Brain and neuroscience advances最新文献

As a gatekeeper of antioxidant and anti-inflammatory cell protection, the transcription factor Nrf2 is a promising therapeutic target for several neurodegenerative diseases, leading to the development of Nrf2 activators targeting Keap1-dependent and independent regulatory mechanisms. Astrocytes play a crucial role in regulating neuronal physiology in health and disease, including Nrf2 neuroprotective responses. As neurons require specific conditions for their differentiation and maintenance, most 2D and 3D co-culture systems use medias that are compatible with neuronal differentiation and function, but also ensure astrocyte survival. Few studies, however, assess the molecular adaptations of astrocytes to changes from astrocyte maintenance medias alone, and their subsequent effects on neurons which may represent technical rather than physiological responses. Our findings show that while Nrf2 can be effectively activated by the Keap1-Nrf2 protein-protein interaction disruptor 18e, and classical Nrf2 activators dimethylfumarate and CDDO-Me, in human primary cortical astrocyte monocultures, their efficacy is lost in LUHMES neuron-astrocyte co-cultures. Further investigation revealed that the Advanced DMEM/F12-based LUHMES differentiation media maximally induced basal Nrf2 activity in astrocytes alone, compared to astrocyte maintenance media, thus preventing pharmacological activation. Although Neurobasal slightly activated basal Nrf2, this was not significant and did not prevent further activation by dimethylfumarate, suggesting that this media has less impact on astrocytic Nrf2 activity relative to Advanced DMEM/F12. As Nrf2 is a key regulator of oxidative damage and neuroinflammation, modelling these common features of neurodegenerative diseases may be confounded by environments that maximally activate basal Nrf2. Our findings thus suggest caution in media selection for neuron-astrocyte co-culture in disease modelling and therapeutic Nrf2 activator discovery, and suggest use of Neurobasal over Advanced DMEM/F12 medias for this purpose.

Understanding the neurocognitive impact of digital integration in education is essential, particularly in sub-Saharan Africa, where socio-economic and geographical disparities amplify the need for effective learning strategies. This study investigated how visuospatial working memory performance is affected by the modality of task presentation (screen versus print) and geographical context (urban, economically advantaged region versus rural, economically disadvantaged region) in Ivorian primary school students. We employed a behavioural approach with 222 students (aged 4-13). Students from urban (Abidjan) and rural (Man) schools were assigned to perform a visuospatial working memory task presented either on a computer screen or using printed physical materials. An analysis of covariance, with age as a covariate, revealed that students performing the task on-screen showed significantly better performance (fewer errors) compared to those using printed materials (p < 0.001). A significant interaction between presentation modality and geographical context was also found (p = 0.009). Specifically, the performance difference between screen and print modalities was larger in the urban setting, primarily due to urban students performing more poorly with printed materials compared to rural students in that same condition; rural students using printed materials outperformed urban students using printed materials (post hoc, p = 0.002). No significant difference in performance on screen-based tasks was found between urban and rural students. The main effect of geographical context was not significant. These findings suggest potential cognitive benefits of screen-based presentation but highlight a complex interplay with geographical context, which itself is intertwined with socio-economic factors and initial age differences that were statistically controlled. Future research should further incorporate direct socio-economic status controls and explore factors like motivation and task engagement, alongside neuroimaging approaches, to elucidate the underlying mechanisms.

Huddling, a tactile, thermoregulatory and affiliative social interaction, is a predominant and conserved behaviour for mammalian and bird species. Huddling is particularly important in early life, when thermoregulation, touch and bonding are influential for survival, brain and behavioural development. Our study aims to understand how tactile, vocal and kinship dynamics develop in rat pups. We designed a huddling apparatus where we synchronise huddle formation with ultrasonic vocalisations (USVs). With development, we see that groups (P6-8 vs older pups) stay longer in triad aggregon (pup huddle) configurations in the huddle trial period. Older pups (P18-20) switch huddle states more often; in all ages, join transitions were preferred to breaking. The spectral characteristics of rat pup USVs change in development, with higher peak frequency in P18-20 pups. In all age-groups, we observe vocal quieting as aggregons form. We hypothesised that kinship is a determinant of huddling dynamics but findings reveal otherwise. When comparing kin versus non-kin groups, we found no differences in aggregon durations or switches. In the youngest age (P6-8), USVs were reduced in kin versus non-kin groups, though not in older pups. To address the role of social touch in quieting, we integrated dividers in the huddle arena. Without skin/fur contact, USVs increased in P6-8, P11-14, but not in P18-20 kin groups. We suggest that rat pups have a strong internal drive towards huddling regardless of whether partners are related by kinship. USV analysis suggests that huddling has a calming effect, where related sibling young pups show less USVs overall; absence of social touch is associated with increased vocalisation in young huddle groups. Thus, huddling is a natural social behaviour shared between both related siblings and unrelated conspecifics. Huddling has calming effects-indicated by USVs-that depend on kinship and tactile social contact during the early stages of development.

Win-paired cues drive maladaptive decision-making in laboratory-based gambling tasks. However, humans prefer these cued games that facilitate gambling addiction. Whether rats prefer tasks that employ win-paired cues is unknown, yet this has consequences for the validity of using rodent models to investigate problem gambling. Here, we allowed rats to choose on a trial-by-trial basis whether to work for cued or uncued rewards on the rat gambling task. We also performed computational modelling to investigate individual differences in decision-making strategies. Rats could be grouped based on preference for task type, which became more pronounced across training, or preference for risky options, as is standard for the rat gambling task. Risk-preferring rats increasingly preferred the cued task over time. Decision-making was marginally riskier on cued trials, particularly in risk-preferring rats, but this was independent of task preference. Pairing of rewards with audiovisual cues accelerated response times and enhanced impulsivity in both cue- and risk-preferring rats. Cued wins also resulted in greater post-reinforcement pauses in risk-preferring animals only. Diffusion model analyses revealed optimal decision-makers have longer non-decision times before risky or impulsive choices, yet this is absent in risk-preferring animals. As such, lapses in cognitive control could be responsible for maladaptive trial outcomes in optimal, but not risk-preferring, rats. Collectively, these data support the use of high-risk preference at baseline as a proxy for vulnerability to problem gambling. Furthermore, diverse computational mechanisms could be responsible for the negative impact of win-paired cues on gambling-like behaviour in at-risk versus resilient individuals.

Protease-activated receptor 2 is proposed to be a novel target for several inflammation-related diseases but its role in the central nervous system remains unclear. Protease-activated receptor 2 activation is protective in cell death and excitotoxicity assays whereas examination into the role of protease-activated receptor 2 in vivo has been hindered due to the lack of suitable pharmacological tools. Recently, a small molecule protease-activated receptor 2 activator, AC264613 (AC), was reported to be a potent and selective protease-activated receptor 2 activator that crosses the blood-brain barrier. Furthermore, peptide mimetic molecules, for example GB88, were developed that were reported to act as protease-activated receptor 2 biased antagonists. Here, we examine their signalling pathways and neuroprotective properties in central nervous system preparations. AC induced significant increases in intracellular Ca²⁺ in both neurons and astrocytes of primary hippocampal cultures, whereas in contrast, GB88 induced a small but significant reduction in intracellular Ca²⁺ in both cell types. However, both AC and GB88 induced receptor internalisation when examined using fluorescently tagged protease-activated receptor 2. Both AC and GB88 did not induce neurotoxicity in organotypic hippocampal slice cultures when applied alone but reduced neurotoxicity when co-applied with kainate in excitotoxicity assays. Furthermore, both AC and GB88 reduced neurotoxicity when applied post kainate insult indicating they exhibit neuroprotective properties even after excitotoxicity is induced. These data indicate that protease-activated receptor 2 activation is neuroprotective but this is independent of Gq-induced Ca²⁺ activation. Given that AC crosses the blood-brain barrier, this highlights its use as a novel tool to examine the protective properties of protease-activated receptor 2 in in vivo models of central nervous system disorders.

Depression is associated with inflammation in the periphery and the central nervous system. People with HIV are at greater risk for depression, which may in part be driven by sustained neuroinflammation, although individuals with severe depression are often excluded from studies of HIV-related co-morbidities. In this exploratory study, we aimed to explore the neuroimaging signatures of severe and persistent depression among people with HIV. We enrolled N = 20 adults with HIV in Brighton, UK, of whom n = 11 had a Patient Health Questionnaire-9 (PHQ-9) score ⩾15 and a history of receiving antidepressant medication. We used diffusion-weighted magnetic resonance spectroscopy (DW-MRS), an emerging neuroimaging technique sensitive to neuroinflammation, to assess neurometabolite diffusion in the anterior cingulate cortex. Participants also underwent standard magnetic resonance spectroscopy (MRS) to assess neurometabolite concentrations in the anterior cingulate cortex, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to assess blood-brain barrier permeability in the whole brain and the thalamus. We observed a significant positive correlation between intracellular diffusion of creatine and depressive symptom severity (ρ = 0.46, p = 0.047). Increased creatine diffusion has previously been reported in conditions characterised by hypermetabolism and neuroinflammation, suggesting that worse depressive symptom severity in people with HIV may be correlated with neuroimmunometabolic alterations. Metabolite concentrations and blood-brain barrier permeability largely did not correlate with depressive symptom severity in this sample. In summary, we explored neuroimaging signatures of severe depression in people with HIV, including by applying diffusion-weighted magnetic resonance spectroscopy in this population. We report early evidence that worse depressive symptom severity in people with HIV may be correlated with neuroimmunometabolic dysfunction, evidenced by increased diffusion of creatine, likely reflecting hypermetabolism and neuroinflammation. Future research may aim to replicate these findings in larger and more diverse samples and compare the diffusion of neurometabolites between people with and without HIV living with severe depression.

There has been significant discussion in recent years whether the increase in cortisol release that accompanies waking is dependent on the waking process itself or instead reflects a continuation of an underlying circadian rhythm. Establishing the origin or indeed existence of the so-called cortisol awakening response is important as disturbances in post-awakening cortisol secretion are associated with a range of stress-related disorders. The study reviewed in this article adopted an innovative in vivo microdialysis approach to measure tissue-free cortisol levels in 201 healthy volunteers before and after awakening in a home setting (Klaas et al., 2025). Rather surprisingly, the rate of increase in cortisol secretion did not change when participants awoke compared with the preceding hour when participants were asleep. However, considerable between-subject variability was observed, which was partly explained by sleep duration and the timing of waking relative to the previous morning. These findings highlight the complexity of the cortisol awakening response and summon caution in the interpretation of cortisol measurements based solely on post-awakening responses.