Search Results (118)

Self-injurious behavior (SIB) is a devastating and potentially life-threatening action with high prevalence in adolescents and patients with neuropsychiatric disorders. Accumulating evidence indicates that disruptions in multiple cellular and circuit mechanisms underlie vulnerability to SIB. We used an inducible SIB rat model to study synaptic modification during SIB. At 0.5 and 1 h after bilateral injection of muscimol (1.0 μg/side) into the rat endopeduncular nucleus (EP, a rodent homolog of the internal globus pallidus (GPi)), which induced SIB in rats, expression of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunit 1 (GluA1) and the phosphorylation of GluA1 at Ser831 and Ser845 were tested in the lateral habenula (LHb), ventral tegmental area (VTA), nucleus accumbens (NAc), amygdala, and medial prefrontal cortex (mPFC) of the rat brain. We also tested if modulation of NAc activity with a GABA_A receptor agonist or antagonist or dopamine receptor agonist or antagonist or inhibiting the mPFC–NAc pathway affected SIB in rats. At 1 h after EP inhibition, total GluA1 expression and phosphorylated GluA1 were decreased in the mPFC, VTA, and NAc, but were increased in the amygdala compared with control rats. When the EP was inhibited by 0.2 μg/side muscimol, hyperactivation of the NAc increased SIB in rats. However, if the EP was inhibited by 1.0 μg/side muscimol, hyperactivation of the NAc had no effects on SIB. Inhibiting the mPFC–NAc pathway increased wound areas in rats with SIB. At the onset of SIB, excitatory synaptic transmission is simultaneously dampened in the reward and control circuitry (VTA, NAc, mPFC) and potentiated in the aversion circuitry (amygdala), indicating that SIB is associated with molecular signatures suggestive of a shift from reward to threat processing. Hyperactivation of the NAc increased SIB incidence in rats, but administration of dopamine receptor agonists and antagonists into the NAc did not significantly affect the incidence of SIB in this study. These findings provide a novel mechanistic perspective on SIB, offering a basis for the treatment of SIB. Full article

Background and Clinical Significance: We report on three patients with traumatic brain injury (TBI) who showed improvement of impaired consciousness and changes in the default mode network (DMN), which was demonstrated on follow-up diffusion tensor tractographies (DTTs). Case Presentation: Three TBI patients underwent comprehensive rehabilitation during their first and second evaluations. Their Coma Recovery Scale-Revised (CRS-R) scores were obtained, and DTT was performed at 98.7 ± 22.0 days (first) and subsequently at 216.0 ± 78.1 (second) after onset. Compared with the first evaluation, the CRS-R scores increased by 12, 8, and 10 points on the second evaluation of the three patients. Although not reconstructed on the results of the first DTT, the second DTT results showed reconstruction of the medial prefrontal cortex (mPFC)–posterior cingulate cortex (PCC) DMN in patients 1 and 2. Regarding the continuously reconstructed DMNs (both mPFC-PCC and mPFC–precuneus), structural thickenings were generally observed in patients 1 and 3; however, narrowing was observed on the right mPFC-PCC DMN of patient 3. On the second DTT, all fractional anisotropy values of the reconstructed DMNs increased in patients 1 and 3, whereas all mean diffusivity values of the reconstructed DMNs decreased. Except for the right mPFC-PCC DMN in patient 3, all tract volume values of the reconstructed DMNs increased on the second DTT. Conclusions: DTT demonstrated changes in the mPFC-PCC/precuneus DMN concurrent with the improvement of impaired consciousness in three patients. In conclusion, recovery of the mPFC-PCC/precuneus DMN is closely associated with improvement of impaired consciousness in TBI patients. Full article

To investigate the neural circuit mechanisms linking the physiological loss of α-synuclein (α-syn) function to depressive-like states, we explored whether constitutive α-syn depletion disrupts the excitation and inhibition balance within the medial prefrontal cortex. We integrated comprehensive behavioral paradigms, whole-cell patch-clamp electrophysiology, and targeted chemogenetics within an α-syn knockout mouse model. Behavioral profiling revealed that α-syn deficiency was accompanied by basal psychomotor hyperactivity and profound stress-coping deficits. Cellular electrophysiology in the medial prefrontal cortex demonstrated a significantly enhanced intrinsic excitability across both GABAergic and glutamatergic populations. Furthermore, targeted chemogenetic suppression of GAD67-positive interneurons partially alleviated the depressive-like phenotype without confounding baseline locomotion. In summary, the physiological depletion of endogenous α-syn is associated with altered stress-coping behaviors and increased mPFC neuronal excitability. Chemogenetic suppression of mPFC GAD67-positive interneurons partially reduces immobility in SYN-KO mice, implicating prefrontal inhibitory circuit dysregulation in these behavioral alterations. These findings underscore the importance of α-syn homeostasis in modulating cortical microcircuits and provide novel insights into the early non-motor manifestations of synucleinopathies. Full article

Morphine addiction is driven in part by persistent reward-associated memory, yet the molecular mechanisms linking translational control to cellular stress responses remain unclear. In the present study, using a mouse morphine-induced conditioned place preference and N2a cell model, we investigated apoptosis-related alterations in the medial prefrontal cortex and the involvement of eIF4E-dependent translational regulation and BDNF/TrkB signaling. Morphine-induced conditioned place preference was associated with an increase in TUNEL-positive cells in the medial prefrontal cortex, accompanied by upregulation of Bax and downregulation of Bcl-2. In N2a cells, morphine induced apoptosis in a dose-dependent manner. Morphine also increased neuronal eIF4E expression in both mPFC tissue and N2a cells, accompanied by upregulation of BDNF and TrkB. Inhibition of the eIF4E/eIF4G interaction with 4EGI-1 significantly affected morphine-induced CPP formation and altered apoptosis-related markers and BDNF/TrkB expression. Notably, intra-mPFC administration of 4EGI-1 suppressed morphine-induced CPP without affecting anxiety-like behavior, locomotor activity, or general learning and memory performance. These findings suggest that eIF4E-dependent translational regulation is functionally associated with morphine-induced reward memory and apoptosis, potentially in association with changes in BDNF/TrkB molecular expression. This study offers novel insight into the molecular basis of morphine addiction and highlights a potentially targetable translational regulatory pathway for therapeutic intervention. Full article

Background/Objectives: Autobiographical memories (AMs) are an essential type of memory for our sense of self. A broad network of brain regions supports the retrieval of AMs, encompassing the medial temporal lobe (MTL), medial prefrontal cortex (mPFC), and parietal and visual cortices. However, little is known about how the subjective qualia of these memories relate to the underlying functional networks supporting their retrieval. Methods: AM cues were generated from early and recent life encompassing both object- and location-specific memories. While undergoing functional imaging, participants were cued on to retrieve differing time (remote, recent) and type (object, location) AMs followed by subjective ratings of each memory cued. Results: Functional activation patterns were consistent across the time and type of memory and reflect the existing literature. Functional connectivity analyses were similar across memory age, with only recent memories having greater connectivity compared to remote memories. Subjective qualia moderated the connectivity between regions for both remote and recent memories. Connections from the mPFC were modulated by multiple ratings across memory age, with important recent memories showing a significant negative connection with the hippocampus (p_FDR < 0.05). Conclusions: Subjective qualia mostly modulated the connectivity profile of the mPFC with other visual and MTL regions underlying the mPFC’s importance during retrieval of autobiographical memories. These connections, in relation to differing subjective qualia across memory age, highlight the possible differences in the reinstantiation of AMs. Full article

Background: Lumbar disc herniation (LDH) is the most common etiological cause of low back pain (LBP). Objective and precise pain evaluation is of significant clinical value. Functional near-infrared spectroscopy (fNIRS) as a noninvasive neuroimaging modality, has been increasingly validated to reflect subjective pain perception through hemodynamic correlates. This study aimed to analyze the fNIRS changes in patients with LDH about to receive Unilateral Biportal Endoscopy and to further explore the feasibility of fNIRS as an objective biomarkers for clinical assessment of LDH. Methods: Resting-state fNIRS data were acquired from 67 preoperative LDH patients and 20 healthy controls (HC). Brain functional maps—including z-standardized fractional amplitude of low-frequency fluctuations (zfALFF) and seed-based functional connectivity (FC)—were extracted and quantified. Group-level comparisons were performed between LDH and HC groups across four predefined regions of interest; additionally, correlation analyses were conducted between fNIRS metrics and clinical assessment scores within the LDH cohort. Results: Compared with HC, LDH patients exhibited significantly altered zfALFF in the medial prefrontal cortex (mPFC): decreased amplitude at channel CH12 (t = −2.031, p = 0.045) and increased amplitude at CH21 (t = 2.462, p = 0.016). Whole-brain FC analysis further revealed widespread changes—particularly between the parietal somatosensory cortex and prefrontal regions. Among all tested FC–clinical indicator associations, 56 reached statistical significance after FDR correction (q < 0.05). VAS_ lumbar and SF-36_SF exhibited the highest number of significant connections. Conclusions: LDH patients with LBP exhibit notable alterations in prefrontal resting-state ALFF and FC between the parietal somatosensory cortex and prefrontal cortex relative to HC. Importantly, these neural alterations exhibit significant associations with both pain severity (VAS) and long-term health-related quality of life (SF-36), thereby strengthening their candidacy as neural correlates meriting prospective validation as objective, mechanism-informed biomarkers for clinical evaluation of lumbar disc herniation (LDH). Moreover, these findings highlight candidate neural targets for future longitudinal studies investigating early prognostic prediction and treatment response monitoring in LDH. Full article

HIV-associated neurocognitive disorders (HAND) persist despite combination antiretroviral therapy (cART) and can be exacerbated by repeated cocaine (COC) exposure. Because COC, HAND, and cART independently disrupt medial prefrontal cortex (mPFC) function, their combined neurotoxic impact is a critical clinical concern. Using patch-clamp electrophysiology in HIV-1 transgenic (Tg) and non-Tg rats, we examined mPFC pyramidal neuron activity following repeated exposure to COC and/or cART. In non-Tg rats, COC and cART independently increased neuronal firing, trending toward an additive hyperactive effect when combined. Conversely, HIV-1 Tg rat neurons exhibited plateaued excitability, with no further firing elevations induced by COC or cART. Under intense depolarizing stimuli, treated neurons displayed overactivation-induced firing declines. These findings indicate that while COC and cART additively disrupt mPFC function in non-Tg rats, excitability mechanisms appear saturated in the HIV-1 Tg model. This restricted experimental context highlights the overlapping neurobiological impacts of cART and stimulant use, providing foundational insights into the comorbidity of COC use disorder and HAND. Full article

Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common chronic disorder of gut–brain interaction characterized by intestinal dysmotility. Central sensitization has a proposed role in intestinal dysmotility, yet the precise neural circuits and mechanisms remain poorly understood. In this study, we established a neonatal maternal deprivation plus restraint stress (NMD + RS) mouse model that recapitulates key diarrhea-like phenotypes. Neural activation mapping revealed a significant upregulation of c-Fos expression within the medial prefrontal cortex (mPFC) and locus coeruleus (LC), which was predominantly localized to glutamatergic neurons. Chemogenetic inhibition of mPFC glutamatergic neurons suppressed intestinal dysmotility, whereas the activation of mPFC glutamatergic neurons evoked intestinal dysmotility in control mice. Furthermore, viral tracing revealed direct projections from mPFC neurons to glutamatergic neurons in the LC. Subsequent chemogenetic manipulation of these LC glutamatergic neurons receiving projection from mPFC neurons similarly regulated intestinal motility, demonstrating a functional downstream node. Critically, selective activation of the mPFC-LC glutamatergic circuit significantly induced intestinal dysmotility in CON mice. In contrast, inhibition of the mPFC-LC glutamatergic circuit significantly ameliorated intestinal dysmotility in NMD + RS mice. Our findings proved that the enhanced activity of the mPFC-LC circuit led to intestinal dysmotility in NMD + RS mice, hopefully providing new mechanistic perspectives and a potential neuromodulatory target for clinical management of IBS. Full article

Background: Resting-state functional connectivity (RSFC) is widely used to identify abnormal brain function associated with depression. Resting-state functional magnetic resonance imaging (fMRI) scans have many potential confounds, and task-based FC might provide complementary information leading to better insight on brain function. Methods: We used MATLAB’s (version 2024b) CONN toolbox (version 22a) to evaluate FC in 40 adults with and without major depressive disorder (MDD) (n_MDD = 23, n_HC = 17). fMRI acquisition was performed while participants were at rest and while performing the Selves Task, an individualized goal priming task. Seed-based analyses were performed using two seeds: medial prefrontal cortex (mPFC) and left hippocampus. Results: Both groups showed strong positive RSFC between the mPFC and other DMN regions, including the anterior cingulate cortex and precuneus, which had more focal positive FC to the mPFC during the task in both groups. Additionally, the MDD group had significantly lower RSFC between the mPFC and several regions, including the right inferior temporal gyrus. The left hippocampus seed-based analysis revealed a pattern of hypoconnectivity to multiple brain regions in MDD, including the cerebellum, which was present at rest and during the task. Conclusions: Our results indicated multiple FC differences between adults with and without MDD, as well as distinct FC patterns and contrast results in resting state and task-based analyses, including differential FC between mPFC–cerebellum and hippocampus–cerebellum. These results emphasize that resting-state and task-based fMRI capture distinct patterns of brain connectivity. Further investigation into combining resting-state and task-based FC could inform future neuroimaging research. Full article

Background: Inter-brain synchrony (IBS)—the temporal alignment of neural activity between individuals during social interactions—has emerged as a key construct in social neuroscience, reflecting shared attention, emotional attunement, and coordinated behavior. Enabled by hyperscanning techniques, IBS has been observed across a range of dyadic contexts, including cooperation, empathy, and communication. This systematic review synthesizes recent empirical findings on inter-brain synchrony (IBS)—the temporal alignment of neural activity between individuals—across psychological and neurodevelopmental conditions, including stress, anxiety, depression, and autism spectrum disorder (ASD). Methods: Drawing on 30 studies employing hyperscanning methodologies (EEG, fNIRS, fMRI), we examined how IBS patterns vary by clinical condition, dyad type, and brain region. Results: Findings indicate that IBS is generally reduced in anxiety, depression, and ASD, particularly in key social brain regions such as the dorsolateral and medial prefrontal cortices (dlPFC, mPFC, vmPFC), temporoparietal junction (TPJ), and inferior frontal gyrus (IFG), suggesting impaired emotional resonance and social cognition. In contrast, stress elicited both increases and decreases in IBS, modulated by context, emotional proximity, and cooperative strategies. Parent–child, therapist–client, and romantic dyads exhibited distinct synchrony profiles, with gender and relational dynamics further shaping neural coupling. Conclusions: Collectively, the findings support IBS as a potentially dynamic, condition-sensitive, and contextually modulated neurophysiological indicator of interpersonal functioning, with implications for diagnostics, intervention design, and the advancement of social neuroscience in clinical settings. Full article

Background: Major depressive disorder (MDD) is a prevalent and disabling psychiatric illness with complex etiologies involving both genetic and environmental factors. While environmental stress is a known risk factor of MDD, the molecular mechanisms linking stress exposure to persistent depressive phenotypes remain incompletely understood. Methods: We established a 24-hour restraint stress-induced depression model in mice and performed integrated transcriptomic and proteomic analyses of the medial prefrontal cortex (mPFC) to investigate stress-related molecular alterations. Results: Behavioral assessments confirmed persistent depression-like phenotypes, including anhedonia and behavioral despair, lasting up to 35 days post-stress. RNA sequencing identified differentially expressed genes related to dopaminergic signaling and oxidative stress. Proteomic analysis identified 105 differentially expressed proteins involved in immune response and energy metabolism. Integrated multi-omics analysis highlighted convergent disruptions in immune regulation, metabolism, and epigenetic processes. Notably, clemastine exerts its antidepressant-like effects in part by mitigating neuroinflammation and preserving mitochondrial function. Conclusions: These findings provide novel insights into the molecular basis of stress-induced depression and suggest that clemastine is a potential therapeutic candidate. Full article

Schizophrenia, depression, and bipolar disorder may represent neurodegenerative conditions involving both degeneration and aberrant regeneration of monoaminergic axons. Negative and cognitive symptoms could arise from monoaminergic axon degeneration, whereas positive symptoms and manic states might result from excessive axonal regeneration and sprouting. The molecular mechanisms driving these opposing processes remain largely unclear. This review considers the possible role of calcium-independent phospholipase A₂ (iPLA2) in regulating monoamine axon degeneration and hyper-regeneration in schizophrenia. Emerging evidence suggests that pro-inflammatory signaling mediated by cytosolic PLA₂ (cPLA2) may promote monoamine axon degeneration, while anti-inflammatory iPLA2 activity could facilitate regeneration and sprouting. Overactivation of iPLA2 might lead to aberrant axonal sprouting, potentially contributing to positive symptoms through hyperdopaminergic states in the medial prefrontal cortex (mPFC). Conversely, axon degeneration in the same region may underlie negative and cognitive symptoms. The review also discusses a potential interplay between dopamine and N-methyl-D-aspartate (NMDA) receptor signaling in distinct neuronal populations of the mPFC and suggests that targeting iPLA2 and its pathways could represent a promising therapeutic strategy. Viewing schizophrenia and related disorders through the lens of monoamine axon pathology may eventually improve diagnostic precision and inform the development of treatments aimed at restoring the balance between degeneration and regeneration. Full article

Background/Objectives: Cerebellar cognitive affective syndrome (CCAS) is a well-recognized postoperative complication in children following resection of brain tumors involving cerebellar midline structures. The fastigial nucleus is regarded as relevant, but the underlying neural mechanisms remain incompletely understood. This study uses an oddball paradigm designed to model attentional and learning processes relevant to CCAS to investigate how early-life lesions of the fastigial nucleus in rats affect cognitive performance and neural information processing in the medial prefrontal cortex (mPFC) in adulthood. Methods: Fastigial lesions were induced stereotaxically in 23-day-old male Sprague Dawley rats [n = 9]. Naïve [n = 9] and sham-lesioned rats [n = 6] served as controls. As adults, all rats were trained in an oddball paradigm requiring discrimination of a rare target tone from a rare distractor and a frequent standard tone. Local field potentials (LFPs) were recorded from electrodes implanted in the mPFC during oddball testing and event-related potentials (ERPs) were analyzed. Results: Rats with fastigial lesions required significantly more training days to reach ≥70% correct performance criterion. In fully trained rats, analysis of neural recordings during behavioral testing revealed reduced ERP amplitudes and prolonged latencies of late ERP components after target stimuli. Developmental fastigial lesions lead to lasting deficits in cognitive learning capacity and neural mPFC processing, highlighting the integrative role of cerebellar midline structures in higher-order cognitive function and sensory discrimination. Conclusions: This rodent model provides a valuable translational platform for further investigating the neural basis of CCAS and may inform neurosurgical strategies aimed at minimizing cognitive sequelae in children undergoing cerebellar tumor resection. Full article

Cognitive flexibility, the ability to adapt behavior to changing environmental demands, is a core deficit in schizophrenia (SZ), that predicts disease progression. This review synthesizes findings on the neural substates of cognitive flexibility by using a framework that distinguishes animal model tasks by their motivational valence: aversive versus appetitive. While human studies using tasks like the Wisconsin Card Sorting Test (WCST) reveal significant cognitive inflexibility in SZ, particularly in set shifting, rodent models provide important mechanistic insights. The current literature suggests that aversive tasks, such as water mazes, and appetitive tasks, such as the Birrel–Brown discrimination task, engage distinct neural circuits, despite assessing supposedly similar cognitive processes. Aversive paradigms primarily rely on hippocampal–medial prefrontal cortex (mPFC) pathways, whereas appetitive tasks heavily involve orbitofrontal cortex (OFC)–striatal circuits, with significant modulation by dopamine and serotonin. Both valences seem to require an intact balance of glutamate and GABA transmission within prefrontal regions. This framework helps clarify inconsistencies in the literature and underscores how motivational context shapes the neural substrates of cognitive flexibility. Full article

Objective: Burning mouth syndrome (BMS) is a chronic and often debilitating orofacial pain condition characterized by a burning sensation in the oral mucosa without clear abnormal lesions. While its etiology is considered multifactorial, the underlying pathophysiology remains unclear. This narrative review aims to synthesize existing functional magnetic resonance imaging (fMRI) studies to shed light on the central neural mechanisms contributing to BMS. Methods: A focused electronic search was conducted across the PubMed and J-STAGE databases for relevant articles published in English from January 2000 to May 2025. The review prioritized studies investigating brain structure and function using fMRI in individuals with BMS. Results: Our synthesis of the literature consistently demonstrated that the brains of individuals with BMS exhibit augmented connectivity within the medial pain system and a diminished gray matter volume in the medial prefrontal cortex (mPFC). These findings suggest a crucial role for altered brain circuitry, particularly a reduction in the output of the basal ganglia dopamine system, in the experience of BMS pain. Conclusions: The consistent fMRI findings strongly indicate that BMS involves significant functional and structural brain alterations. The observed changes in the mPFC and its connections to the basal ganglia dopamine system highlight this pathway as a potential target for both pharmacological and non-pharmacological neurological interventions for individuals with BMS. Full article