bims-adhine 2026-07-19 papers

Issue of 2026–07–19
seven papers selected by
Tamara J. Buijs, Universiteit van Amsterdam

Front Neurosci. 2026 ;20 1833016

Enhancing adult neurogenesis attenuates hippocampal-related behavioral deficits in an Alzheimer's mouse model.

Alzheimer's disease (AD) is the most prevalent form of dementia, characterized by progressive memory loss, cognitive decline, and emotional dysregulation. Adult hippocampal neurogenesis (AHN) critically contributes to cognition and mood but undergoes precipitous decline during AD progression. Here, we investigated whether enhancing AHN through genetic expansion of endogenous neural stem cells (NSC) ameliorates AD-related phenotypes. Using lentiviral overexpression of the cell cycle regulators Cdk4 and CyclinD1 in the dentate gyrus of 3xTg-AD mice, we show that enhancing AHN is accompanied by partial improvements in selected behavioral measures associated with hippocampal function, including in the open-field test and Morris water maze. These findings indicate that the AD-compromised neurogenic niche remains responsive to NSC-targeted stimulation and support the use of AHN as a potential additional avenue for multi-modal therapeutic strategies for AD.

Keywords: 3xTg-AD mouse model; Alzheimer’s disease; adult hippocampal neurogenesis; hippocampal behavior; neural stem cell

DOI: https://doi.org/10.3389/fnins.2026.1833016

J Neurochem. 2026 Jul;170(7): e70521

Etv5 Is Required for Proper Maturation and Dendritic Development of Adult-Born Granule Cells in the Dentate Gyrus.

Antonella S Ríos, Solana F López, Fernando Federicci, Paula A Fontanet, Gustavo Paratcha, Fernanda Ledda.

Adult neurogenesis in the dentate gyrus (DG) of the hippocampus is a dynamic and tightly regulated process that is finely regulated by a diverse array of transcription factors. While the transcription factor Etv5, a member of the Erythroblast Transformation Specific (ETS) family, has been implicated in embryonic development by regulating cell proliferation and differentiation across various tissues, its specific role in adult hippocampal neurogenesis remains unexplored. Here, we show that conditional ablation of Etv5 specifically in adult-born granule cells (GCs) increases the proportion of Doublecortin (DCX)-positive immature GCs at the expense of mature neurons, without affecting the proportion of neither radial glia-like cells (RGCs) nor SOX2+ progenitor cells within the neurogenic niche. Furthermore, Etv5 conditional mutant mice exhibit reduced dendritic complexity and defects in spine development, indicating impaired neuronal maturation and suggesting deficits in synaptic integration of adult-born GC neurons.

Keywords: Pea3 transcription factors; adult hippocampal neurogenesis; neuron maturation; neuron morphology

DOI: https://doi.org/10.1111/jnc.70521

Stroke. 2026 Jul 16.

Aberrant Hippocampal Neurogenesis Is a Conserved Response to Stroke in Mice: A Multicenter Multimodel Study.

BACKGROUND: Adult hippocampal neurogenesis is altered after cerebral ischemia. Although stroke increases newborn neuron production, many cells display aberrant morphological and positional features that may impair functional integration and contribute to long-term cognitive deficits. Given the clinical heterogeneity of ischemic stroke and limited translational success of preclinical studies relying on single models, it remains unclear whether poststroke neurogenic alterations are conserved across experimental paradigms. This study aimed to identify common and model-specific features of hippocampal neurogenesis across focal ischemia models.
METHODS: We conducted a multicenter, multimodel analysis within the Stroke-IMPaCT consortium using permanent and transient middle cerebral artery occlusion paradigms, including distal middle cerebral artery occlusion under normoxic or hypoxic conditions (distal middle cerebral artery occlusion+hypoxia), and filament-based transient middle cerebral artery occlusion, across 6 sites. Adult C57BL/6J mice were analyzed at 3 days, 7 days, and 2 months after ischemia, sham, or naïve conditions. Hippocampal proliferation (Ki67) and neuroblasts (DCX [doublecortin]) were quantified; morphological maturation of newborn neurons was assessed through high-resolution analyses of dendritic architecture and somatodendritic polarity.
RESULTS: Across all stroke models, ischemia induced a robust bilateral increase in hippocampal proliferation, most pronounced at 3 days and still elevated at 7 days, returning to baseline by 2 months. Neuroblast density was similarly increased at 7 days, particularly in the ipsilateral hippocampus, but normalized over time. Despite recovery in cell number, long-term analyses revealed a consistent reduction in apical dendrite length and increased proportion of neurons with aberrant features, including ectopic positioning, polarity defects, and abnormal lateral growth, across models and centers.
CONCLUSIONS: Aberrant hippocampal neurogenesis represents a robust hallmark of poststroke pathology in mice, independent of ischemia type or surgical approach, despite known differences in the spatial distribution of primary injury across models. Our findings underscore the importance of considering structural quality, and not only quantity, of newborn neurons when evaluating poststroke plasticity and developing therapeutic strategies.

Keywords: cognitive dysfunction; dementia; hippocampus; neurogenesis; stroke

DOI: https://doi.org/10.1161/STROKEAHA.126.055693

Cell Rep. 2026 Jul 13. pii: S2211-1247(26)00763-1. [Epub ahead of print]45(7): 117685

Tanycyte BMAL1 regulates high-fat diet weight gain and shapes arcuate neurogenesis in female mice.

Daniel Maxim Iascone, Pavel Pivarshev, Jianing Yang, Mariela Lopez Valencia, Sara B Noya, Hongtong Lin, Corey D Holman, Ron C Anafi, Joseph L Bedont, Amita Sehgal.

The hypothalamic radial-glia-like tanycyte population plays important and intertwined roles in metabolism, reproduction, and seasonality. Although these processes are circadian-regulated, the role of the molecular clock in tanycytes themselves has not yet been examined. We report that clock genes cycle with much higher amplitude in ventral tanycytes compared to more dorsal ependymocytes and that adult, tanycyte-specific knockout of core clock gene Bmal1 reduces diet-associated weight gain and fat mass in female mice. Fate mapping studies show that female mice have higher baseline tanycyte-derived neurogenesis than males, with many of the resulting neurons localizing to the feeding-relevant arcuate nucleus. Female but not male mice show reduced tanycyte-derived arcuate neurogenesis after adult Bmal1 deletion, with an increased proportion of newborn neurons acquiring a feeding-suppressing POMC neuropeptidergic fate. Together, our data support a role for tanycyte BMAL1 as a sex-specific regulator of body composition and hypothalamic adult neurogenesis.

Keywords: Bmal1; CP: neuroscience; arcuate; circadian; feeding; glia; hypothalamus; neurogenesis; sex; tanycyte; weight

DOI: https://doi.org/10.1016/j.celrep.2026.117685

J Biosci. 2026 ;pii: 29. [Epub ahead of print]51

Delta-9-tetrahydrocannabinol delineates D-galactose and aluminium chloride-induced cognitive dysfunction and neurodegeneration in the hippocampus of the Wistar rat model.

Fatin Nadzirah Zakaria, Mohamad Taufik Hidayat Baharuldin, Che Norma Mat Taib, Hasiah Ab Hamid, Hafizah Abdul Hamid, Samaila Musa Chiroma, Mohamad Aris Mohd Moklas.

Alzheimer's disease (AD) is a neurodegenerative disorder characterised by neurodegeneration and a decline in cognition and memory. D-galactose (D-gal) and aluminium chloride (AlCl3) have been used to induce cognitive deterioration in rat models that mimic the alterations observed in AD. This study assessed the neurotherapeutic effect of Δ9-tetrahydrocannabinol (Δ9THC) on cognitive abilities, brain morphology, neurogenesis activity and neuropathological markers in Wistar rats induced by D-gal plus AlCl3. Male albino Wistar rats received D-gal (60 mg/kg, intraperitoneally) and AlCl3 (200 mg/kg, orally) daily for 10 weeks. The rats were then treated with increasing concentrations of Δ9THC (0.75, 1.5 and 3.0 mg/kg) for 28 days. Cognitive performance was evaluated using the novel object recognition and modified elevated plus maze tests. Dentate gyrus viable granule cells, neurogenesis markers, amyloid precursor protein and phosphorylated tau (p‑tau Thr231) were assessed histologically and molecularly. Δ9THC treatment improved cognitive performance, prevented granule cell loss in the dentate gyrus, increased neurogenesis-related markers (GFAP+, DCX+, calbindin+ and NeuN immunoreactivity), and reduced amyloid precursor protein and p‑tau Thr231 expression. These findings suggest that Δ9THC possesses promising therapeutic potential against Alzheimer's disease.

Transl Psychiatry. 2026 Jul 15.

Fatigue after COVID-19 infection is associated with peripheral immunometabolic alterations affecting neuroimmune responses in the hippocampus.

Nicole Mariani, Daniel Martins, Federico Imbeni, Madeline Kirkpatrick, Nuriza Tukiran, Silvia Alboni, Carmine Pariante, Alessandra Borsini.

Fatigue is a common and disabling symptom reported following SARS-CoV-2 infection, yet the underlying biological mechanisms remain poorly understood. In this study, we investigated whether fatigue severity in individuals previously infected with SARS-CoV-2 is associated with immune and metabolic alterations in serum and whether these peripheral changes can influence hippocampal cell function in vitro. Serum cytokines, kynurenine pathway, and tryptophan-derived and monoamine-related metabolites were measured in a total of 38 individuals with past COVID-19 infection. Human hippocampal progenitor cells were exposed to 1% patient serum during proliferation and differentiation, with readouts including cytokine release, metabolite production, and markers of neurogenesis (doublecortin, DCX) and astrocytic reactivity (glial fibrillary acidic protein, GFAP; aquaporin-4, AQP4). Results show that fatigue severity correlates with lower serum levels of interleukin-8 (IL-8) and with lower levels of metabolites of the kynurenine pathway and tryptophan-derived and monoamine-related metabolites, including kynurenine (KYN) and quinolinic acid (QUIN), and 5-hydroxyindoleacetic acid (5HIAA). Exposure of hippocampal cells to serum from individuals with higher fatigue was associated with increased endogenous production of interleukin-13 (IL-13) and the kynurenine metabolite anthranilic acid (ANA) in the cell supernatant, as well as with increased neurogenesis (increased DCX expression) and enhanced astrocytic reactivity (increased GFAP expression). Notably, serum IL-8 level was inversely correlated with both cellular outcomes. Likewise, serum 5-HIAA levels were negatively correlated with IL-13 release, with mediation analysis indicating that 5-HIAA significantly mediated the association between fatigue severity and IL-13 production (71% explained). Overall, our results suggest that fatigue after COVID-19 infection is associated with neuroimmune and metabolic changes in hippocampal cells, involving peripheral serotonin metabolism (5-HIAA) and cytokine signalling (IL-13).

DOI: https://doi.org/10.1038/s41398-026-04250-9

Exp Neurol. 2026 Jul 15. pii: S0014-4886(26)00296-7. [Epub ahead of print] 115931

Forty-hertz auditory stimulation restored hippocampal-prefrontal synchrony and attenuated hippocampal hyperexcitability in an STZ-induced Alzheimer's model.

Afsaneh Asgari Taei, Farnaz Karimani, Neda Kaveh, Pariya Khodabakhsh, Mohammad-Reza Abolghasemi Dehaqani, Leila Dargahi.

Dysfunction of neuronal networks such as aberrant excitability and disrupted oscillatory activity, especially within theta and gamma bands, in memory-related areas including the hippocampus and prefrontal cortex, is increasingly recognized as an important contributor to cognitive impairment in Alzheimer's disease (AD). In this context, targeting network dysfunction via gamma sensory entrainment, such as 40 Hz auditory stimulation, has emerged as a promising non-invasive therapeutic approach; however, the therapeutic mechanisms by which 40 Hz auditory stimulation ameliorates network-level deficits remain poorly understood. We studied the effects of long-term 40 Hz auditory stimulation in STZ-induced AD rats on the hippocampal-prefrontal network activity. Daily auditory stimulation was applied for 21 days, and its impact was assessed using electrophysiological recordings, behavioral testing, histological staining, and molecular analyses. STZ-treated rats exhibited impaired theta-gamma coupling, reduced hippocampal-prefrontal theta coherence, increased interictal epileptiform discharges, and significant deficits in spatial memory. These network abnormalities were associated with Aβ accumulation, tau hyperphosphorylation, altered expression of insulin/PI3K/Akt pathway-associated genes, and reduced expression of neurogenesis-related markers. Remarkably, 40 Hz auditory stimulation reversed many of these impairments: it restored functional connectivity and cross-frequency coupling, reduced epileptiform activity, improved memory performance, attenuated Aβ and tau pathology, partially normalized insulin/PI3K/Akt pathway-associated gene expression, and upregulated genes related to adult neurogenesis. Our findings indicated that 40 Hz auditory stimulation can effectively target both neural circuit dysfunction and molecular markers of AD, highlighting its potential as a simple, accessible, and multifaceted therapeutic strategy.

Keywords: Alzheimer's disease; Auditory stimulation; Gamma entrainment; Insulin signaling; Neural oscillations; Neurogenesis

DOI: https://doi.org/10.1016/j.expneurol.2026.115931