOR dysregulation. Altogether, these results indicate that Ddit4 overexpression recapitulates some of the broad molecular, cellular, and behavioral adaptations observed following chronic stress exposure through a cell-autonomous mechanism.Significance Statement This work provides more context for the neurobiological effects of neuronal DNA Damage-Inducible Transcript 4 (Ddit4). Ddit4, an inhibitor of the mammalian target of rapamycin (mTOR) pathway, exhibits increased expression in the prefrontal cortex (PFC) of both rats exposed to pre-clinical chronic stress models and humans diagnosed with major depressive disorder (MDD). Our findings demonstrate that Ddit4 overexpression specifically in neurons is sufficient to reduce spine density in the PFC, impair temporal order memory, and induce transcriptional changes associated with stress and depression. These results indicate that neuronal Ddit4 can disrupt PFC function and cognitive performance in a cell-autonomous manner.
Alexander M. Kuhn, Kelly E. Bosis, Madeline M Mairose et al.· eNeuro· 0 citations