Left-right brain asymmetry is an important feature of human neuroanatomy, with implications for cognition, behaviour, and vulnerability to mental disorders. Despite evidence for lateralized sensitivity to hormonal fluctuations, the cortical and subcortical asymmetry profile of individuals with premenstrual dysphoric disorder (PMDD), a hormone-related mood disorder associated with alterations in brain structure, remains unexplored. In this study, a total of 68 females with PMDD and 51 healthy females underwent magnetic resonance imaging (MRI) during the luteal phase of the menstrual cycle. Structural asymmetry was assessed using voxel-wise whole-brain analysis and region of interest (ROI) approaches for grey matter volume (GMV), as well as ROI-based analysis of cortical thickness. Associations between asymmetry and symptom severity were also investigated. Whole-brain analyses revealed significantly greater leftward GMV asymmetry in PMDD participants in two clusters within the anterior fusiform gyrus and the anterior insula. ROI-based analyses did not show any asymmetry group differences in either GMV or cortical thickness. Within the PMDD group, greater leftward asymmetry in the amygdala GMV was moderately associated with higher irritability. These findings provide novel, region-specific evidence for structural asymmetry in PMDD and suggest that lateralized brain architecture may contribute to affective symptom expression in this disorder.
Epilepsy is a chronic neurological disorder characterized by recurrent seizures, with variants in ion channel genes such as SCN1A, SCN1B, and CACNA2D2 implicated in neuronal excitability. This research aims to explore genetic polymorphisms in the SCN1A, SCN1B, and CACNA2D2 genes among Turkish epilepsy patients and assess their impact on responsiveness to anti-seizure medications (ASMs). Targeted next-generation sequencing (tNGS) was applied to genomic DNA from 29 patients. Common 15 variants were analyzed in CACNA2D2 (rs2239801, rs56287038), SCN1A (rs2298771, rs3032638, rs11394960, rs67636132, rs566839, rs1461193, rs6432861, rs2020318), and SCN1B (rs72556351, rs2278995, rs557140301, rs67701503, rs55742440). A statistically significant difference in ASM response was observed in the recessive model of SCN1A rs2298771: C>T (TT vs. CC+CT) (p = 0.044), with the TT genotype associated with improved response. CACNA2D2 rs56287038:G>T showed significance in the allelic model (p = 0.012); the T allele was found only in resistant patients. SCN1A haplotype analysis revealed reduced C allele frequency in responders (p = 0.041). The CT (rs2298771+rs2020318), CG (rs2298771+rs1461193), and CC (rs2298771+rs6432861) haplotypes also showed considerable differences among groups (p = 0.041, p = 0.023, p = 0.041, respectively). Moreover, CTG (rs2298771+rs2020318+rs1461193), CCG (rs2298771+rs6432861+rs1461193), and CTCG (rs2298771+rs2020318+rs6432861+rs1461193) haplotypes were significantly associated with treatment response (p = 0.023, p = 0.023, p = 0.022). However, none of these associations remained statistically significant after false discovery rate correction, and all findings should therefore be interpreted as exploratory. CACNA2D2 rs56287038:G>T and SCN1A rs2298771:C>T may effect ASM response.
Cancer-related cognitive impairment (CRCI) is a frequent adverse effect observed in patients, but the underlying mechanisms are still unclear. Cortisol has been proposed as a potential contributor to CRCI, so the aim of this review is to systematically evaluate the evidence on the role of cortisol in CRCI. This review followed PRISMA guidelines and was registered in PROSPERO (CRD42024570561). The search was conducted in PubMed, Web of Science, SCOPUS, ProQuest, OSF PREPRINTS, OATD, NDLTD Global E-Theses and Dissertations, and EBSCO. Inclusion criteria were studies on adult cancer patients/survivors assessing cortisol and CRCI, published in English from inception to January 30, 2025. The risk of bias was analyzed with the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, and a qualitative GRADE-like summary of the certainty of the evidence. Twelve articles were finally included and analyzed using content analysis methods. Overall, findings suggest that altered diurnal cortisol rhythm (i.e. blunted cortisol secretion pattern) might be involved in CRCI; although results are inconsistent and the exact mechanisms remain unknown. Stress response associated to diagnosis, surgery, and life changes, as well as certain treatments, of cancer patients may contribute to dysregulated cortisol secretion, which in turn has been linked to CRCI. Additionally, personality traits and sociodemographic factors may act as mediators between cortisol release and CRCI. Recent data suggest cortisol relates to CRCI; however, future research should standardize cognitive outcomes and cortisol assessment methods, and consider clinical, sociodemographic, and psychological factors that may modulate stress responses.
The zebrafish (Danio rerio) is a widely used model organism for studying neurobehavioral processes and neuropsychiatric disorders. Numerous protocols in adult zebrafish assess anxiety-like, locomotor, social and cognitive responses. The increasing experimental complexity and experimentation throughput has led many studies to combine multiple assays into behavioral test batteries. However, the methodological implications of such multi-test designs remain insufficiently understood. Here, we examined current practices in zebrafish behavioral batteries through an initial laboratory survey followed by a systematic literature analysis. Responses from 24 active zebrafish behavioral neuroscience laboratories were used to characterize experimental workflows and guide a targeted PubMed literature search. We further analyzed 357 studies employing the novel tank test (NTT) to assess the prevalence of multi-assay designs, identify commonly co-reported behavioral paradigms, and evaluate methodological variability. Our analyses confirm the central role of the NTT, frequently combined with the light-dark, open field, social interaction, and Y-maze tasks, and indicate that multi-assay experimental designs are common in the literature. However, methodological descriptions also often lacked sufficient clarity on whether assays were conducted sequentially in the same animals (as test batteries) or performed in independent cohorts. These findings highlight an important methodological gap in the field, and emphasize the need for greater clarity and consistency in the design and reporting of zebrafish behavioral batteries to improve the interpretability and comparability of multi-domain behavioral phenotyping.
The zebrafish (Danio rerio) has emerged as a valuable model system in neuroscience due to their genetic tractability, conserved neuroanatomy, sensitivity to pharmacological manipulations, and suitability for high-throughput screening. Among the many applications of zebrafish in neurobiology, the investigation of glutamatergic (glutamate-based) and GABAergic (gamma-aminobutyric acid-based) signaling has gained increasing relevance, as these two neurotransmitter systems maintain the critical excitatory-inhibitory balance crucial for normal brain function. Dysregulation of this balance underlies a range of psychiatric and neurological disorders, such as epilepsy and seizure disorders, schizophrenia, anxiety-related disorders, and autism spectrum disorders. Zebrafish models demonstrate conserved receptor subtypes and behavioral phenotypes paralleling human conditions, as well as predictable responses to clinically relevant drugs, such as N-methyl-D-aspartate (NMDA) receptor antagonists, GABA agonists, and anticonvulsants. In this review, we integrate these findings to highlight how zebrafish research has contributed to understanding glutamate and GABA pathway dynamics at molecular, cellular, and behavioral levels. We critically outline experimental strategies used to model these pathologies in zebrafish and summarize key genetic, biochemical, and behavioral endpoints for assessing neurotransmitter function. Finally, we discuss current limitations and propose future directions to enhance the translational impact of zebrafish models in neuropsychiatric research.
Women exhibit distinct stress-response patterns shaped by dynamic interactions between ovarian hormones, the autonomic nervous system (ANS), and cortical stress-processing circuits. Across the female lifespan, hormonal transitions, including the menstrual cycle, pregnancy, postpartum period, perimenopause, and menopause, are associated with heightened vulnerability to mood and anxiety disorders, underscoring the need for sex-specific physiological frameworks. This narrative review synthesizes current evidence on how hormonal fluctuations modulate stress physiology in women, with a particular focus on noninvasive biomarkers derived from heart rate variability (HRV), electrodermal activity (EDA), and electroencephalography (EEG). HRV emerges as a core biomarker of female stress reactivity, reflecting shifts in sympathetic-parasympathetic balance that vary across hormonal states and life stages. Estrogen is generally associated with enhanced vagal modulation and higher HRV, whereas progesterone and estrogen withdrawal are linked to sympathetic dominance and reduced HRV, patterns that are especially pronounced during the luteal phase, pregnancy progression, postpartum, and menopause. Complementary measures provide additional insight: EDA indexes sympathetic arousal and captures hormonally driven changes in emotional reactivity, while EEG reflects cortical dynamics underlying affective style, cognitive control, and stress sensitivity. Evidence indicates that multimodal HRV-EDA-EEG approaches improve detection of stress-related vulnerability by integrating autonomic and cortical signatures rather than relying on a single system. By consolidating findings across key female life stages, this review highlights how hormonal modulation of ANS-brain interactions contribute to sex-specific stress profiles and psychiatric risk. We conclude that multimodal physiological assessment holds substantial promise for advancing personalized prevention and intervention strategies in women's mental health, while emphasizing the need for standardized methodologies, longitudinal designs, and hormone-informed analytic frameworks in future research.
<p>Introduction: Intrusive memories are a central identifying symptom of post-traumatic stress disorder (PTSD), and their development can be modelled in experimental settings with the trauma film paradigm. Neurosteroids and sex hormones, such as allopregnanolone and testosterone, respectively, have recently become potential targets for PTSD pharmacological treatment due to their influence on the stress response. In the current study, 49 healthy female participants underwent stress induction and viewed a trauma film. Plasma allopregnanolone, testosterone, and cortisol responses to stress induction and the trauma film were recorded, and stress-induced responses were modelled as predictors of intrusive memory frequency using negative binomial regression models. Compared to baseline, plasma allopregnanolone and cortisol levels, along with subjective stress, were significantly higher after the stress induction. Plasma cortisol and subjective stress responses to the stress induction task significantly predicted intrusive memories. Allopregnanolone and testosterone did not predict intrusive memories, though allopregnanolone and cortisol stress responses were significantly correlated. These findings expand our current understanding of the biochemical processes of intrusive memory formation under stress. Additionally, changes in allopregnanolone were observed in response to stress, which contributes towards the discussion of neurosteroids and sex hormones as potential pharmacological targets for the treatment of PTSD. </p>.
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Intersegmental neural modulation refers to the influence of voluntary activation of one limb on the excitability and inhibitory balance of remote motor representations. Recent evidence suggests that high-intensity upper-limb isometric contractions can transiently enhance corticospinal excitability and modulate intracortical or interhemispheric inhibition of lower-limb motor areas, yet the consistency of these findings remains unclear. This systematic review synthesized evidence on the effects of upper-limb isometric contractions on corticospinal excitability and inhibitory mechanisms of lower-limb motor representations in healthy adults. Following PRISMA 2020 guidelines, searches were conducted in PubMed/MEDLINE, Scopus, Web of Science, Embase, and Cochrane CENTRAL. Eligible studies included healthy adults (18-65 years) performing upper-limb isometric contractions quantified as percentage maximal voluntary contraction (%MVC), with outcomes assessing lower-limb corticospinal excitability or intracortical/interhemispheric inhibition. Two independent reviewers screened studies, extracted data, and assessed risk of bias. Seventeen studies (n = 351) met inclusion criteria. Most reported increases in lower-limb motor evoked potential amplitude during upper-limb contractions, particularly at intensities ≥ 70% MVC. Reductions in short-interval intracortical inhibition were common, indicating transient disinhibition of lower-limb primary motor cortex representations. Findings for interhemispheric inhibition were inconsistent, likely attributable to variability in contraction tasks and transcranial magnetic stimulation parameters. Upper-limb isometric contractions consistently facilitate lower-limb corticospinal excitability and reduce intracortical inhibition in healthy adults. Although mechanistic patterns converge, methodological heterogeneity limits confidence in the magnitude of effects. Future studies require standardized experimental protocols and adequate sample sizes to clarify intensity-response relationships and underlying neurophysiological mechanisms.
In humans, disruptions in social behaviour are characteristic of many neuropsychiatric disorders, where both genetic risk factors and synaptic dysfunctions can contribute to the phenotype. Among the genes implicated in synaptic regulation, the synaptic adhesion protein leucine-rich repeat transmembrane protein 4 (LRRTM4) has been identified as a key player in maintaining synaptic function and neuronal circuit integrity. However, the potential involvement of LRRTM4 in modulating social behaviour and its contribution to social deficits has yet to be explored. In the current study, we used zebrafish to study how deficiency in lrrtm4l1, a zebrafish orthologue of LRRTM4, affects sociality. For this, the social behaviour of homozygous lrrtm4l1-/- mutant zebrafish was analysed in multiple behavioural assays and the brain transcriptome of mutant animals was investigated by RNAseq. Mutant zebrafish displayed a pro-social phenotype in multiple behavioural assays. Groups of lrrtm4l1-/- zebrafish formed more cohesive shoals and mutant individuals spent more time in the vicinity of conspecifics during a social interaction test. They were also less aggressive and in contrast to wild-type zebrafish did not differentiate in their interactions with known and unknown groups of fish. Neurotranscriptomic analysis revealed 560 differentially expressed genes including changes in glutamatergic neurotransmitter signalling, tryptophan-kynurenine metabolism and synaptic plasticity. These findings suggest that lrrtm4l1 is an important regulator of social behaviour in zebrafish. In a translational perspective, LRRTM4 is a promising potential therapeutic target that warrants further investigation in the framework of neuropsychiatric conditions characterized by major social impairments.
Osteoarthritis (OA) is the leading cause of chronic pain worldwide. Functional studies showed a critical role of descending facilitation, involving the rostral ventromedial medulla (RVM), in the establishment of pain chronicity. Glial cells such as microglia and astrocytes can contribute to chronic pain through the facilitation of neuronal excitability. This work aimed to characterize the morpho-structural changes in the RVM induced by experimental OA (eOA) pain and to identify potential sexual dimorphisms. The kaolin/carrageenan model of eOA was induced in 23 male and 22 female Wistar Han rats. Four weeks later, brain samples were collected and divided into two analyses: stereological evaluation of changes in neuronal/glial cell density within the RVM, and immunohistochemical analysis of glial activation, astrocyte proliferation and structural changes. While no major differences were found in the RVM volume or area, osteoarthritic females exhibited a higher glia-to-neuron ratio (95%CI: 0.13-0.76; p=0.006), driven by increased glial cell density. A significant increase in GFAP-positive cells was observed in females (95%CI: 1.95-25.8; p=0.025), without a corresponding increase in Iba1 immunoreactivity, an effect not seen in males. Increased mitotic activity and structural complexity of astrocytes in osteoarthritic females were further confirmed by immunofluorescence and Sholl analysis, respectively. Our findings highlight the intricate relationship between eOA-related pain and the RVM cellular dynamics, revealing sex-specific astrocyte activation following eOA and its potential role in the mediation pain processing and chronification. These results suggest targeting astrocyte-mediated mechanisms as potential sex-specific therapeutic strategy for OA pain management.
Motor overflow, a neuromotor phenomenon characterized by involuntary activation of muscles during voluntary movement, reflects impairments in interhemispheric and intracortical inhibition and is commonly observed in conditions such as stroke, cerebral palsy, dystonia, and Parkinson's disease. Transcranial Magnetic Stimulation (TMS) is a non-invasive neuromodulatory technique with potential to modulate the cortical excitability underlying overflow-related dysfunctions. This systematic review aimed to evaluate the efficacy of TMS in reducing motor overflow across neurological populations. Seven randomized controlled trials (RCTs) were included, encompassing participants with stroke, cerebral palsy, Parkinson's disease, and focal hand dystonia. Protocols varied in frequency (1-10 Hz), target area (M1, SMA, PSC, PMC), and design (e.g., crossover, combined protocols with constraint-induced therapy or cerebellar stimulation; Motor overflow was directly assessed in only two studies, one involving Parkinson's disease and one involving dystonia, thereby limiting cross-study comparisons. Therefore, evidence supporting a direct effect of TMS on motor overflow remains preliminary and condition-specific. In dystonia, high-frequency rTMS (10 Hz) targeting the primary somatosensory cortex led to significant reductions in overflow, demonstrated by handwriting kinematics. In Parkinson's disease, although physiological modulation (reduced IHI) was observed after SMA stimulation, mirror movements remained unchanged. In stroke and cerebral palsy populations, overflow was not directly evaluated, though improvements in motor function, spasticity, and cortical excitability were consistently reported. Risk of bias was low in most included studies, although gaps in allocation reporting and standardization of outcome measures were noted. This review highlights the potential of TMS, particularly high-frequency protocols, to modulate motor overflow in focal dystonia. However, the lack of targeted assessment in other neurological conditions suggests a critical need for future trials with standardized protocols and specific outcome measures focused on overflow to clarify the therapeutic role of TMS in rehabilitation.
Enhanced game-related specific Pavlovian-to-instrumental transfer (SPIT) has been observed in Internet gaming disorder (IGD). However, it remains unclear whether this effect is malleable. This study examined whether short-term abstinence from gaming modulates game-related SPIT effect in this population. Sixty young adults with IGD were recruited and assigned to two groups. The abstinence group (n = 29) refrained from gaming for 7 days, with compliance verified through daily mobile screenshots and self-reports; the control group (n = 31) maintained their usual gaming routines. Game-related SPIT was measured before (D0) and after (D7) the abstinence period, and social-reward general PIT (GPIT) was assessed as a comparison. During the Pavlovian phase, three abstract patterns (conditioned stimuli, CSs) were each paired with game-, social-, or shopping-related rewards. In the instrumental phase, 2 keys (G and F) were paired separately with game- and shopping-related rewards. Game and pleasure- and arousal-matched shopping and social-reward images were used as rewards in training. Finally, the influence of the CSs on instrumental responses (PIT effects) were tested in the transfer phase. Linear mixed models were applied to assess the change of SPIT and GPIT effects. (1) We observed a significant three-way CS × time × group interaction in the choice rate for game-related rewards; the abstinence group demonstrated a significant declined G-key choices from D0 to D7 (b = -1.413, z = -3.521, p < 0.001, OR = 0.243), whereas the control group remained stable, indicting a selective attenuation of SPIT effect following abstinence. (2) There was a significant time × group interaction for IGDS scores (F1, 58 = 8.008, p = 0.006, ηp2 = 0.121), where the abstinence group showed more reduction in IGDS scores over time than controls. (3) Within the abstinence group, the magnitude of the SPIT reduction was significantly correlated with the decrease in IGDS scores (r = 0.395, p = 0.046). (4) No significant changes of social-reward-related GPIT effect were observed in either group. Our findings demonstrate a declined game-related SPIT effect in young adults with IGD after a brief period of gaming abstinence. This points to a reversible incentive sensitization process in IGD, where heightened motivational salience attributed to gaming cues may diminish following abstinence, supporting the potential clinical value of integrating short-term, supervised abstinence within therapeutic interventions for IGD.
Monoamine neurotransmitters, including catecholamines (i.e., norepinephrine, epinephrine, and dopamine), and the indolamine serotonin play important roles in signaling in the central and peripheral nervous systems. Alterations in neurotransmission may be suggestive of neuroendocrine or psychiatric disorders, may reflect therapeutic responses, and are often considered relevant to mental health. Monoamine modulators and their metabolites are detectable in saliva, suggesting that saliva could represent an attractive, non-invasive, and cost-effective matrix for identifying and monitoring conditions in both healthy and diseased individuals. Accordingly, measuring salivary monoamine neurotransmitters may have scientific and possible clinical relevance. In this review, we summarize and critically evaluate current evidence on salivary dopamine, norepinephrine, epinephrine, serotonin and their respective metabolites. Although further research is required to clarify their biological significance and clinical applicability, existing findings suggest that salivary monoamine measurement may hold potential, albeit with important limitations.
Among the possible risk factors for dyslexia and specific learning disabilities (SLD) in children, being exposed to heavy metals in the environment has been considered a significant one, serving as a biological marker. The precise mechanisms by which heavy metals affect cognitive functions were discussed. However, their shared affinity for NMDA receptors or the Na+/K+ ATPase pump can disrupt the balance between reactive oxygen species and antioxidants. Several studies have scrutinized the effect of heavy and toxic metals on dyslexia. Consequently, this research aimed to systematically assess the most recent evidence of the effects of heavy metals on SLD and dyslexia. Four databases (i.e., Scopus, Web of Science, Google Scholar, and PubMed/Medline) were searched; 450 studies published up to 2024 were found. After applying inclusion/exclusion criteria, five studies were selected, and data regarding the participants' age, measurement instruments, the year of the studies, and the outcomes were extracted and analyzed. Generally, the total sample size in the five studies was 1,909 individuals. These studies examined 25 heavy metals, with selenium (Se), copper (Cu), lead (Pb), zinc (Zn), and nickel (Ni) showing consistent associations with dyslexia and SLD. Metals such as aluminum (Al), arsenic (As), antimony (Sb), cadmium (Cd), cobalt (Co), mercury (Hg), iron (Fe), and manganese (Mn) were cited only once. Notably, heavy metals such as Pb, Al, Sb, and Cd had a definitive role in the neuropathogenesis of SLD. These findings highlighted the importance of implementing environmental control measures to minimize children's exposure to toxic heavy metals.
Chronic neuropathic pain (NP) is frequently accompanied by anxiety- and depression‑like symptoms, reflecting maladaptive interactions between nociceptive and affective brain networks. The anterior insular cortex (AIC) integrates sensory and emotional dimensions of pain and represents a potential target for pharmacological modulation. Cannabidiol (CBD) exhibits analgesic and anxiolytic/antidepressant‑like properties through interactions with endocannabinoid and serotonergic systems. We investigated whether CBD microinjection into the AIC modulates NP and its affective comorbidities, and whether these effects depend on CB1 and 5‑HT1A receptors. Male Wistar rats were subjected to chronic constriction injury (CCI) of the sciatic nerve. Fourteen days later, guide cannulae were implanted into the AIC. On day 21 post‑CCI, animals received intra‑AIC microinjections of CBD (15, 30, or 60 nmol/200 nL) or vehicle. Mechanical (von Frey test) and cold (acetone test) allodynia, anxiety‑like behavior (open field and elevated plus maze tests), and depression‑like behavior (forced swim and sucrose spray tests) were assessed by different psychobiological tests. The role of cannabinoid and serotonergic receptors was addressed by intra‑AIC pretreatment with either the CB1 receptor antagonist AM251 or the 5‑HT1A receptor antagonist WAY-100,635 in independent groups. AIC pretreatment with CBD dose‑dependently reduced mechanical and cold allodynia and anxiety‑ and depression‑like behaviors, with the most robust effects observed at 60 nmol. AIC Pretreatment with either AM251 or WAY-100,635 abolished the antinociceptive and affective effects of CBD. CBD administration within the AIC produces integrated analgesic, anxiolytic, and antidepressant-like effects in a model of neuropathic pain. These effects are consistent with the involvement of CB1 and 5-HT1A receptor signaling. The findings identify the AIC as a relevant cortical substrate linking nociceptive and affective processes and support CBD as a promising psychopharmacological strategy for NP associated with emotional comorbidities.
<p>Introduction: Emotion regulation (ER) is essential for psychological functioning and daily life. Deficits in ER are associated with various psychiatric disorders and are important targets for therapeutic interventions. Self-compassion, the practice of responding to one's own suffering with kindness, has been proposed to support adaptive ER. This study examined changes during a 6-week psychiatric inpatient rehabilitation program to evaluate the effects of a mindfulness- and self-compassion-based intervention on ER. In a randomized controlled trial, 168 psychiatric inpatients were allocated to either a Mindful Self-Compassion (MSC) intervention group (n = 95) or an active control group receiving Progressive Muscle Relaxation (PMR; n = 73). Participants completed assessments at baseline and post-treatment, including the Self-Compassion Scale (SCS), the Emotion Regulation Questionnaire (ERQ), and the Positive and Negative Affect Schedule (PANAS). At post-treatment, the Reappraisal Inventiveness Test (RIT) was additionally administered. Data were analyzed using mixed-design ANOVAs and independent t tests. Both MSC and PMR groups showed significant increases in self-compassion, positive affect, and self-reported cognitive reappraisal. No significant changes were observed in expressive suppression, and no between-group differences were found for reappraisal inventiveness as measured by the RIT. Participation in either intervention was associated with enhanced use of cognitive reappraisal, suggesting that both MSC and PMR may foster adaptive ER in psychiatric rehabilitation. Further research is warranted to clarify the specific mechanisms and potential long-term benefits of mindful self-compassion interventions in clinical populations. </p>.
Autism spectrum disorder (ASD) lacks disease-modifying therapies. Gene therapy offers a promising avenue to target the underlying molecular causes of ASD, particularly in monogenic or syndromic forms where single-gene mutations play a central role. A scoping review was conducted following the PRISMA-ScR framework. We searched PubMed, Scopus, Web of Science, PsycINFO, and the Cochrane Library (2000-July 2025), with the last search completed in July 2025. Eligible studies included preclinical or translational investigations involving gene-therapy modalities (e.g., AAV vectors, ASOs, CRISPR-based editing) targeting high-confidence ASD-linked genes; non-gene-therapy studies, unrelated conditions, reviews, and non-English papers were excluded. Data were charted using a standardized extraction form and synthesized descriptively across two evidence streams. Stream 1 evaluated preclinical studies of gene therapy, while Stream 2 examined translational advances and ethical considerations. Twenty-one preclinical studies were identified in Stream 1, focusing on genes such as UBE3A, MECP2, FMR1, SHANK3/2, SCN2A, and SYNGAP1. Most demonstrated molecular correction and improvements in synaptic, electrophysiological, and behavioral outcomes, with therapeutic effects observed from early developmental to adult timepoints. Stream 2 synthesized 12 studies highlighting translational challenges, including delivery innovations (e.g., engineered viral capsids, nanoparticles), safety concerns (immune responses, dose-dependent toxicities), and ethical considerations (pediatric consent, neurodiversity perspectives, equity in access). Limitations include heterogeneity across models, reliance on rodent studies, and absence of completed human clinical trials. Gene therapy for ASD shows considerable promise but faces significant translational and ethical hurdles. Standardized study designs, comprehensive safety evaluation, and transparent stakeholder engagement will be critical for developing responsible and effective clinical applications.
Anhedonia and reward processing deficits are core features of Major Depressive Disorder (MDD). However, their persistence following remission remains unclear, hindering the differentiation between state versus trait characteristics. This study investigated clinically assessed anhedonia and reward-related learning in individuals with current MDD (MD), remitted MDD (RMD), and healthy controls (HC). We assessed 26 individuals with current MDD, 35 with RMD, and 37 HC. Anhedonia was measured using the Clinician-Administered Snaith-Hamilton Pleasure Scale (SHAPS-C-TR). Reward-related learning was evaluated using the Probabilistic Reward Task (PRT). Depressive and anxiety symptoms were also assessed. The MD group exhibited significantly higher anhedonia and greater depressive and anxiety symptoms compared to both RMD and HC groups. Crucially, anhedonia scores did not differ between the RMD and HC groups. While a significant learning effect on the PRT was observed across the entire sample, there were no significant differences in task performance among the three groups, even after controlling for covariates. Clinically assessed anhedonia appears to be a state-dependent symptom that normalizes with remission. In contrast, reward-related learning, assessed via the PRT, was not significantly impaired in either current or remitted depression. These findings suggest a potential dissociation between the experience of clinically assessed anhedonia and reward learning deficits in MDD.
Depression and pain share overlapping central neurobiological pathways that represent key pharmacological targets in neuropsychiatric and pain research. However, the neuropharmacological mechanisms by which unpredictable chronic stress (UCS) modulates nociception in translational vertebrate models remains poorly understood. Here, we characterized a zebrafish model of stress-induced sensitization to a visceral chemical challenge by exposing adult fish to a 7- or 14-day UCS protocol (UCS7/UCS14) followed by intraperitoneal acetic acid (AA) injection (1.0-5.0% v/v). In unstressed fish, AA at 1.0% remained subthreshold for inducing the characteristic writhing-like body curvature endpoint, whereas at 5.0% produced a robust response, hence validating the assay. In contrast, UCS exposure revealed a marked nociception-like response to AA 1.0%, reflected by increased body curvature index, indicating a lowered response threshold after chronic stress. Locomotor endpoints exhibited stress-dependent cross-over effects: AA at 1.0% decreased distance traveled in unstressed fish but increased locomotion and reduced immobility in UCS-exposed fish. Pharmacological validation (in UCS7) showed that morphine attenuated the UCS-sensitized body curvature response, whereas diclofenac did not, consistent with an opioidergic contribution to the nociception-like endpoint. Whole-body cortisol levels were elevated by UCS exposure (with or without AA 1.0%) and reduced by morphine in the UCS + AA condition, whereas diclofenac was inactive. Together, these findings establish a pharmacologically tractable adult zebrafish model of stress-induced sensitization with translational relevance for CNS-targeted analgesic discovery and mechanistic studies of stress-pain comorbidity.