Progress in Neurobiology最新文献

{"title":"Targeted interneuron ablation in an mTORopathy model: testing a two-hit mechanism of epileptogenesis.","authors":"Austin W Drake, Mary R Dusing, Candi L LaSarge, Carlie McCoy, Lilian Jerow, Sanskriti Vaghela, Justin V Ruksenas, Steve C Danzer","doi":"10.1016/j.pneurobio.2026.102925","DOIUrl":"https://doi.org/10.1016/j.pneurobio.2026.102925","url":null,"abstract":"<p><strong>Objective: </strong>Somatic mutations in mechanistic target of rapamycin (mTOR) pathway genes produce focal brain malformations that can lead to epilepsy. Malformations show a high degree of mosaicism, sometimes with less than 1% of neurons carrying the mutation. Seizures are hypothesized to be driven by mutation-carrying dysmorphic excitatory neurons, but lesions in patients and animal models also show loss of interneurons. Here, we queried whether interneuron loss could act as a second hit, releasing the brake on excitatory dysmorphic neurons and increasing epilepsy severity.</p><p><strong>Methods: </strong>To test this hypothesis, we developed a two-hit mouse model in which we combined loss of the mTOR pathway inhibitor phosphatase and tensin homologue (Pten) from excitatory hippocampal dentate granule cells with ablation of local parvalbumin or somatostatin interneurons. Pten was deleted from roughly 3% of granule cells, a level which is subthreshold for producing frequent generalized seizures, thus facilitating assessment for synergistic effects.</p><p><strong>Results: </strong>Pten loss alone produced occasional seizures, while interneuron ablation alone initiated frequent seizures lasting for about one week, followed by a significant decline in seizure incidence in subsequent weeks. The combination of Pten deletion and interneuron ablation did not produce a synergistic increase in seizure incidence over ablation alone.</p><p><strong>Interpretation: </strong>Findings confirm the potential for interneuron loss to drive epileptogenesis, but do not support the hypothesis that rapid disinhibition of Pten knockout granule cells enhances their ictogenic potential. Results provide new insights into the role of GABAergic inhibitory input in regulating the activity of mTOR hyperactive neurons.</p>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":" ","pages":"102925"},"PeriodicalIF":6.1,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147841980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytic glycogenolysis gates Warburg-like metabolic reprogramming that promotes neuropathic pain chronification.","authors":"Jun Seo Park, Kwang Hwan Kim, Hye Won Jun, Se-Young Choi, Seung Bum Park, Sung Joong Lee","doi":"10.1016/j.pneurobio.2026.102924","DOIUrl":"https://doi.org/10.1016/j.pneurobio.2026.102924","url":null,"abstract":"<p><p>Chronic pain remains a major unmet medical challenge, yet the metabolic checkpoints that govern its persistence are poorly defined. Astrocytes are increasingly recognized as chemically programmable hubs that tune neuronal excitability through metabolic circuits. Building on reports that astrocyte-neuron lactate shuttling (ANLS) in the anterior cingulate cortex (ACC) supports chronic pain, we asked how astrocytic metabolic states evolve over the course of pain chronification. Using untargeted metabolomics of the ACC combined with GFAP-RiboTag-based astrocyte-specific transcriptomics, we provide a time-resolved map of astrocytic metabolism across the transition from acute nociception to chronic neuropathic pain. This analysis reveals a biphasic glycogen program-an acute glycogenolysis-triggered glycogen supercompensation-that culminates in the emergence of a Warburg-like metabolic signature associated with late astrocyte-enriched glycolytic and lactate-related changes and persistent circuit activation. Using glycogen phosphorylase inhibitors (GPI-1, GPI-2) as pharmacological probes, we show that early glycogenolysis blockade attenuates this Warburg-like shift, partially normalizes ACC metabolic signatures, and reduces long-lasting mechanical hypersensitivity, without impairing acute nociceptive sensitization. These findings identify astrocytic metabolic reprogramming as a pharmacologically tractable circuit-level process and nominate glycogenolysis as an upstream biochemical gate and potential therapeutic control point in neuropathic pain.</p>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":" ","pages":"102924"},"PeriodicalIF":6.1,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147841916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Cortical hyperexcitability drives dying forward amyotrophic lateral sclerosis symptoms and pathology in mice”[Prog. Neurobiol. 252 (2025) 102809]","authors":"Mouna Haidar ,&nbsp;Aida Viden ,&nbsp;Christin Daniel ,&nbsp;Brittany Cuic ,&nbsp;Taide Wang ,&nbsp;Marius Rosier ,&nbsp;Doris Tomas ,&nbsp;Samuel A. Mills ,&nbsp;Alistair Govier-Cole ,&nbsp;Elvan Djouma ,&nbsp;Nirma D. Perera ,&nbsp;Sophia Luikinga ,&nbsp;Valeria Rytova ,&nbsp;Samantha K. Barton ,&nbsp;David G. Gonsalvez ,&nbsp;Lucy M. Palmer ,&nbsp;Catriona McLean ,&nbsp;Matthew C. Kiernan ,&nbsp;Steve Vucic ,&nbsp;Bradley J. Turner","doi":"10.1016/j.pneurobio.2026.102910","DOIUrl":"10.1016/j.pneurobio.2026.102910","url":null,"abstract":"","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"260 ","pages":"Article 102910"},"PeriodicalIF":6.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147575205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ABCA7 deficiency exacerbates glutamate excitotoxicity in Alzheimer’s disease mice – A new pharmacological target for Glu-related neurotoxicity","authors":"Anna Maria Górska ,&nbsp;Irene Santos-García ,&nbsp;Aleš Kvasnička ,&nbsp;Dana Dobešová ,&nbsp;David Friedecký ,&nbsp;Jacob Gildenblat ,&nbsp;Jens Pahnke","doi":"10.1016/j.pneurobio.2026.102891","DOIUrl":"10.1016/j.pneurobio.2026.102891","url":null,"abstract":"<div><div>Increasing attention has been directed towards the perturbation of glutamate (Glu) and γ-aminobutyric acid (GABA) homeostasis during the pathogenesis of Alzheimer's disease (AD). The prevailing disequilibrium, stemming from hyperactivation of the glutamatergic system, culminates in progressive neuronal impairment and cognitive deterioration. This study aimed to elucidate the contributory role of the ATP-binding cassette transporter A7 (ABCA7), identified as the second most critical genetic determinant in AD, in glutamatergic-associated neurotoxicity. This endeavor sought to advance molecular comprehension of neurological disorders where Glu-GABA neurotransmission represents a pivotal pharmacotherapeutic target. Utilizing multi-omics approaches, we rigorously analyzed four distinct mouse models, both with and without APPtg and ABCA7 expression, to simulate varied pathological and ABCA7-deficient states. Our results revealed amyloid-beta (Aβ) deposition as a catalyst for surging glutamatergic transmission. Notably, ABCA7 ablation exacerbated glutamatergic-induced neurotoxicity, attributed to diminished enzymatic activity related to neurotransmitter degradation and amplified expression levels of specific neurotransmitter transport proteins and receptor subunits, notably NMDA, AMPA, and GABA_A. These findings furnish the first comprehensive description elucidating ABCA7's amplification of neurotoxic effects through modulation of Glu-GABA neurotransmission systems in neurodegenerative contexts, primarily mediated by lipid interaction. The evidence underscores ABCA7's imperative role in shaping future pharmacological strategies aimed at counteracting neurodegeneration precipitated by Glu-mediated neurotoxicity. This research advances the frontier for therapeutic exploration to ameliorate the deleterious neural consequences characteristic of neurodegenerative pathologies.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"259 ","pages":"Article 102891"},"PeriodicalIF":6.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146133096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The flexible synapse – How mossy fiber architecture adapts to changing needs","authors":"Felicitas Bruentgens ,&nbsp;Dietmar Schmitz ,&nbsp;Marta Orlando","doi":"10.1016/j.pneurobio.2026.102882","DOIUrl":"10.1016/j.pneurobio.2026.102882","url":null,"abstract":"<div><div>Hippocampal mossy fiber boutons are unique, highly plastic synapses within the hippocampal circuitry. Despite mossy fiber bouton’s potential role in learning and memory processes, the precise underlying mechanisms leading to their strengthened synaptic connections are still not fully understood. Here, we provide an overview of the structural changes occurring during long-term potentiation of large presynaptic terminals formed by mossy fiber onto CA3 pyramidal cells. Such changes encompass (1) adaptations in the number, shape and size of the bouton; (2) changes in availability of synaptic vesicles as well as the number and occupancy of release sites within single boutons; and (3) nano-architectural changes in the molecular composition and spatial arrangements within active zones. We describe these changes and possible implications for mossy fiber function. Furthermore, we discuss open questions, current methodology, and possible future directions.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"258 ","pages":"Article 102882"},"PeriodicalIF":6.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sustained inhibitory dysfunction in complement component C1qa-deficient mice underlies epilepsy and comorbidities","authors":"Joseane Righes Marafiga ,&nbsp;Thy Vu ,&nbsp;Jessica Bowlus ,&nbsp;Scott C. Baraban","doi":"10.1016/j.pneurobio.2026.102881","DOIUrl":"10.1016/j.pneurobio.2026.102881","url":null,"abstract":"<div><div>Neuronal networks undergo critical refinement throughout development and adulthood to maintain proper brain function. Dysregulation of complement component C1qa—including both up- and downregulation—has been linked to circuit dysfunction and neurological disorders such as epilepsy, primarily through effects on excitatory synapses. However, the impact of C1qa downregulation on inhibitory circuits remains poorly understood. We show that germline deletion of C1qa disrupts layer 6 somatostatin (SST)-expressing interneurons in the somatosensory cortex, which we propose underlies enhanced excitatory synaptic transmission, electrographic spike-and-wave discharges, anxiety-like behavior, and impaired sensory-driven behavior. Transplantation of medial ganglionic eminence (MGE)-derived interneuron precursors rescued behavioral deficits but did not abolish the seizure phenotype, underscoring the critical role of C1qa in maintaining inhibitory network integrity—while also suggesting that additional mechanisms beyond interneuron dysfunction contribute to the pathophysiology of absence seizures.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"258 ","pages":"Article 102881"},"PeriodicalIF":6.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Orthogonal neural geometry of orientation, spatial frequency, and ocular dominance in macaque V1","authors":"Xin Wang ,&nbsp;Sheng-Hui Zhang ,&nbsp;Shi-Ming Tang ,&nbsp;Cong Yu","doi":"10.1016/j.pneurobio.2025.102874","DOIUrl":"10.1016/j.pneurobio.2025.102874","url":null,"abstract":"<div><div>The classical ice-cube model of Hubel and Wiesel proposes that V1 neurons are spatially organized into orthogonal maps of orientation and ocular dominance to optimize wiring efficiency. However, extending this framework to include additional features such as spatial frequency imposes constraints on how these features can be spatially arranged on the cortical surface. A recent two-photon imaging study of ours found that cellular-resolution maps of orientation, spatial frequency, and ocular dominance in macaque V1 lack consistent orthogonal or parallel spatial arrangements. To investigate whether these features are instead represented in population activity space, we applied principal component analysis (PCA) to these and additional datasets. We found that population responses formed near-orthogonal geometries in representational space, supporting the idea that feature encoding relies more on population-level activity than spatial layout. This orthogonal structure remained robust to dimensionality changes and was absent in response-shuffled control data, in which feature axes collapsed to chance-level alignment. Furthermore, artificially disrupting orthogonality, either by aligning feature axes or randomizing trial positions in PCA space, severely impaired the decodability of stimulus features, demonstrating that orthogonal representations are critical for maintaining feature separability. These findings suggest that V1 population responses follow an orthogonal encoding geometry, and that population codes, rather than spatial maps, better capture feature representation. This principle may also serve as an important benchmark for V1-inspired deep neural networks.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"258 ","pages":"Article 102874"},"PeriodicalIF":6.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prefrontal cortex interneurons and their contributions to attention, working memory, and adaptive behavior","authors":"Kianoush Banaie Boroujeni ,&nbsp;Pooja Balaram ,&nbsp;Paul Tiesinga ,&nbsp;Thilo Womelsdorf","doi":"10.1016/j.pneurobio.2025.102873","DOIUrl":"10.1016/j.pneurobio.2025.102873","url":null,"abstract":"<div><div>Inhibitory interneurons play central roles in regulating the input and output of cortical circuits, which in prefrontal cortices (PFC) subserve attention control, working memory and adaptive behavior. Understanding how interneurons support these higher order cognitive functions is a key question in a growing number of studies. Here, we delineate recent progress by surveying molecular, functional and computational motifs of interneurons in the prefrontal cortex of nonhuman primates and rodents. Among multiple transcriptomic and molecular subtypes of neurons several electrophysiologically identified <em>'eType'</em> interneurons are recruited during attention, learning, and working memory tasks. In nonhuman primate PFC, <em>eType</em> neurons with an inhibitory effect on the local circuit encode behaviorally relevant cues, unexpected outcomes, and tune working memory representations. These response profiles are consistent with the functional specializations proposed for PV+ , SST+ and VIP+ interneurons in rodents, which are recruited during attention and memory-guided tasks. We survey how these functional studies of interneuron types are supported by newly developed molecular and analytical tools and guided by computational studies that suggest unique circuit motifs for distinct types of interneurons to flexibly route synaptic inputs, compute prediction errors, and facilitate information retention in working memory.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"258 ","pages":"Article 102873"},"PeriodicalIF":6.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanisms of age-related vulnerability to traumatic brain injury","authors":"Pallavi Joshi ,&nbsp;Raghu Vemuganti","doi":"10.1016/j.pneurobio.2026.102890","DOIUrl":"10.1016/j.pneurobio.2026.102890","url":null,"abstract":"<div><div>Aging is associated with increased vulnerability to a wide variety of diseases and conditions, including traumatic brain injury (TBI). While advanced age is a known predictor of poorer outcomes following TBI, the molecular mechanisms underlying this susceptibility haven’t been completely characterized. This review discusses some of the primary pathways and physiological changes that are affected by aging and how they influence the post-TBI recovery in both experimental and clinical settings. Some of the age-related alterations implicated in geriatric TBI include loss of white matter, compromised blood-brain-barrier integrity, aggravated oxidative stress, mitochondrial dysfunction, higher cell death and synapse loss, increased and more prolonged neuroinflammation, compromised neural repair mechanisms, dysregulated proteasomal degradation leading to misfolded protein aggregation, and systemic changes such as peripheral organ dysfunction. This review further focuses on how the underlying molecular mechanisms involved in these changes influence long-term functional and behavioral outcomes after TBI. Lastly, some of the current and potential therapeutic interventions for geriatric TBI have also been discussed.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"258 ","pages":"Article 102890"},"PeriodicalIF":6.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mixed-selective organization of reach and grasp in the primate fronto-parietal network","authors":"Alireza Fathian ,&nbsp;Sebastian J. Lehmann ,&nbsp;Jonathan A. Michaels ,&nbsp;Hansjörg Scherberger","doi":"10.1016/j.pneurobio.2026.102889","DOIUrl":"10.1016/j.pneurobio.2026.102889","url":null,"abstract":"<div><div>Reaching and grasping in primates require coordinated control of several parameters, such as grip type, wrist orientation, spatial position, and hand laterality. The anterior intraparietal (AIP) and rostral ventral premotor (F5) areas are key hubs in this process. This study used electrophysiological data to investigate how these parameters are co-represented in AIP and F5. The results indicate that neurons predominantly show mixed selectivity with stable temporal organization related to movement and pre-movement phases. This uncategorizable mixture of selectivity allows flexible decoding. Despite condition-dependent shifts, selectivity preferences were largely preserved across task conditions. Notably, object-related factors (orientation and position) remained more stable during grip type changes in AIP, whereas grip type was more stable in F5, suggesting a functional hierarchical organization of context-dependent coding in both areas. Together, despite the continuous range of mixed selectivity at the single-neuron level, neural ensembles exhibit a stable organization on the temporal and functional scales, enabling flexible readouts.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"258 ","pages":"Article 102889"},"PeriodicalIF":6.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}