Acute Neurobehavioral and Glial Responses to Explosion Gas Inhalation in Rats.

Military personnel, firefighters, and fire survivors exhibit a higher prevalence of mental health conditions such as depression and post-traumatic stress disorder (PTSD) compared to the general population. While numerous studies have examined the neurological impacts of physical trauma and psychological stress, research on acute neurobehavioral effects of gas inhalation from explosions or fires is limited. This study investigates the early-stage neurobehavioral and neuronal consequences of acute explosion gas inhalation in Sprague-Dawley rats. Rats were exposed to simulated explosive gas and subsequently assessed using behavioral tests and neurobiological analyses. The high-dose exposure group demonstrated significant depression-like behaviors, including reduced mobility and exploration. However, neuronal damage was not evident in histological analyses. Immunofluorescence revealed increased density of radial glia and oligodendrocytes in specific brain regions, suggesting hypoxia and axon damage induced by gas inhalation as a potential mechanism for the observed neurobehavioral changes. These findings underscore the acute impact of explosion gas inhalation on mental health, highlighting the habenula and dentate gyrus of hippocampus as the possible target regions. The findings are expected to support early diagnosis and treatment strategies for brain injuries caused by explosion gas, offering insights into early intervention for depression and PTSD in affected populations.

Prolonged exposure to the synthetic glucocorticoid dexamethasone induces brain damage via oxidative stress and apoptotic response in adult Daniorerio.

Due to its extensive use as a painkiller, anti-inflammatory, and immune modulatory agent, as well as its effectiveness in treating severe COVID-19, dexamethasone, a synthetic glucocorticoid, has gained attention not only for its impact on public health but also for its environmental implications. Various studies have reported its presence in aquatic environments, including urban waters, surface samples, sediments, drinking water, and wastewater effluents. However, limited information is available regarding its toxic effects on nontarget aquatic organisms. Therefore, this study aimed to investigate the mechanism of toxicity underlying dexamethasone-induced brain damage in the bioindicator Danio rerio following long-term exposure. Adult zebrafish were treated with environmentally relevant concentrations of dexamethasone (20, 40, and 60 ng L-1) for 28 days. To elucidate the possible mechanisms involved in the toxicity of the pharmaceutical compound, we conducted a behavioral test battery (Novel Tank and Light and Dark tests), oxidative stress biomarkers, acetylcholinesterase enzyme activity quantification, histopathological analysis, and gene expression analysis using qRT-PCR (p53, bcl-2, bax, caspase-3, nrf1, and nrf2).The results revealed that the pharmaceutical compound could produce anxiety-like symptoms, increase the oxidative-induced stress response, decrease the activity of acetylcholinesterase enzyme, and cause histopathological alterations, including perineuronal vacuolization, granular and molecular layers deterioration, cell swallowing and intracellular spaces. The expression of genes involved in the apoptotic process (p53, bax, and casp-3) and antioxidant defense (nrf1 and nrf2) was upregulated in response to oxidative damage, while the expression of the anti-apoptotic gene bcl-2 was down-regulated indicating that the environmental presence of dexamethasone may pose a threat to wildlife and human health.

Real-world smartphone data can trace the behavioural impact of epilepsy: A case study.

BACKGROUND: Neurobehavioural comorbidities have a detrimental effect on the quality of life of people with epilepsy, yet tracking their impact is challenging as behaviour may vary with seizures and anti-seizure medication (ASM) side effects. Smartphones have the potential to monitor day-to-day neurobehavioural patterns objectively. We present the case of a man in his late twenties with drug-resistant focal epilepsy in whom we ascertained the effects of ASM withdrawal and a convulsive seizure on his touchscreen interactions. METHODS: Using a dedicated app, we recorded over 185 days the timestamps of 718,357 interactions. We divided the various smartphone behaviours according to the next-interval dynamics of the interactions by using a joint interval distribution (JID). During two ASM load transitions, namely before versus during tapering and tapering versus restarting medication, we used cluster-based permutation tests to compare the JIDs. We also compared the JID of the seizure day to the average of the previous 3 days. RESULTS: The cluster-based permutation tests revealed significant differences, with accelerated next-interval dynamics during tapering and a reversal upon medication restart. The day of the convulsion exhibited a marked slowing of next-interval dynamics compared to the preceding 3 days. CONCLUSION: Our findings suggest that the temporal dynamics of smartphone touchscreen interactions may help monitor neurobehavioural comorbidities in neurological care.

Management of neurological symptoms in Lesch-Nyhan disease: A systematic review.

Lesch-Nyhan Disease (LND) is an X-linked recessive genetic disorder arising from hypoxanthine phosphoribosyltransferase 1 gene mutations, leading to a complete deficiency. LND presents a complex neurological profile characterized by generalized dystonia, motor dysfunctions and self-injurious behavior, which management is challenging. We conducted a systematic review of studies assessing the efficacy of pharmacological and non-pharmacological interventions in management of neurological symptoms in LND (PROSPERO registration number:CRD42023446513). Among 34 reviewed full-text papers; 22 studies were rated as having a high risk of bias. Considerable heterogeneity was found in studies regarding the timing of treatment implementation, adjunctive treatments and outcome assessment. Single-patient studies and clinical trials often showed contradictory results, while therapeutic failures were underreported. S-Adenosylmethionine and Deep Brain Stimulation were the most studied treatment methods and require further research to address inconsistencies. The evidence from levodopa studies underlines that optimal timing of treatment implementation should be thoroughly investigated. Standardized study design and reducing publication bias are crucial to overcome current limitations of assessing intervention efficacy in LND.

Sex-specific effects of alcohol on neurobehavioral performance and endoplasmic reticulum stress: an analysis using neuron-specific MANF deficient mice.

Excessive alcohol exposure can cause neurobehavioral deficits and structural alterations in the brain. Emerging research evidence suggests that endoplasmic reticulum (ER) stress plays an important role in alcohol-induced neurotoxicity. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress inducible protein and is responsible to maintain ER homeostasis. MANF is highly expressed in both the developing and mature brain. We have previously shown that MANF deficiency exacerbated alcohol induced neurodegeneration and ER stress in the developing brain. However, little is known regarding the role of MANF in alcohol induced neuronal damage in the adult brain. In this study, we used a neuron-specific MANF knockout (KO) mouse model to investigate the effect of MANF deficiency on acute binge alcohol exposure-induced neurobehavioral deficits and ER stress. Adult male and female MANF KO mice and littermate controls received daily alcohol gavage (5 g/kg) for 10 days and then subjected to a battery of neurobehavioral tests including rotarods, balance beam, DigiGait, open field, elevated plus maze, Barnes maze, and three-chamber sociability task. Female MANF KO animals were more susceptible to alcohol-induced body weight loss. Alcohol exposure did not affect motor function, however female but not male MANF KO mice exhibited an increased locomotor activity in open field test. Learning and memory was not significantly impaired, but it was altered by MANF deficiency in females while it was affected by alcohol treatment in males. Both alcohol-exposed male and female MANF KO mice displayed increased sociability. Alcohol induced the expression of ER chaperones GRP78 and GRP94 and altered the levels of several unfolded protein response (UPR) and neuroinflammation markers in MANF KO mice in a sex-specific manner. The expression of MANF interacting proteins neuroplastin, PDIA1, and PDIA6 was increased in MANF KO mice, and was further induced by alcohol. In conclusion, alcohol exposure and neuronal MANF deficiency interacted to alter neurobehavioral outcomes, ER homeostasis and neuroinflammation in a sex-specific manner.

Changes in higher order cognitive function between four watch keeping schedules.

Maritime industries utilize many different watch keeping schedules to maintain vigilance and crew safety around the clock. These schedules can be fatiguing, negatively impacting vigilant attention. This has led to the consideration of schedules that might allow for more sleep time, but how these schedules impact higher order cognitive function remains unclear. These schedules require assessment with tasks that are relevant to real-world operations on maritime vessels. This study investigated the effect of four schedules on higher order cognitive function. N = 27 (16 female) participants were recruited to a 10-day laboratory study, comparing four schedules. The schedules investigated were eight-on/eight-off/four-on/four-off (8/8/4/4) with sleep from 09:30 to 16:00 (condition A); six-on/six-off (6/6) with sleep from 08:30 to 12:30 and 21:30 to 00:00 (condition B); four-on/four-off (4/4/4/4/4/4) with sleep from 18:00 to 00:30 (condition C); and four-on/four-off (4/4/4/4/4/4) with sleep from 01:30 to 08:00 (condition D). Higher order cognitive function was assessed 2-3× daily whilst "on watch" using tests of visual scanning, learning, working memory, mental flexibility, and visuomotor control. Conditions were ranked and stability of performance on watch was compared between conditions using Kruskal-Wallis tests. Cognitive function within condition B was ranked the worst for most of the tasks. However, the stability of higher order cognitive function was poorest across the waking day within condition A. These findings highlight the variability in cognitive capacities during different watch keeping schedules.

Linear growth and neurobehavioural outcome in preterm neonates (<34 weeks) at term corrected gestational age: a prospective observational study.

The present study explores the association between linear growth and neurobehavioral outcome in preterm (<34 weeks) when evaluated by NAPI score (Neurobehavioral Assessment of Preterm Infants) at term gestational age (GA). 80 preterm neonates were enrolled for this study and divided into two groups based on the increase in length/week at term corrected gestational age (CGA). Anthropometric parameters were calculated at various time points of study and Z scores were calculated. Neurobehavioral assessment of the enrolled infants was done by NAPI score at 37 and 40 weeks of CGA. After controlling for GA, weight Z scores, and head circumference Z scores, the median score of NAPI-motor development-vigor at 37 weeks and NAPI alertness orientation at 40 weeks were positively related to length Z scores at 37 weeks (p = 0.04) and 40 weeks (p = 0.035), respectively. Neonates with suppressed linear growth have poor short-term neurological outcomes. We recommend linear growth monitoring along with weight gain in the developed countries and diminished linear growth in the neonate as a marker to predict deviation in cognitive outcome in the future.

Survey on diagnosis of post-brain injury "higher brain dysfunction" in patients with cognitive impairment. Family/caregiver response.

In Japan, the diagnostic criteria for the higher brain dysfunction (HBD) emerged in 2005 in response to social needs for support for the patients and their families. The issue of cognitive dysfunction after brain trauma is not unique to Japan. The purpose of this study was to reveal the current status of family members of HBD patients from their perspective, focusing on the changes before and after the establishment of diagnostic criteria in Japan. We conducted a questionnaire survey for family members supporting the HBD patients. The questionnaire included the causative condition, explanation on HBD by health professionals, and problems/difficulties they encountered. This research involved family members of 278 HBD cases (males = 211, age 49 years). The major underlying cause was head injury (n = 139). Compared to patients diagnosed pre-2005, a significantly larger proportion of family members after 2005 received information on the condition during the acute phase (within one month) (p < 0.001), including that from physicians (p < 0.001). Nearly half of the families cited a lack of awareness of HBD among the professionals as a problem. In Japan, awareness of HBD in the society is gradually increasing especially after the current diagnostic criteria were implemented, and there has been a steady increase over time in early diagnosis. Yet, there still remain those not appropriately diagnosed. To salvage those patients and the families left behind, we are suggesting several recommendations to further augment clinical practice and the healthcare systems in Japan.

Neurological and neurobehavioral effects of welders in Egypt exposed to manganese containing welding fumes.

PURPOSE: Welders are more likely to develop neurobehavioral disorders because of their exposure to neurotoxic metals such as manganese. This study aimed to measure the neurobehavioral performance of welders occupationally exposed to manganese at welding enterprises and its relationship with the workplace environment. METHODS: It is a comparative cross-sectional study carried out on 130 welders working at 50 welding enterprises in Menoufia governorate, Egypt, compared to 130 non-occupationally exposed controls. RESULTS: It was found that the environments of the studied welding enterprises had levels of respirable dust, manganese, and total welding fumes that exceeded internationally permissible limits. In addition, the mean blood manganese levels were significantly higher among welders (4.16 ± 0.61) than the controls (1.72 ± 0.41). Welders had a significantly higher prevalence of neurological manifestations and lower performance of neurobehavioral tests. Lower neurobehavioral performance among welders was significantly correlated with increased work duration and blood levels in some tests. CONCLUSION: To lessen the fumes in the breathing zone of workers, it is therefore strongly recommended to regularly wear high-quality personal protective equipment, especially masks, and to ensure proper ventilation.

Contextual fear conditioning in zebrafish: Influence of different shock frequencies, context, and pharmacological modulation on behavior.

Contextual fear conditioning is a protocol used to assess associative learning across species, including fish. Here, our goal was to expand the analysis of behavioral parameters that may reflect aversive behaviors in a contextual fear conditioning protocol using adult zebrafish (Danio rerio) and to verify how such parameters can be modulated. First, we analyzed the influence of an aversive stimulus (3 mild electric shocks for 5 s each at frequencies of 10, 100 or 1000 Hz) on fish behavior, and their ability to elicit fear responses in the absence of shock during a test session. To confirm whether the aversive responses are context-dependent, behaviors were also measured in a different experimental environment in a test session. Furthermore, we investigated the effects of dizocilpine (MK-801, 2 mg/kg, i.p.) on fear-related responses. Zebrafish showed significant changes in baseline activity immediately after shock exposure in the training session, in which 100 Hz induced robust contextual fear responses during the test session. Importantly, when introduced to a different environment, animals exposed to the aversive stimulus did not show any differences in locomotion and immobility-related parameters. MK-801 administered after the training session reduced fear responses during the test, indicating that glutamate NMDA-receptors play a key role in the consolidation of contextual fear-related memory in zebrafish. In conclusion, by further exploring fear-related behaviors in a contextual fear conditioning task, we show the effects of different shock frequencies and confirm the importance of context on aversive responses for associative learning in zebrafish. Additionally, our data support the use of zebrafish in contextual fear conditioning tasks, as well as for advancing pharmacological studies related to associative learning in translational neurobehavioral research.

Validation of the ND-PAE Diagnosis in Children with Heavy Prenatal Alcohol Exposure.

This study evaluated criteria for neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE). Kable et al. (Child Psychiatry Hum Dev 55:426, 2022) assessed the validity of this diagnosis in a sample with low exposure to alcohol. The current study expanded this assessment to a sample with a wider age range and heavier alcohol exposure. Data were collected from participants (5-17 years) with prenatal alcohol exposure (PAE) and typically developing controls at six Collaborative Initiative on Fetal Alcohol Spectrum Disorders sites using neuropsychological assessment and caregiver reports. Impairment was tested at 1SD, 1.5SD, and 2SD below the normative average and a modification of the adaptive functioning requirement was tested. Testing impairment at 1SD resulted in the highest endorsement rates in both groups. Our findings replicated the study by Kable et al. and show that current criteria captured a high rate of those with PAE and that requiring fewer adaptive functioning criteria resulted in higher sensitivity to PAE.

Does perceived caregiver HIV stigma and depression increase adolescent neuro-behavioral difficulties? A mediation analysis in the Asenze Cohort.

People living with HIV (PLWH) often experience HIV related stigma that is, in turn, associated with several negative health outcomes including depression, harmful drinking, and intimate partner violence. Despite knowledge of these proximal impacts of HIV stigma on PLWH, less is known about the impact that Caregivers living with HIV's perception of stigma has on the health and behavior of adolescents in their care. Utilizing data from adolescents and their primary caregivers from the population-based Asenze cohort study in KwaZulu-Natal, South Africa, we conducted a path analysis to determine if caregiver depression [operationalized as mental health functioning] is a mediator of the hypothesized association between caregiver HIV stigma and adolescent neurodevelopmental behavior including internalizing and externalizing behaviors. Results suggest good model fit and a statistically significant relationship between caregiver HIV stigma and caregiver mental health functioning. However, neither the direct nor indirect (including potential mediator caregiver mental health functioning) effect of HIV stigma on adolescent behavioral difficulties was statistically significant. This paper builds on previous research demonstrating the relationship between HIV stigma and depression, highlighting the need for continued study of underlying mechanisms that impact the stigma and health of PLWH and others important to them such as their children.

Characterizing Neurobehavioral Dysregulation Among Former American Football Players: Findings From the DIAGNOSE CTE Research Project.

OBJECTIVE: Neurobehavioral dysregulation (NBD), a core clinical feature of traumatic encephalopathy syndrome, encompasses neuropsychiatric symptoms reported among individuals with a history of repetitive head impact exposure, including contact sport athletes. The objective of this study was to examine the construct and subconstructs of NBD through a series of factor and cluster analyses. METHODS: Six clinician-scientists selected self-report questionnaire items relevant to NBD from seven available neuropsychiatric scales through a blinded voting process. These items were subjected to confirmatory factor analyses in a sample of 178 former college and professional American football players and 60 asymptomatic individuals without a history of repetitive head impact exposure. All participants were enrolled in the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Factor scores were generated on the basis of the optimal expert-informed model for NBD. Construct validity was assessed with neuropsychiatric scales not included in generation of the factor scores. Cluster analyses with NBD factor scores were used to examine symptom profiles. RESULTS: Factor analyses confirmed that NBD was composed of four subconstructs: explosivity, emotional dyscontrol, impulsivity, and affective lability. Cluster analyses indicated four distinct symptom profiles of NBD in this group of former football players: asymptomatic (N=80, 45%), short fuse (N=33, 19%), high affective lability (N=34, 19%), and high NBD (N=31, 17%). CONCLUSIONS: These findings characterize NBD as a multifaceted clinical construct with a heterogeneous presentation, providing a foundation for empirical work on the diagnostic criteria for traumatic encephalopathy syndrome and research on the neurobiological underpinnings of NBD.

Linalool-rich rosewood essential oil (Aniba rosaeodora Ducke) mitigates emotional and neurochemical impairments induced by ethanol binge-like exposure during adolescence in female rats.

Linalool-rich Rosewood oil (Aniba rosaeodora Ducke) is a natural compound widely used in perfumery industry. Evidence suggests that linalool exerts antidepressant and anxiolytic effects. Conversely, ethanol binge drinking (i.e., intermittent and episodic consumption) during adolescence elicits neurobehavioral alterations associated with brain damage. Here, we investigated whether linalool-rich Rosewood oil administration can improve the emotional and molecular impairments associated with ethanol binge-like exposure during adolescence in female rats. Rosewood oil was obtained by hydrodistillation and posteriorly analyzed. Adolescent female Wistar rats received four-cycles of ethanol binge-like pattern (3 g/kg/day, 3 days on/4 days off) and daily Rosewood oil (35 mg/kg, intranasally) for 28 days. Twenty-four hours after treatments, it was evaluated the impact of ethanol exposure and Rosewood oil treatment on the putative emotional impairments assessed on the splash and forced swimming tests, as well as the levels of brain-derived neurotrophic factor (BDNF), S100B, oxidative parameters, and inflammatory cytokines in prefrontal cortex and hippocampus. Results indicated that Rosewood oil intranasal administration mitigated emotional impairments induced by ethanol exposure accompanied by a marked increase in BDNF, S100B, glutathione (GSH), and antioxidant activity equivalent to Trolox (TEAC) levels in brain areas. Rosewood oil treatment also prevented the ethanol-induced increase of interleukin-1ß, interleukin-6, tumor necrosis factor α (TNF-α), and neurofilament light chain (NFL) levels. These findings provide the first evidence that Rosewood oil intranasal administration exerts protective effects against emotional and molecular impairments associated with adolescent ethanol binge-like exposure, possibly due to linalool actions triggering neurotrophic factors, rebalancing antioxidant status, and attenuating proinflammatory process.

Pioglitazone ameliorates sepsis-associated encephalopathy through SIRT1 signaling pathway.

Sepsis is a severe immune response to an infection. It is associated with multiple organ dysfunction syndrome (MODs) along with systemic and neuronal inflammatory response. This study focused on the acute neurologic dysfunction associated with sepsis by exploring the role of PPARγ/SIRT1 pathway against sepsis. We studied the role of this axis in ameliorating sepsis-associated encephalopathy (SAE) and its linked neurobehavioral disorders by using pioglitazone (PIO). This PPARγ agonist showed neuroprotective actions in neuroinflammatory disorders. Sepsis was induced in mice by LPS (10 mg/kg). Survival rate and MODs were assessed. Furthermore, behavioral deficits, cerebral oxidative, inflammatory, and apoptotic markers, and the cerebral expression level of SIRT1 were determined. In this study, we observed that PIO attenuated sepsis-induced cerebral injury. PIO significantly enhanced survival rate, attenuated MODs, and systemic inflammatory response in septic mice. PIO also promoted cerebral SIRT1 expression and reduced cerebral activation of microglia, oxidative stress, HMGB, iNOS, NLRP3 and caspase-3 along with an obvious improvement in behavioral deficits and cerebral pathological damage induced by LPS. Most of the neuroprotective effects of PIO were abolished by EX-527, a SIRT1 inhibitor. These results highlight that the neuroprotective effect of PIO in SAE is mainly SIRT1-dependent.

Exposure to polystyrene microplastics reduces sociality and brain oxytocin levels through the gut-brain axis in mice.

The rising global prevalence of microplastics (MPs) has highlighted their diverse toxicological effects. The oxytocin (OT) system in mammals, deeply intertwined with social behaviors, is recognized to be vulnerable to environmental stressors. We hypothesized that MP exposure might disrupt this system, a topic not extensively studied. We investigated the effects of MPs on behavioral neuroendocrinology via the gut-brain axis by exposing adolescent male C57BL/6 mice to varied sizes (5 µm and 50 µm) and concentrations (100 µg/L and 1000 µg/L) of polystyrene MPs over 10 weeks. The results demonstrated that exposure to 50 µm MPs significantly reduced colonic mucin production and induced substantial alterations in gut microbiota. Notably, the 50 µm-100 µg/L group showed a significant reduction in OT content within the medial prefrontal cortex and associated deficits in sociality, along with damage to the blood-brain barrier. Importantly, blocking the vagal pathway ameliorated these behavioral impairments, emphasizing the pivotal role of the gut-brain axis in mediating neurobehavioral outcomes. Our findings confirm the toxicity of MPs on sociality and the corresponding neuroendocrine systems, shedding light on the potential hazards and adverse effects of environmental MPs exposure on social behavior and neuroendocrine frameworks in social mammals, including humans.

Occupational exposure to pesticides and neurobehavioral outcomes. Impact of different original and recalled exposure measures on the associations.

BACKGROUND: Several measures of occupational exposure to pesticides have been used to study associations between exposure to pesticides and neurobehavioral outcomes. This study assessed the impact of different exposure measures for glyphosate and mancozeb on the association with neurobehavioral outcomes based on original and recalled self-reported data with 246 smallholder farmers in Uganda. METHODS: The association between the 6 exposure measures and 6 selected neurobehavioral test scores was investigated using linear multivariable regression models. Exposure measures included original exposure measures for the previous year in 2017: (i) application status (yes/no), (ii) number of application days, (iii) average exposure-intensity scores (EIS) of an application and (iv) number of EIS-weighted application days. Two additional measures were collected in 2019: (v) recalled application status and (vi) recalled EIS for the respective periods in 2017. RESULTS: Recalled applicator status and EIS were between 1.2 and 1.4 times more frequent and higher for both pesticides than the original application status and EIS. Adverse associations between the different original measures of exposure to glyphosate and 4 neurobehavioral tests were observed. Glyphosate exposure based on recalled information and all mancozeb exposure measures were not associated with the neurobehavioral outcomes. CONCLUSIONS: The relation between the different original self-reported glyphosate exposure measures and neurobehavioral test scores appeared to be robust. When based on recalled exposure measures, associations observed with the original exposure measures were no longer present. Therefore, future epidemiological studies on self-reported exposure should critically evaluate the potential bias towards the null in observed exposure-response associations.

Methylmercury exposure at dosage conditions that do not affect growth can impair memory in adolescent mice.

Methylmercury is an environmental pollutant that can induce serious central nervous system damage. Its ubiquitous presence in the environment in trace amounts has raised concerns about potential adverse effects on human health. Although many studies have evaluated the effects of methylmercury on neural development in fetal and neonatal mice, there has been less focus on studies using adolescent mice. Therefore, in this study, the effects of methylmercury on brain neurodevelopment and maturation were evaluated by various neurobehavioral trials using adolescent mice exposed to 30 ppm methylmercuric chloride (approximately 24 ppm methylmercury) for up to 8 weeks. Under these administration conditions, weight gain in adolescent mice was unaffected by methylmercury exposure. Furthermore, methylmercury exposure in adolescent mice had no effect on sociability as assessed by the social interaction test, impulsivity as assessed by the cliff avoidance reaction test, depressive behavior as assessed by the tail-suspension test, or locomotor activity as assessed using the Supermex system. In contrast, short-term memory assessed by the Y-maze test, as well as long-term memory assessed by novel object recognition and passive avoidance tests, revealed impairments induced by methylmercury exposure in adolescent mice. These results suggest that long-term exposure to methylmercury during adolescence potentially impairs memory function, and the nervous pathway of brain areas involved in learning and memory are particularly vulnerable to the adverse effects of methylmercury. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-024-00239-y.

Role of FMRP in AKT/mTOR pathway-mediated hippocampal autophagy in fragile X syndrome.

Fragile X syndrome (FXS) is caused by epigenetic silencing of the Fmr1 gene, leading to the deletion of the coding protein FMRP. FXS induces abnormal hippocampal autophagy and mTOR overactivation. However, it remains unclear whether FMRP regulates hippocampal autophagy through the AKT/mTOR pathway, which influences the neural behavior of FXS. Our study revealed that FMRP deficiency increased the protein levels of p-ULK-1 and p62 and decreased LC3II/LC3I level in Fmr1 knockout (KO) mice. The mouse hippocampal neuronal cell line HT22 with knockdown of Fmr1 by lentivirus showed that the protein levels of p-ULK-1 and p62 were increased, whereas LC3II/LC3I was unchanged. Further observations revealed that FMRP deficiency obstructed autophagic flow in HT22 cells. Therefore, FMRP deficiency inhibited autophagy in the mouse hippocampus and HT22 cells. Moreover, FMRP deficiency increased reactive oxygen species (ROS) level, decreased the co-localization between the mitochondrial outer membrane proteins TOM20 and LC3 in HT22 cells, and caused a decrease in the mitochondrial autophagy protein PINK1 in HT22 cells and Fmr1 KO mice, indicating that FMRP deficiency caused mitochondrial autophagy disorder in HT22 cells and Fmr1 KO mice. To explore the mechanism by which FMRP deficiency inhibits autophagy, we examined the AKT/mTOR signaling pathway in the hippocampus of Fmr1 KO mice, found that FMRP deficiency caused overactivation of the AKT/mTOR pathway. Rapamycin-mediated mTOR inhibition activated and enhanced mitochondrial autophagy. Finally, we examined whether rapamycin affected the neurobehavior of Fmr1 KO mice. The Fmr1 KO mice exhibited stereotypical behavior, impaired social ability, and learning and memory impairment, while rapamycin treatment improved behavioral disorders in Fmr1 KO mice. Thus, our study revealed the molecular mechanism by which FMRP regulates autophagy function, clarifying the role of hippocampal neuron mitochondrial autophagy in the pathogenesis of FXS, and providing novel insights into potential therapeutic targets of FXS.