Search Results (750)

Objectives: Habitual exercise has been associated with a lower risk of emotional disorders and greater emotional stability. However, it remains unclear whether the beneficial effects of habitual aerobic exercise primarily emerge during the stage of emotion elicitation or during the subsequent regulation of negative emotions. The present study examined the association of habitual aerobic exercise with the intensity of negative emotion elicitation, the effectiveness of emotion regulation strategies, and patterns of prefrontal activation measured using functional near-infrared spectroscopy. Methods: Sixty-four participants were recruited, including individuals with habitual aerobic exercise (trained group, n = 32) and those without regular exercise habits (untrained group, n = 32). Participants completed an emotion regulation task consisting of four conditions: viewing neutral images, viewing negative images, cognitive reappraisal, and expressive suppression. The comparison between neutral and negative viewing conditions was used to assess emotional elicitation, whereas comparisons between the regulation conditions and passive viewing of negative images were used to assess emotion regulation effects. Results: Compared with the untrained group, the trained group showed a lower emotional elicitation effect, accompanied by lower right ventrolateral prefrontal cortex (rVLPFC) activation during picture viewing at a more liberal threshold. The two groups showed similar reductions in negative emotional experience during emotion regulation, whereas individuals with habitual exercise showed a trend toward lower right dorsolateral prefrontal cortex (rDLPFC) activation during expressive suppression. Conclusions: Habitual aerobic exercise is associated with greater emotional stability, characterized by reduced initial emotional reactivity during emotion elicitation. Habitual exercisers may also show more efficient neural processing, reflected in distinct prefrontal activation patterns during emotional processing and regulation, although these exploratory findings require confirmation in future research. Full article

Alzheimer’s disease (AD) is increasingly recognized as a disorder not only of cognition but also of motivation and emotional regulation. Apathy and anhedonia often precede memory deficits, implicating early dysfunction in reward-related circuits. This study investigated whether chronic infusion of palmitoylethanolamide (PEA), a lipid-derived PPARα agonist, could restore motivational behavior and dendritic plasticity in the Tg2576 mouse model of AD. The motivational behavior of mice that received sustained-release PEA pellets for 6 months was assessed by using the conditioned place preference (CPP) paradigm. Morphological and molecular analyses were conducted in the entorhinal cortex (EC), dentate gyrus (DG), and prefrontal cortex (PFC). In Tg2576 mice, PEA significantly rescued CPP performance, increased basal dendritic spines in WT mice in the EC, and both basal and apical dendritic expression in EC and DG from Tg2576 mice, and upregulated the expression of both PPAR-α and brain-derived neurotrophic factor (BDNF) in the PFC. Interestingly, the BDNF increase occurred even in the absence of baseline deficits, suggesting a trophic-enhancement effect. These findings suggest that the PEA-PPARα-BDNF axis may be a potential mechanism for restoring motivation and synaptic integrity in an AD-like mouse model. Lipid-based neuromodulation may therefore offer novel therapeutic routes for addressing non-cognitive symptoms and affective circuitopathy in neurodegenerative diseases. Full article

Background and Objectives: Parkinson’s disease (PD) is a neurodegenerative disorder marked by bradykinesia, rigidity, and tremor. While deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) effectively alleviates motor symptoms, the potential of targeting the substantia nigra pars reticulata (SNr) is less understood. This study investigates the effects of mid-term DBS of the SNr on motor function and neuroplasticity in a 6-hydroxydopamine (6-OHDA) rat model of PD. Methods: Adult male Sprague-Dawley rats (280–300 g) were divided into healthy control (n = 10), PD (n = 9), sham-DBS (n = 7), and SNr-DBS (n = 7) groups. Bilateral striatal 6-OHDA lesions induced PD. High-frequency (130 Hz, 60 µs) SNr-DBS was delivered for 14 days. Locomotor activity (open-field), gait (footprint method), and motor coordination (rotarod) were assessed. Tyrosine hydroxylase (TH) expression in the SN and c-Fos and BDNF expression in the cerebellum, prefrontal cortex (PFC), and ventrolateral thalamus were analyzed histologically. Results: SNr-DBS significantly improved ambulation and horizontal activity compared to the PD group (p < 0.05). Gait analysis showed significant improvements in forelimb/hindlimb stride length and stance width, while rotarod performance indicated enhanced motor coordination (p < 0.05). Histology revealed increased TH expression in the SN and elevated c-Fos and BDNF levels in the cerebellum, PFC, and thalamus in the SNr-DBS group vs. PD rats (p < 0.05). Conclusions: Mid-term SNr-DBS produced significant functional gains in motor activity and coordination in a 6-OHDA PD model, together with molecular evidence of dopaminergic enhancement and neuroplastic activation. These translational findings suggest that targeting the SNr may offer a clinically relevant alternative for patients with PD, particularly for those who may not optimally respond to conventional STN or GPi stimulation. Full article

Scopolamine, also known as hyoscine, is a naturally occurring tropane alkaloid derived from plants of the Solanaceae family. Clinically, the compound has long been used for the prevention of motion sickness and postoperative nausea and vomiting, as well as for ophthalmological procedures requiring mydriasis and cycloplegia. However, beyond these established indications, increasing attention has been directed toward its broader neuropharmacological actions. This narrative review aims to summarise current knowledge regarding the pharmacological properties of scopolamine, with particular emphasis on its mechanisms of action and emerging implications in neuroscience and neuropsychiatric disorders. Scopolamine acts as a non-selective antagonist of muscarinic receptor subtypes M1–M5, interfering with cholinergic neurotransmission. Experimental and clinical studies demonstrate that scopolamine induces transient cognitive impairment. This property has led to its widespread use as a pharmacological model of Alzheimer’s disease, enabling investigation of cholinergic contributions to cognitive decline. More recently, several early clinical studies suggested that intravenous administration may produce rapid reductions in depressive symptoms, possibly through modulation of glutamatergic neurotransmission and activation of mTORC1-dependent synaptic plasticity pathways in the prefrontal cortex. Nevertheless, subsequent trials have yielded inconsistent results, and the therapeutic relevance of these findings remains uncertain. Current evidence indicates that scopolamine’s neuropsychiatric effects likely arise from complex interactions between cholinergic, glutamatergic, and neurotrophic signalling systems. Taken together, scopolamine represents both a valuable experimental tool for studying cholinergic function and a mechanistic framework for the development of novel therapeutics targeting rapid neuroplastic processes in neuropsychiatric disorders. Full article

SARS-CoV-2 is the etiological agent responsible for COVID-19. While most research has focused on structural proteins, the accessory protein Open Reading Frame 8 (ORF8) has attracted attention for its role in immune evasion and the induction of a cytokine storm. Although the exact mechanisms underlying viral pathogenicity remain to be elucidated, oxidative stress has been proposed as a key contributing factor. In this study, we evaluated the effect of intranasal administration of ORF8 on arterial blood pressure and the antioxidant system in different organs of male BALB/c mice at 2- or 8 weeks post-administration. A significant increase in blood pressure and renal total antioxidant capacity was observed in the 8-week group, and decreased catalase activity in the prefrontal cortex was observed in the 2-week group. These findings suggest that ORF8 may contribute to long-term renal alterations and potentially to mechanism relevant to cognitive dysfunction associated with COVID-19. Full article

Background: Translational circuit neuroscience delivers many candidate neurons whose manipulation could ameliorate psychiatric symptoms. However, the translation of these cellular targets into molecular targets—proteins selectively expressed in those neurons that could be pharmacologically manipulated for treatment—remains scarce. To what extent such a translation is possible or is actually impeded by a lack of highly cell type-specific expression of druggable proteins is unknown. Methods: We performed combinatorial differential expression analysis for over 7200 putatively druggable genes (Illuminating the Druggable Genome database) on large-scale single-cell RNAseq datasets from mouse and human cortex (Allen Institute Cell Types Database) to identify selectively expressed genes in important cellular candidates: several pyramidal cell types and parvalbumin, somatostatin and VIP interneurons of the prefrontal and anterior cingulate cortex and hippocampus in mice, and the cingulate cortex in humans. Results: We identified dozens of targets, including some with psychiatric relevance and/or suitability to modulate neural activity, like ion channels, GPCRs and transporters. However, none of them were expressed with absolute specificity in any of the analysed target cell types but only stood out in some comparisons, not others. Generally, results depended strongly on selectivity criteria: less conservative approaches (such as moderate p-value adjustment or grouping of contrast cell sets) yielded more targets, whereas the introduction of additional plausible constraints (difference in proportion of expressing cells, beta; absence of expression in contrast cell type) drove numbers towards zero. Generally, interneurons showed more selectively expressed targets in comparison to cells of the same region compared to excitatory ones (intra-regional comparisons), whereas the reverse was found in inter-regional contrasts comparing the same cell type across regions. Conclusions: The lack of high selectivity in the expression of genes encoding druggable targets constitutes a principal biological limit for manipulating cortical neurons of one type, specifically to leverage therapeutic action. While, currently, this conclusion is limited to the investigated neocortical and hippocampal regions, it highlights the need to develop biological heuristics for identifying targets expressed with relative specificity. Full article

Background/Objectives: Tobacco use is a leading cause of preventable death worldwide and is linked to major health and economic burden. Many smokers attempt to quit, yet long-term success rates with current medicines and counseling are still modest. Long-term nicotine exposure distorts brain systems involved in reward, craving, and self-control. These changes weaken inhibitory control and strengthen responses to smoking cues, which increases the risk of relapse. Transcranial magnetic stimulation (TMS) is a non-invasive technique that delivers magnetic pulses to specific cortical regions, most commonly the dorsolateral prefrontal cortex, to influence neural activity. This narrative review explored how transcranial magnetic stimulation may aid smoking cessation by acting on neural circuits linked to nicotine dependence. Methods: Five major databases were searched for studies published between 2015 and 2026. After removal of duplicates and screening, a total of 34 studies were included in this narrative synthesis. Randomized controlled trials, clinical studies, and neuroimaging investigations involving adults with nicotine dependence were included. A thematic narrative method was employed to synthesize findings due to the differences in study designs, protocols, and outcome measures. Results: TMS has been shown to attenuate cravings, decrease daily cigarette consumption, and decrease nicotine dependence in various studies. Several trials reported higher abstinence rates with active stimulation compared with sham treatment. Meta-analytic findings indicate stronger effects with 10 Hz stimulation and treatment courses of 20 sessions or more. Neuroimaging studies report changes in functional connectivity within reward, executive control, and salience networks, suggesting partial restoration of disrupted circuits. Treatment response varies according to age, educational level, baseline dependence, and stimulation parameters. Conclusions: These findings support transcranial magnetic stimulation as a promising brain-based approach for smoking cessation, while further well-designed trials with longer follow-up are still needed. Full article

Objective: The classic excitation/inhibition dichotomy may be insufficient to describe rTMS mechanisms in the aging brain. This study investigated immediate whole-brain resting-state functional connectivity effects of 10 Hz (high-frequency) and 1 Hz (low-frequency) rTMS over the left dorsolateral prefrontal cortex (DLPFC) in healthy older adults. Methods: Thirty healthy older adults (aged 60–75 years) participated in a randomized, single-blind, crossover study, and underwent 20-min 10 Hz and 1 Hz rTMS in separate visits. A 106-channel fNIRS system was used to record resting-state activity before and immediately after each intervention. Functional connectivity was analyzed at the channel, region-of-interest (ROI) and network summary levels, including graph-theoretic metrics and distance-stratified connectivity summaries. Results: At the network summary level, 10 Hz stimulation was associated with relatively more positive changes in global topology and spatially distributed connectivity summaries, whereas 1 Hz stimulation showed the opposite overall trend. In the graph-theoretic analyses, stimulation frequency × time interaction effects were observed for global efficiency, local efficiency, clustering coefficient, and mean node strength. At the edge level, only a small number of effects survived FDR correction, and the broader connection-wise patterns were therefore interpreted as exploratory. Uncorrected analyses suggested widespread enhancement after 10 Hz stimulation and widespread reduction after 1 Hz stimulation, together with localized paradoxical effects, including selective decreases after 10 Hz and selective increases after 1 Hz (e.g., bilateral primary motor cortex connectivity). Conclusions: These findings suggest that 10 Hz and 1 Hz rTMS over the left DLPFC are associated with different patterns of immediate whole-brain network reconfiguration in healthy older adults. The presence of localized paradoxical effects further suggests that rTMS responses in the aging brain may involve more complex forms of reorganization than a simple excitatory/inhibitory dichotomy would predict. Significance: The present study provides preliminary support for a network-level perspective on neuromodulation in older adults and highlights the value of whole-brain fNIRS for characterizing distributed responses to rTMS. Larger, sham-controlled, behavior-linked, and longitudinal studies are needed to determine the robustness and functional significance of these effects. 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

This study presents a modular and scalable wearable functional near-infrared spectroscopy (fNIRS) system for high-resolution cerebral hemodynamic signal acquisition. The system is based on compact optoelectronic modules and supports mixed measurements using short-separation and long-separation channels, offering good scalability and spatial adaptability. The integrated quartz light guide structure improves optical coupling efficiency between the probe and scalp. A series of in vivo experiments validated system performance. In a forearm arterial occlusion experiment, the system accurately captured concentration changes in oxygenated and deoxygenated hemoglobin during blood flow blockade and reperfusion, with large effect sizes (Cohen’s d > 0.9). In a prefrontal cortex Valsalva experiment, the biphasic response characteristic of neurovascular coupling was successfully resolved. In a 2-back working memory task, the system identified a task-related frequency component (0.0227 Hz) and right-lateralized prefrontal cortex activation (p = 0.023). These results demonstrate that the system exhibits a good signal-to-noise ratio and temporal dynamic response, enabling high-resolution mapping of regional hemodynamic changes. This work provides an effective solution for the development of wearable, modular, and high-precision multi-channel fNIRS systems. Full article

Stress states are increasing with global urbanization, but evidence on the physiological impact of urban blue-space exposure remains limited compared to green spaces. In this randomized within-subject crossover study, we examined the physiological effects of seascape viewing from the 29th floor of an office building in 44 healthy young adults. Each participant underwent visual stimulation with a seascape window view (blue space) and a blind-covered window (control) for 90 s each after a 60 s rest. Prefrontal cortex activity was recorded using near-infrared spectroscopy, and the left–right difference (LRD) in Δoxy-Hb concentrations was used as an indicator. Autonomic nervous system activity was assessed using heart rate variability, and psychological outcomes were measured using a semantic differential scale and the Profile of Mood States—2 short form. Seascape viewing significantly increased LRD, indicating left-dominant prefrontal activation relative to the control. It also increased comfort and relaxation and improved mood states. Correlation analyses showed that LRD was positively correlated with comfort and relaxation. These findings suggest that intentional window-view design, including exposure to high-rise blue-space views, represents a promising environmental approach to support occupants’ well-being and provide practical implications for window-view design and operation in high-rise office environments. Full article

Background/Objectives: Evidence indicates that aberrant glutamate transporter function and expression are linked to the pathophysiology of comorbid major depressive disorder (MDD) and pain. We have previously reported that cefepime (CFP) attenuates lipopolysaccharide (LPS)-evoked pain and depression by regulating hyperglutamatergic activity in male mice. However, the effects of CFP on LPS-evoked pain, depression-related anxiety, and cognitive impairment in female mice regarding sex-specific glial mechanisms remain unknown. Methods: Using behavioral paradigms, we evaluated the therapeutic potential of CFP in mitigating LPS-evoked pain, depression-related anxiety, and cognitive impairment in female mice. Furthermore, we used Western blot analysis to examine the effects of CFP on ionized calcium-binding adaptor molecule 1 (Iba-1) and glutamate transporter 1 (GLT-1) protein levels in the prefrontal cortex (PFC) and hippocampus (HPC). We also measured tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) concentrations in the HPC and PFC after CFP treatment using ELISA. Results: Pretreatment with CFP significantly increased the mechanical threshold and withdrawal latency in female mice. Additionally, systemic treatment with CFP markedly reduced immobility during the forced swim and tail suspension tests. Moreover, pretreatment with CFP remarkably augmented the open arm time during elevated plus maze test and spontaneous alternation between arms during Y-maze test. Western blot analysis indicated that systemic administration of CFP significantly reversed the downregulation of astroglial GLT-1 expression and reduced the microglial Iba-1 protein levels in the HPC and PFC. Furthermore, pretreatment with CFP significantly attenuated the LPS-evoked increase in the production of pro-inflammatory cytokines in the HPC and PFC. Conclusions: These results represent the novel inaugural report of a combined pain-MDD phenotype in female mice. The findings imply that positive glutamate transporter modulator CFP could be a novel treatment for comorbid pain and MDD in female patient population. Full article

HIV-associated neurocognitive impairment persists despite combination antiretroviral therapy, largely driven by chronic microglial activation that sustains neuroinflammation and neuronal injury. Activated microglia contribute to HIV-associated brain pathology by releasing proinflammatory mediators that disrupt synaptic integrity and impair cognition. N-acetylaspartylglutamate (NAAG), an abundant neuropeptide that maintains glutamatergic homeostasis, is hydrolyzed by glutamate carboxypeptidase II (GCPII) to glutamate. We previously demonstrated that reduced brain and cerebrospinal fluid NAAG levels in people living with HIV correlate with cognitive impairment, and that pharmacological GCPII inhibition with 2-(phosphonomethyl)-pentanedioic acid (2-PMPA) elevates brain NAAG and improves cognition in EcoHIV-infected mice. To enhance brain delivery and preferentially target activated microglia, we conjugated 2-PMPA to a generation 4 hydroxyl poly(amidoamine) (PAMAM) dendrimer (D-2-PMPA). Our findings demonstrate that D-2-PMPA achieves preferential microglial drug delivery, resulting in a >600% increase in cerebrospinal fluid NAAG levels. At doses 8.3-fold lower than free 2-PMPA, this formulation reversed EcoHIV-induced deficits in social interaction, novel object recognition, and fear-conditioned memory without altering locomotor activity or anxiety-like behavior. D-2-PMPA also restored prefrontal cortex synaptic density and preserved dendritic architecture. Together, these findings demonstrate that microglia-targeted GCPII inhibition represents a potent nanotherapeutic strategy to restore synaptic integrity and cognitive function in HIV-associated neurocognitive impairment. Full article

Background: Maternal immune activation (MIA) during pregnancy is a known risk factor for several neurodevelopmental and psychiatric disorders, including schizophrenia. In rodent models, MIA is commonly induced using polyinosinic/polycytidylic acid (Poly(I/C)), a viral mimetic that activates Toll-like receptor 3 (TLR3) signaling and elicits an inflammatory response in both the dam and the fetuses. MIA results in various behavioral abnormalities in offspring, including deficits in social interaction. Recent studies have shown that MIA decreases the ability to maintain mitochondrial membrane potential (ΔΨm), the electrical component of the electrochemical gradient required for ATP production and alters mitochondrial protein expression in brain tissue isolated from adult offspring. Methods: In the present study, we monitor ΔΨm non-invasively in vivo using a previously published bioluminescence probe in juvenile and adult MIA offspring. We then investigated gene expression in the medial prefrontal cortex of MIA offspring by analyzing a previously published RNA sequencing dataset in combination with MitoCarta3.0, a comprehensive inventory of genes involved in mitochondrial function. Finally, we tested the hypothesis that this mitochondrial dysfunction contributes to the behavioral deficits observed in MIA offspring. Results: We have observed impaired ΔΨm maintenance in juvenile MIA offspring that persists into adulthood. Also, we found that MIA alters the expression of many genes associated with mitochondrial energy production. We demonstrated that nicotinamide riboside, a precursor to NAD⁺ known to restore ΔΨm, significantly attenuates MIA-induced social interaction deficits. Conclusions: Together, these findings highlight mitochondrial function as a promising therapeutic target for symptoms associated with schizophrenia and support the potential for drug discovery aimed at enhancing mitochondrial health. Full article

Major depressive disorder (MDD) is one of the most prevalent mental illnesses and, despite the availability of multiple treatment options, remains difficult to treat for a substantial proportion of patients. Repetitive transcranial magnetic stimulation (rTMS) is an important therapeutic approach for depression, modulating brain activity through targeted magnetic pulses in a non-invasive manner. This review examined scientific evidence from clinical trials, large-scale analyses, and laboratory investigations regarding the effectiveness and safety of rTMS, as well as its role within contemporary therapeutic strategies for depression. In addition to conventional rTMS, the review addresses theta-burst stimulation (TBS), deep TMS, and various approaches aimed at enhancing treatment efficacy or accelerating clinical response, while also discussing the practical utility of different stimulation devices. rTMS applied to specific regions of the prefrontal cortex has demonstrated significant antidepressant effects, and intermittent theta-burst stimulation (iTBS) appears to achieve comparable outcomes within a shorter time frame. Research further indicates that rTMS is associated with neurobiological changes in brain connectivity, modulation of neurotransmitter systems, and the promotion of neuroplasticity. Across studies, rTMS is generally considered safe, with reported adverse effects being mild and transient. However, further research is needed to optimize stimulation protocols, clarify medium and long-term effects, individualize treatment approaches, and determine the durability of therapeutic benefits. Full article