Thalamofrontal (TF) dysconnectivity is one of the most consistent circuit-level abnormalities reported in patients with schizophrenia and is linked to deficits in short-term memory (STM). However, the biological mechanisms underlying TF weakening remain unclear. Here, we show that repeated adolescent N-methyl-d-aspartate receptor (NMDAR) antagonism produces STM deficits by impairing TF synaptic transmission. In mice repeatedly exposed to ketamine, STM impairment coincided with reduced release probability and attenuated short-term depression at mediodorsal thalamus (MD) → dorsomedial prefrontal cortex (dmPFC) synapses, without detectable changes in corticocortical synaptic release probability, intrinsic excitability, or gross synaptic ultrastructure. These presynaptic deficits were accompanied by diminished direction-selective population coding in the dmPFC and impaired delayed alternation performance. Chemogenetically strengthening MD → dmPFC projections restored both neural selectivity and behavior. These findings identify a projection-specific presynaptic mechanism through which adolescent NMDAR hypofunction weakens TF communication and produces cognitive impairment, offering a biological explanation for clinically observed TF dysconnectivity and establishing TF synapses as a therapeutic target.

Early-life enteric infection disrupts the developing microbiota-gut-brain (MGB) axis. Using a neonatal Enteropathogenic Escherichia coli (EPEC) model, we show that intestinal epithelial cell (IEC) nucleotide oligomerization domain (NOD)1 signaling coordinates neuroimmune outcomes throughout early development and into adulthood. Neonatal mice infected at postnatal day (P)7 exhibited ileal inflammation, with increased pro-inflammatory cytokines and monocyte/macrophage infiltration, and loss of myenteric neurons in wild-type mice but not in NOD1 conditional knockout (Nod1ΔIEC) mice. These deficits persisted into adulthood (P56), with increased intestinal permeability, sustained inflammatory/repair signatures, neuroinflammation, altered neurogenesis, and impaired recognition memory, which were absent in Nod1ΔIEC mice, establishing a crucial role for IEC NOD1 in long-term MGB remodeling. Last, bioactive peptidoglycan fragments (muropeptides) were isolated from probiotic Lactobacillus strains and tested as possible therapeutics. Excitingly, supplementation of muropeptides attenuated neonatal EPEC-induced mucosal inflammation and enteric neuron loss without altering bacterial burden, potentially via IEC NOD2. Together, these findings identify IEC NOD-dependent signaling linking early-life enteric infection to enduring gut-brain dysfunction and reveal probiotic-derived muropeptides as candidate therapeutics.

KBG syndrome is a genetic syndrome characterized by developmental delay, mild autism spectrum disorder (ASD), variable cognitive disorders and distinctive craniofacial and skeletal features. Posterior fossa arachnoid cysts (PFACs) have been reported in this condition as in other syndromic forms of ASD, but their impact remains uncertain. Here, we report a ten-year follow-up of a patient with KBG syndrome and PFAC shunted for progressive cyst enlargement and his clinical symptoms, who showed important cognitive and behavior improvement post-drainage. Preoperative neuropsychological assessment revealed severe ASD, heterogeneous cognitive profile with below-average IQ (82, average ≥90), slow processing speed (66, cut-off <70), prominent executive function and memory impairments but normal verbal index and working memory. Whole-brain arterial spin labelling MRI showed a markedly reduced cerebral blood flow in the left superior temporal sulcus (STS), a key region for social cognition. Eighteen-month post cystoperitoneal shunt, cyst volume had decreased (34 vs 10 mL), STS perfusion was no longer different from controls and high cognitive improvements were observed (IQ: +1SD, verbal index: +2SD, executive functions planning and flexibility: +3SD, emotional regulation: +1SD, verbal memory: +3SD). At 22 years, autistic traits had decreased, cognitive gains persisted and executive functions progressed again. Visual-motor processing speed, theory of mind and fine motor skills remained low. Resting-state functional MRI seeded from STS showed strengthened temporal connectivity and diffusion imaging revealed increased fibre density in the left temporal lobe. The parallel trajectories of behavioural and neuroimaging improvements may suggest that PFAC surgery could have enabled functional reorganisation within temporal networks in addition to therapeutic interventions, supporting improved cognitive and social outcomes. These results suggest a possible role of the posterior fossa in modulating neurodevelopmental outcomes in ASD-related genetic conditions.

Obesity and metabolic syndrome are associated with low-grade systemic inflammation and neuroinflammation, potentially contributing to structural brain alterations and cognitive decline. This study evaluated brain volumetry, metabolic disturbances, neuroinflammation markers, and behavioral outcomes in a rat model of diet-induced obesity. Male Wistar rats were fed either a standard diet (CTRL; n = 6) or a cafeteria diet (CAF; n = 6) for five months from weaning. Metabolic parameters (weight, glucose tolerance, blood pressure, lipids), behavior (Open Field, Novel Object Recognition), and brain regional volumes (4.7 T MRI) were assessed. Neuroinflammatory markers (tumor necrosis factor-α levels (TNF-α) and glial fibrillary acidic protein (GFAP)) were quantified in the hypothalamus and olfactory bulb. CAF rats developed a metabolic syndrome-like phenotype characterized by abdominal adiposity, insulin resistance, hypertension, and dyslipidemia (p < 0.05). They also showed higher hypothalamic GFAP and TNF-α levels, higher relative orbitofrontal cortex volume (p < 0.05) than controls, whereas lower relative hypothalamic and corpus callosum volumes did not reach significance. Behaviorally, CAF rats exhibited reduced locomotor activity, impaired short-term memory, and higher grooming activity (p < 0.05). Multivariate modeling identified hypothalamic neuroinflammation, severity of continuous metabolic syndrome z-score, and reduced corpus callosum volume as key predictors of cognitive and behavioral impairments. Long-term consumption of a CAF diet induces key features of human metabolic syndrome, hypothalamic neuroinflammation, region-specific brain volumetric alterations, and cognitive deficits. These findings support a role for the metabolic-inflammatory axis in brain vulnerability and suggest that preservation of neuroimmune homeostasis may be important for maintaining cognitive health in obesity-associated metabolic disorders.

This essay explores the role of visual images in dream imagery as a space where unconscious processes intersect with historical forces. It offers a comparative reading in Freud's Interpretation of Dreams (1900) and Benjamin's Arcades Project (1982). Freud conceptualizes dream images as condensed memory traces that navigate between perception and hallucination, revealing repressed desires. Conversely, Benjamin's dream images critique modernity's loss of aura, offering moments of "Now-Time" as opportunities for historical creation. The essay argues that both Freud and Benjamin share a foundational premise: turning a blind eye to the obscure and unknown dimensions of individual and collective experience fosters crises and destruction, whereas striving to reveal these hidden areas promotes transformation. Exploring disruptions and ruptures in the continuity of experience challenges the inclination to act according to Freud's concept of repetition compulsion or Nietzsche's eternal return, as interpreted by Benjamin. These ideas are explored through the dream of the burning child presented by Freud and the ghost dream presented by Benjamin. The dialectic of insight and blindness, alongside the image of open doors in both dreams, invite us to consider how, even amidst loss and rupture, dream images can open pathways to new realms of experiencing and remembering.

Sleep disturbances are associated with poor long-term memory (LTM) formation, yet the underlying cell types and neural circuits involved have not been fully decoded. Dopamine neurons (DANs) are involved in memory processing at multiple stages. Here, using both male and female flies, Drosophila melanogaster, we show that, during the first few hours of memory consolidation, disruption of basal activity of a small subset of protocerebral anterior medial DANs (PAM-DANs), by either brief activation or inhibition of the two dorsal posterior medial (DPM) neurons, impairs 24 hr LTM. Interestingly, these brief changes in activity using female flies result in sleep loss and fragmentation, especially at night. Importantly, pharmacological rescue of sleep after manipulation restores LTM. A specific subset of PAM-DANs (PAM-α1) that synapse onto DPM neurons specify the microcircuit that links sleep and memory. MBON-α1 also contributes to the integration of sleep and memory by acting as an additional parallel circuit. PAM-DANs, including PAM-α1, form functional synapses onto DPM mainly via two dopamine receptor subtypes. Dop1R1 primarily mediates the link between sleep and memory. This PAM-α1 to DPM microcircuit exhibits a synchronized, transient, post-training change in activity during the critical memory consolidation window, suggesting an effect of this microcircuit on maintaining the sleep necessary for LTM consolidation. Our results provide a new molecular and circuit basis for the complex relationship between sleep and memory.

Surface ozone (O3) induces chronic oxidative stress and lipid peroxidation in the brain, increasing the risk of neurodegenerative disease. Lipid metabolic coupling between neurons and astrocytes is vital for brain health. However, its response to O3-induced oxidative stress remains largely unexplored. In this study, subacute O3 exposure (0.5 or 1.5 ppm, 4 h/day, for 28 days) resulted in learning and memory impairments, accompanied by neuronal loss, glial cell activation, neuroinflammation, and lipid peroxidation in mice. An important outcome of exposure to reactive oxygen species (ROS) generated by O3 is the buildup of lipid droplets in the astrocytes. Interestingly, in neurons, O3 exposure activates c-Jun N-terminal kinase and sterol regulatory element-binding protein, promoting lipogenesis. As cells attempt to cope with this stress, O3 interferes with the liver X receptor/apolipoprotein E/ATP-binding cassette transporter A1 pathway in astrocytes, reducing the efficiency of lipid transport from neurons to astrocytes. This imbalance(?)where the astrocytic transport machinery fails to compensate for accelerated neuronal lipid synthesis(?)leads to a breakdown of lipid detoxification processes. Meanwhile, impaired expression of genes related to lipid degradation exacerbates O3-induced lipotoxicity and neuronal damage. Supplementation with N-acetylcysteine or citicoline sodium mitigated the O3-induced disordered lipid metabolism and learning and memory impairments. This study highlights the role of neuron-astrocyte lipid metabolic coupling in mediating O3-induced neurotoxicity and offers a potential approach for addressing O3 pollution-induced neurodegenerative diseases.

Objective: To investigate the clinical efficacy and neural mechanisms of targeted 810-nm transcranial near-infrared stimulation (tNIRS) over the bilateral angular gyrus in Alzheimer's disease (AD). Impact Statement: We provide the first clinical evidence that targeted tNIRS ameliorates AD cognitive deficits by dynamically reconfiguring large-scale brain networks, establishing a precise, mechanistic neuromodulation strategy. Introduction: While tNIRS shows potential for AD, conventional whole-brain irradiation lacks anatomical precision and yields inconsistent outcomes. Resolving these elusive network-level mechanisms requires targeted stimulation paradigms. Methods: In a randomized, sham-controlled trial, 36 biomarker-confirmed AD patients received 810-nm tNIRS targeted at the bilateral angular gyrus or sham stimulation (20 min/side daily, 15 d). Baseline and post-intervention neuropsychological assessments, resting-state functional magnetic resonance imaging (fMRI), and transcranial magnetic stimulation-electroencephalography (TMS-EEG) were utilized to decode cognitive improvements and network dynamics. Results: Targeted tNIRS obviously improved cognition, memory, language, attention, and executive functions while reducing neuropsychiatric symptoms. fMRI revealed enhanced intra-network connectivity within the default mode network (DMN) and promoted functional synergy between the DMN, dorsal attention, frontoparietal, and limbic networks. TMS-EEG demonstrated enhanced information flow and dynamic nodal reconfiguration, specifically boosting prefrontal and temporo-occipital activation. Conclusion: Bilateral angular gyrus targeted tNIRS may effectively mitigate AD cognitive impairment potentially through modulation of functional connectivity and adaptively reconfiguring higher-order cognitive networks, serving as a highly promising clinical neuromodulation therapy.

Tailored multidomain lifestyle modifications are recommended for reducing dementia risk in mild neurocognitive disorder (mNCD). However, evidence of their capacity to modify disease trajectories and restore functional brain abnormalities remains limited. We aimed to explore functional brain adaptations and correlate underlying cognitive improvements in response to a personalized "exergame as medicine" program ("Brain-IT") for secondary mNCD prevention. Participants were randomized to 12 weeks home-based "Brain-IT" (physical-motor-cognitive with integrated biofeedback breathing training; 120 min/week, moderate intensity) + usual care or usual care alone. Resting-state functional connectivity at the seed(hippocampus)-to-voxel level and task-based full-factorial analysis of variance for functional activation (Blood Oxygenation Level Dependent signal responses) and their correlations with episodic memory performance were analyzed. Data from 32 mNCD participants (71.9 ± 8.1 years; 28% females) with mostly biomarker-supported Alzheimer's etiology (57%) were analyzed. Key findings were significantly (p < 0.0001) reduced hippocampus hyperactivation during memory encoding (partial η[2] = 0.19) and compensatory functional activation increases in the right precuneus (d = 0.76) and middle cingulate gyrus (d = 0.26) that correlated with memory retrieval accuracy changes-all in favor of "Brain-IT." These exploratory findings are consistent with a potential short-term brain-protective role of personalized "exergame as medicine" therapy in mNCD that require confirmation in hypothesis-driven and adequately powered RCTs. Given the overlooked role of exergames in dementia prevention, hybrid implementation-effectiveness research with long-term follow-up measuring biomarker-related and clinical progression should evaluate whether potential brain-protective effects translate to delaying and/or preventing progression to dementia. Registration: https://clinicaltrials.gov/ct2/show/NCT05387057 (May 18, 2022).

Immunosenescence-the age-associated remodeling of the immune system-has emerged as a potential modifier of chronic inflammatory disease. This review examines the evidence that immunosenescence may contribute to the chronicity, refractoriness, and therapeutic heterogeneity of uveitis, and considers the clinical and translational implications of this framework. It first outlines the features of immune aging, including thymic involution, contraction of the naïve T cell pool, accumulation of memory and terminally differentiated populations, and a chronic low-grade inflammatory state (inflammaging), and discusses signaling pathways that have been associated with these processes, including AMPK-mTOR, NF-κB, cGAS-STING, and JAK-STAT. It then evaluates three complementary but unequal lines of evidence relevant to uveitis: direct human observations from peripheral blood and intraocular fluids, mechanistic support from experimental models, and contextual inference from age-associated ocular disorders. Collectively, these data suggest that age-related immune remodeling may promote breakdown of ocular immune privilege, blood-retinal barrier dysfunction, persistent cytokine signaling, and incomplete response to conventional therapy in selected uveitis phenotypes. Finally, this review discusses therapeutic implications, including Treg enhancement, cytokine-directed approaches, and advanced drug delivery, while emphasizing that direct evidence of immune rejuvenation in human uveitis remains lacking. Ageing does not simply amplify ocular inflammation; it may attenuate selected acute immune responses while impairing resolution and tissue resilience, with effects that depend on disease context. By bridging geroscience and ocular immunology, this review offers a translational framework for understanding refractory intraocular inflammation and highlights future priorities for biomarker development, patient stratification, and precision medicine in uveitis.