BackgroundPrenatal stress (PS) is a major risk factor for depression later in life, yet the cellular mechanisms linking early-life adversity to long-term affective vulnerability remain incompletely understood. Neuropeptide receptors have emerged as important modulators of stress-related psychopathology, but their roles in mitochondrial regulation within limbic circuits remain largely unexplored.MethodsA rat model of PS was established to assess depression-like behaviors in adulthood. Mitochondrial ultrastructure, ATP production, and the expression of Galanin receptor 2 (GalR2) and key components of the PINK1/Parkin mitochondrial quality control machinery were examined in the ventral hippocampus (vHPC). The effects of intranasal administration of the GalR2 agonist AR-M1896 on behavioral and mitochondrial alterations were evaluated in vivo. To directly test whether the vHPC mediates these effects, we performed unilateral intra−vHPC infusion of AR−M1896. In vitro, glucocorticoid exposure and pharmacological manipulation of GalR2 were used to assess their impact on mitochondrial function and PINK1/Parkin signaling.ResultsPS induced persistent anhedonia-like behavior and behavioral despair phenotypes in adult offspring, accompanied by marked mitochondrial structural abnormalities, reduced ATP production, and downregulation of GalR2 and PINK1/Parkin-associated mitochondrial quality control signaling in the vHPC. Intranasal AR-M1896 partially normalized reward-related behavioral deficits and ameliorated mitochondrial dysfunction. Importantly, direct intra−vHPC infusion of AR−M1896 elevated ATP, PINK1 and Parkin levels in the ipsilateral vHPC, providing causal evidence that the vHPC is a critical site for GalR2−mediated PINK1/Parkin-related mitophagy−restoring effects. In cell-based assays, glucocorticoid exposure suppressed, whereas GalR2 activation enhanced, mitochondrial membrane potential and PINK1/Parkin-related signaling.ConclusionThese findings identify a GalR2–mitochondrial axis in the ventral hippocampus that is disrupted by PS and associated with vulnerability to depression-like phenotypes. The complementary intra−vHPC infusion experiments establish a causal role for vHPC GalR2 signaling in rescuing mitochondrial deficits, directly demonstrating that intranasal AR−M1896 acts at least in part via the vHPC. This receptor–organelle pathway may represent a neurobiological mechanism linking early-life adversity to long-term affective dysfunction.
Mapping the neuroimaging landscape of inflammatory bowel disease: a bibliometric analysis and systematic scoping review
BackgroundInflammatory bowel disease (IBD) is recognized as a prototypical disorder of brain-gut interaction. Although neuroimaging research in this field has advanced rapidly in recent years, the findings remain fragmented across multiple disciplines, and a systematic integration of the literature is lacking.ObjectiveThis study presents the first integrated bibliometric analysis and literature review to map the landscape and evolving trends of neuroimaging research in IBD over the past two decades and to identify the knowledge base and research frontiers.MethodsWe conducted a systematic search of the Web of Science Core Collection and Scopus databases for IBD-related neuroimaging literature published between January 2000 and January 2026. Following the PRISMA guidelines, two independent reviewers screened titles, abstracts, and full texts. A total of 175 articles met the inclusion criteria. Data were extracted on study characteristics, neuroimaging modalities, and clinical findings. For the synthesis, we employed a dual approach: (1) a bibliometric analysis using VOSviewer, Biblioshiny, and CiteSpace to map publication trends, collaboration networks, and research hotspots; and (2) a structured literature review across five predefined dimensions: technical modalities, brain region–symptom associations, subtype differences, mechanistic pathways, and clinical translation.ResultsThe systematic search and selection process identified 175 articles for final synthesis. The field has entered a phase of rapid expansion since 2021, with China and the United States as core contributing countries. Emerging frontiers include the “brain-gut axis” and the “default mode network.” The literature synthesis indicates that: (1) brain alterations are predominantly localized within an emotional and interoceptive network (anterior cingulate cortex, insula, and amygdala), with abnormalities generally associated with abdominal pain, anxiety, and depression; and (2) Crohn’s disease and ulcerative colitis appear to exhibit distinguishable neuroimaging phenotypes, though direct comparative studies remain limited.ConclusionThis study systematically clarifies the knowledge structure of the IBD neuroimaging field, demonstrates that the available neuroimaging evidence is consistent with the brain-gut axis as a central theoretical framework, and identifies subtype-specific neural characteristics. Future efforts should prioritize large-sample multicenter validation, longitudinal designs capable of testing mechanistic hypotheses, and multimodal data integration to transition the field from descriptive observations toward clinically meaningful applications,though substantial barriers—including small sample sizes, methodological heterogeneity, and lack of standardization—must first be overcome.
Functional MRI evidence of brain alterations in premenstrual dysphoric disorder: a systematic review
IntroductionPremenstrual Dysphoric Disorder (PMDD) affects approximately 1.6% of women of reproductive age and significantly impacts quality of life. Despite its prevalence, the underlying pathophysiology remains incompletely understood. First-line treatment typically involves selective serotonin reuptake inhibitors (SSRIs); however, approximately 40 percent of women with PMDD do not respond to these medications. This systematic review synthesizes current evidence on functional brain alterations in women with PMDD, as assessed using functional magnetic resonance imaging (fMRI), with the goal of identifying potential novel therapeutic strategies.MethodsData from 598 participants, including 294 PMDD patients and 304 healthy controls, were analyzed.ResultsThe findings suggest alterations in both topdown regulatory mechanisms and large-scale brain networks, including the salience network, default mode network, and executive control network. These alterations are characterized by decreased activation in the anterior cingulate cortex, dorsolateral prefrontal cortex, medial orbitofrontal cortex, and postcentral gyrus, alongside increased activation in the amygdala and insula, as well as impairments in corticolimbic connectivity.DiscussionThese results highlight the complexity of PMDD, implicating widespread neural circuits rather than a single localized dysfunction. Targeting these mechanisms may inform the development of novel interventions for symptom relief.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251174749.
Transcriptional signatures of the cortical morphometric similarity network gradient in left temporal lobe epilepsy with different seizure symptoms
BackgroundTemporal lobe epilepsy (TLE) manifests with diverse seizure symptoms, including focal to bilateral tonic—clonic seizures (FBTCS), linked to widespread brain network disruptions. The role of cortical morphometric similarity (MS) network gradients and their relationship with gene expression in TLE remains unclear.MethodsWe studied MS network gradient abnormalities through group comparisons among 87 left TLE patients (48 FBTCS−, 39 FBTCS+) and 63 healthy controls (HC). In addition, partial least squares (PLS) regression analysis was performed to investigate the association between gradient changes and whole-brain gene expression in left FBTCS+ TLE patients.ResultsFBTCS+ patients showed significant reductions in the principal MS network gradient within default mode network (DMN) regions compared to healthy controls, while FBTCS− patients exhibited no such abnormalities. Gradient alterations in FBTCS+ were linked to whole-brain expression of genes involved in neurobiological pathways, cell types, and cortical layers.ConclusionFBTCS+ TLE is associated with distinct MS network gradient alterations, which may reflect underlying molecular mechanisms contributing to structural changes linked to severe seizure symptoms.
<![CDATA[Patient selection, monitoring, and counseling on dissociation are critical to safe ketamine treatment.]]>
Vascular endothelial growth factor receptor-1 (VEGFR-1) knock-down is protective against hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril -induced neuronal cell death: implications in AD pathogenesis
IntroductionRecent transcriptome analysis has demonstrated increased expression of Vascular Endothelial Growth Factor receptor-1 (VEGFR-1/FLT1) and in AD brain. Increased expression of VEGFR1 and its ligand VEGFB were associated with a more rapid rate of cognitive decline, providing evidence of a potential link between increased VEGFR-1 expression in AD pathogenesis. In this study, we explored the potential role of VEGFR-1 expression in neurons on AD pathology.MethodsTo confirm VEGFR1 expression in AD brains, we first performed immunostaining in AD brain sections (AD – Braak stage V-VI, and normal controls – Braak 0-II). And to determine a potential detrimental role of neuronal VEGFR1 expression on AD associated pathologies, we exposed SH-SY5Y human neuroblastoma cells and mouse primary neurons to either hypoxia conditions (1%O2) or 5 μ Aβ1-42 oligomers or fibrils for 24, 28 and 72hrs.ResultsIn this study, we found preferential staining of VEGFR-1 in the neuropil and neuronal cell bodies both in AD and Control hippocampus and increased VEGFR-1 immunoreactivity in dystrophic neuritic processes in the vicinity of Thio-S positive amyloid plaques in AD brains. And treatment of SH-SY5Y human neuroblastoma cell line and mouse primary neurons, with either hypoxia conditions or Aβ1-42 oligomers, resulted in increased VEGFR-1 expression and cleaved caspase 3 activation, leading to neuronal toxicities/cell death. Similarly, treatment with Aβ1-42 fibrils also increased VEGFR-1 and cleaved caspase 3 protein levels in the SH-SY5Y cells whereas treatment with Aβ1-42 monomers had no effect on VEGFR-1 expression. In addition, we show that over-expression of VEGFR-1 intracellular domains in SH-SY5Y cells directly induced neuronal toxicities and importantly, siRNA-mediated knockdown of VEGFR-1 in neurons prevented the hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril-induced toxicities and cell death phenotypes. Treatment with either hypoxia or Aβ1-42 oligomers also reduced expression of cell survival genes including VEGFR-2 and Hippo pathway YAP1 and siRNA-mediated VEGFR-1 knockdown in the neurons normalized expression of both VEGFR-2 and YAP1. Using differential gene expression analysis, we demonstrated upregulation of several inflammatory/interferon-stimulated genes (ISGs) as well as increased expression of genes involved in activation of oxidative stress and cell death pathways in response to Aβ1-42 oligomers treatment in mouse primary neurons. And siRNA-mediated VEGFR-1 knockdown in the mouse primary neurons, reduced gene expression of both the ISGs and oxidative stress/cell death pathways in response to Aβ1-42 oligomer treatment.DiscussionIn summary, these results show that siRNA-mediated knockdown of VEGFR-1 in neurons significantly prevented hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril-induced cellular toxicities and cell death phenotypes, indicating a potential detrimental role of aberrant VEGFR-1 expression and signaling in response to AD associated pathologies.
Women’s Memory Decline Linked to ECM Changes from Brain Estrogen Loss
New research from investigators at Northwestern Medicine, published in Aging Cell, shows that loss of estrogen production in the brain after menopause is associated with changes in the brain’s extracellular matrix (ECM), a structure between brain cells that supports communication and memory. The findings suggest that estrogen decline may alter hippocampal brain environment in ways that contribute to memory impairment and may help explain why nearly two-thirds of all people with Alzheimer’s disease (AD) are women.
“This study tells us that females—but not males—may be uniquely sensitive to loss of brain estrogen at old age, potentially contributing to an increased risk of Alzheimer’s disease,” said senior author Hong Zhao, MD, PhD, a research professor of obstetrics and gynecology in the division of reproductive science in medicine at Northwestern University Feinberg School of Medicine.
The researchers found that estrogen loss, aging, and female sex are closely linked to changes in the ECM in the hippocampus, a brain region central to learning and memory. The ECM is a network of molecules that fills the spaces between neurons and glial cells to support cell communication and function. It makes up nearly 20% of brain volume and is important for memory and brain development.
To date, most research into AD has focused on neurons and glial cells, with less attention paid to the ECM. In the Northwestern study, ECM changes were examined as a central feature of brain biology affected by estrogen loss, the first study of its kind, the researchers noted.
For their research, the investigators use genetically engineered mouse models in which estrogen production was disrupted by removing aromatase, an enzyme required for estrogen synthesis. The enzyme was eliminated either throughout the body or restricted to the brain. The investigators examined young and old male and female mice, allowing comparison of sex-specific and age-related effects. The team assessed, behavior and social function, and also collected data on genome-wide gene expression changes in the hippocampus.
The research also built upon the current understanding of estrogen’s role in brain function. In the brain, estrogen has been associated with memory and mood-related functions.
“We have provided some of the most compelling evidence that estrogen is so important for memory function and other mood functions in the female brain,” said author Serdar Bulun, MD, chair of the department of obstetrics and gynecology at Feinberg and a Northwestern Medicine physician. “This should motivate clinicians to be more aware of the essential role of estrogen for women’s brains, because once memory is gone, it’s gone.”
The findings indicate that loss of brain estrogen may disrupt ECM organization in the hippocampus, which may impair communication between brain cells. Because the ECM provides a structural and signaling environment for neurons, any alterations of the ECM potentially affect processes required for memory formation and maintenance.
Prior research has shown that women with AD may have lower brain estrogen levels than women without AD. Hormone replacement therapy (HRT), created restore estrogen levels, has produced mixed results in clinical studies however.
The investigators noted that understanding how estrogen affects brain structures such as the ECM may help explain variability in HRT outcomes and could serve as a new avenue for developing future treatments. Rather than focusing only on restoring hormone levels, future therapies could address downstream changes in brain architecture.
ECM restoration could represent one such therapeutic approach. If estrogen loss leads to ECM disruption in the hippocampus, then interventions aimed at normalizing ECM structure before memory decline may support brain function in postmenopausal women.
The Northwestern team are continuing their investigation of how estrogen regulates ECM composition and signaling in specific brain regions, and whether these changes directly drive memory impairment. The noted that more research is also needed to determine how ECM-related mechanisms interact with other known AD pathways.
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Virtual Reality Could Pinpoint Early Signs of Alzheimer’s
Researchers in Japan have developed a test that can predict future neurodegeneration in cognitively healthy individuals using virtual reality. The test evaluates an individual’s spatial navigation ability—one of the first skills affected by Alzheimer’s and related diseases before memory loss or cognitive decline can start being noticed.
“Our approach may allow earlier identification of risk of neurodegenerative diseases, including Alzheimer’s disease,” said Kazuya Kawabata, MD, PhD, senior assistant professor at the department of neurology in Fujita Health University. “Over the longer term, it may contribute to a shift toward earlier detection, potentially enabling timely therapeutic interventions at preclinical stages and delaying disease progression, thereby preserving cognitive function and quality of life.”
Subtle changes in the brain leading to Alzheimer’s can emerge years before symptoms become evident. Among the brain regions that are first impacted are the hippocampus and the entorhinal cortex, both of which are involved in spatial navigation. In addition, a region within the entorhinal cortex is one of the first sites where tau neurofibrilary tangles start accumulating in Alzheimer’s.
In their study, published in Alzheimer’s Research & Therapy, Kawabata and colleagues investigated whether deteriorating spatial navigation skills could be an early indication of future cognitive decline in healthy individuals.
They designed an immersive virtual reality (VR) test to assess path integration, a key component of navigation that refers to our ability to track our position and direction as we move around based on internal cues. Participants navigated a circular virtual environment where they were asked to visit two checkpoints and then return to their starting point without relying on any landmarks or visual cues. Their performance was measured by calculating the distance to the original starting point and how much their direction deviated from that leading back to the starting point.
The study followed 71 cognitively healthy adults for approximately one year after completing the VR navigation test. High-resolution MRI scans and plasma biomarkers, including p-tau181 and glial fibrillary acidic protein (GFAP), were also analyzed in each participant one year apart in order to compare their navigation skills with established indicators of early Alzheimer’s.
Results revealed that individuals with poorer performance in the VR path integration test showed greater levels of cortical thinning and volume loss in brain regions affected by early Alzheimer’s and increased levels of p-tau181 and GFAP markers. The test was also able to identify those who experienced the fastest brain decline with high accuracy, especially in parahippocampal regions of the brain.
These findings indicate that the VR test is able to capture both molecular and structural signatures of early neurodegenerative processes that emerge before clinical symptoms can lead to an Alzheimer’s diagnosis. Although more research will be needed to validate this approach before it can be used in a clinical setting, this dual link supports its potential as a tool for early detection and monitoring of an individual’s risk of Alzheimer’s and related conditions, even when they are still cognitively healthy.
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Gene Therapy Shows Promise Against TDP‑43 Neurodegeneration in Mice
Among the proteins implicated in age‑related neurodegeneration, TDP‑43 has taken on growing importance: its misfolding and mislocalization are now linked to frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and are estimated to be present in more than half of Alzheimer’s cases. Faster cognitive decline, greater brain atrophy, and worsening memory loss are all associated with TDP-43.
Now, researchers at the University of California, San Diego (UCSD), are testing a gene‑therapy strategy designed not to remove TDP‑43, but to help neurons withstand its toxicity. In a study published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, the team reports that systemic delivery of a gene called SynCav1 to brain cells protected cognition and preserved neuronal structure in a mouse model of TDP‑43 proteinopathy. The study is titled, “Systemic delivery of synapsin-promoted caveolin-1 overexpression ameliorates pathological TDP-43–induced cognitive decline and neurodegenerative changes.”
The approach centers on caveolin‑1, a scaffolding protein that organizes membrane signaling domains and supports neuronal resilience. The researchers packaged SynCav1 into a modified AAV vector capable of crossing the blood–brain barrier—a notable departure from many CNS gene therapies that require direct injections into brain tissue. Once delivered, SynCav1 boosted caveolin‑1 expression across the brain and spinal cord.
“Many therapies for neurodegenerative disease focus on removing toxic proteins, but neurons are also losing their ability to cope with that stress,” said senior author Brian Head, PhD, professor of anesthesiology at UCSD School of Medicine and research career scientist at the Veterans Affairs San Diego Healthcare System. “Our findings suggest that strengthening the neuron’s resilience itself may be a powerful therapeutic strategy, even when toxic proteins are already present.”
In treated TDP-43A315T mouse models, SynCav1 preserved learning and memory deficits, behavioral domains typically impaired by TDP‑43 pathology. The therapy also reduced levels of pathological TDP‑43 in the cortex and hippocampus. At the subcellular level, SynCav1 protected mitochondrial structure, stabilized membrane lipid rafts (MLR), and maintained MLR-associated GluN2A receptor expression, which is essential for excitatory synaptic signaling.
The mechanistic insight emerged from a striking observation: in diseased mice, TDP‑43 mislocalized to membrane lipid rafts, disrupting signaling hubs and degrading synaptic ultrastructure. “We found that TDP‑43 is not only accumulating in the wrong subcellular compartments…but also disrupts cellular processes that are essential for neurons to communicate with one another,” said co‑corresponding author Shanshan Wang, MD, PhD, assistant professor of anesthesiology at UCSD School of Medicine. “SynCav1 appears to help preserve this molecular machinery and subcellular localization.”
Electron microscopy revealed that SynCav1 also mitigated mitochondrial hyper‑fragmentation and excessive fission signaling. Axonal myelin integrity was preserved as well, as reported in the study.
“What is especially exciting is that we saw protection across multiple levels—behavior, synapses, axons, membrane signaling, and mitochondrial structure,” Head added. “That kind of broad neuroprotection is exactly what is needed in complex disorders like TDP‑43‑related dementias.”
The authors emphasize that the work is preclinical, but the results support SynCav1 as a neuron‑centric therapeutic candidate that could be applicable across multiple TDP‑43‑linked diseases.
Brian P. Head, PhD, holds equity in and serves as a non‑paid scientific advisory board member for Eikonoklastes Therapeutics. Other authors reported no competing interests.
The post Gene Therapy Shows Promise Against TDP‑43 Neurodegeneration in Mice appeared first on GEN – Genetic Engineering and Biotechnology News.
A bibliometric analysis of neuroimaging studies on cognitive control in autism spectrum disorder (2000–2025)
ObjectiveThis study aims to systematically analyze neuroimaging research on cognitive control in Autism spectrum disorder (ASD) from 2000 to 2025 using bibliometric methods, in order to reveal the evolutionary trajectory, core knowledge base, research hotspots, and future frontiers of the field.MethodsA search was conducted on the Web of Science Core Collection and Scopus databases, resulting in the inclusion of 1,581 relevant articles. VOSviewer and the Bibliometrix package in R were utilized to conduct a comprehensive visualization and quantitative analysis of annual publication volume, country/institution/author collaboration networks, keyword co-occurrence, document co-citation, and thematic evolution.Results(1) The volume of research literature showed exponential growth, with an annual growth rate of 21.61%, entering a period of rapid development particularly after 2012, which is closely related to the popularization of functional magnetic resonance imaging (fMRI) technology. (2) “Functional connectivity,” “executive function,” and “default mode network” were the most central keywords. “Functional connectivity” rapidly became a hub connecting various themes after 2010, marking a paradigm shift from “functional localization” to “brain network dysregulation.” (3) The “Triple network model” proposed by Menon was the most cited document, laying the core theoretical foundation for understanding ASD as a disorder of large-scale brain network dysfunction. (4) “Transdiagnostic” research has emerged as a new hotspot, while “multimodal imaging,” “machine learning,” and “dynamic connectivity” represent highly promising future directions.ConclusionOver the past two decades, neuroimaging research on cognitive control in ASD has undergone a profound paradigm shift: from focusing on abnormal activation in isolated brain regions to exploring the static and dynamic dysregulation of large-scale brain networks. The research perspective has also expanded from a single-disorder model to a transdiagnostic framework that includes comparisons with other neurodevelopmental disorders (e.g., ADHD). Future research should focus on the fusion of multimodal data, the application of computational psychiatry methods, and the translation of basic research findings into personalized clinical interventions.