Progress In Neurobiology[JOURNAL]
Sun
200 papers
Glial dynamics in brain aging: Cellular heterogeneity and regional vulnerability.
Suk K
Prog Neurobiol · 2026 Jun · PMID 41956196 · Publisher ↗
Brain aging involves progressive structural, functional, and molecular changes that impair cognition and increase vulnerability to neurodegenerative diseases. While neurons have traditionally received primary research fo...
Brain aging involves progressive structural, functional, and molecular changes that impair cognition and increase vulnerability to neurodegenerative diseases. While neurons have traditionally received primary research focus, recent advances in single-cell transcriptomics, spatial genomics, and functional imaging reveal that glial cells-microglia, astrocytes, and oligodendrocytes-undergo profound, heterogeneous alterations during aging that actively drive brain dysfunction. These changes include microglial transition from homeostatic surveillance to inflammatory, dystrophic states; astrocyte shift from metabolic support to atypical reactive phenotypes with impaired neurovascular coupling; and oligodendrocyte dysfunction causing progressive myelin degeneration. Critically, glial aging exhibits marked regional heterogeneity, with hippocampus and prefrontal cortex showing heightened vulnerability while cerebellum remains relatively preserved, patterns mirroring cognitive decline topography. At the molecular level, glial senescence involves interconnected mechanisms including cellular senescence with senescence-associated secretory phenotype (SASP), oxidative stress and mitochondrial dysfunction, impaired proteostasis and autophagy, epigenetic alterations favoring inflammatory gene expression, and dysregulated inflammatory signaling pathways. These changes propagate through complex glial-glial and neuron-glia interaction networks, amplifying dysfunction beyond individual cellular deficits. Importantly, glia retain plasticity enabling therapeutic intervention through diverse strategies: senolytic elimination of senescent cells, microglial phenotype modulation, remyelination enhancement, metabolic interventions, and lifestyle modifications including exercise and dietary approaches. This review synthesizes current understanding of glial heterogeneity, regional vulnerability patterns, underlying molecular mechanisms, and emerging therapeutic opportunities, providing an integrated framework for targeting glial dysfunction to promote healthy brain aging and prevent cognitive decline.
Epm2b and Epm2b knock-in mouse models of Lafora disease exhibit distinct and pronounced neurological alterations.
Iglesias-Cabeza N, Zafra-Puerta L, Worby CA … +10 more , Fernández-Burgos D, Sciaccaluga M, Imperatore V, Fermont L, Sánchez-Martín G, Mitra S, Gentry MS, Costa C, Serratosa JM, Sánchez MP
Prog Neurobiol · 2026 Jun · PMID 41936809 · Publisher ↗
Lafora disease is a rare, autosomal recessive neurodegenerative disorder characterized by the progressive accumulation of abnormal, insoluble, and hyperphosphorylated forms of glycogen, known as Lafora bodies, in the bra...
Lafora disease is a rare, autosomal recessive neurodegenerative disorder characterized by the progressive accumulation of abnormal, insoluble, and hyperphosphorylated forms of glycogen, known as Lafora bodies, in the brain and other tissues. The disease typically manifests during early adolescence with myoclonus, seizures, and rapidly progressive cognitive decline, ultimately leading to severe neurological deterioration and death within a decade of onset. Mutations in the EPM2A or EPM2B genes, which encode the proteins laforin and malin-key regulators of glycogen metabolism-are the underlying cause of Lafora disease. Current research focuses on understanding the molecular mechanisms of the disease and exploring potential therapeutic approaches, including gene therapy, antisense oligonucleotides, enzyme-based therapies, and pharmacological interventions aimed at mitigating glycogen accumulation and alleviating disease symptoms. Multiple mouse models have been generated to advance our understanding of disease pathogenesis and facilitate treatment development. These include models deficient in Epm2a or Epm2b gene expression, the Epm2a and Epm2b mouse models, and a knock-in mouse model harboring the most frequent mutation in the Epm2a gene, the R240X mutation. Recently, we developed two new knock-in mouse models with Epm2b gene mutations. In this work, we describe the generation and characterization of these malin knock-in mice and compare their phenotype with Epm2b mice. These new models exhibit distinct neurological alterations, including motor and cognitive impairments, epileptic-like activity and altered synaptic plasticity. Based on these results, they can serve as valuable models for studying specific aspects of Lafora disease, providing more suitable tools for future research.
Microglial P2Y12 signaling phase-shifts glymphatic circadian rhythms and alters sleep architecture in mice.
Su L, Tian M, Hao Y … +4 more , Zhang X, Liu X, Liu L, Yao E
Prog Neurobiol · 2026 Jun · PMID 41935776 · Publisher ↗
Microglia regulate neural circuits and vascular-glial interfaces, yet whether microglial purinergic signaling coordinates glymphatic function and brain state remains unclear. We tested the role of the microglial Gi-coupl...
Microglia regulate neural circuits and vascular-glial interfaces, yet whether microglial purinergic signaling coordinates glymphatic function and brain state remains unclear. We tested the role of the microglial Gi-coupled receptor P2Y12 using acute pharmacological inhibition with MRS2395 in adult mice. Glymphatic influx was quantified across circadian time by cisterna-magna tracer infusion and whole-brain fluorescence imaging, and related to microglial density and morphology assessed by Iba1 immunofluorescence and Sholl analysis in cortex, hippocampus, and amygdala. Sleep-wake architecture and cortical oscillations were evaluated by continuous 24-h EEG/EMG. In controls, microglial density and process complexity showed robust circadian rhythms that aligned with glymphatic timing. P2Y12 blockade reduced microglial density, flattened or rephased structural rhythms, and shifted glymphatic influx across the day-night cycle while preserving overall rhythmicity. Regionally, amygdala tracer signal correlated with Iba1⁺ cell density in controls and this coupling was lost after P2Y12 inhibition. Across regions, glymphatic readouts associated more strongly with microglial morphology than with cell number. EEG/EMG revealed no change in total sleep time with MRS2395, yet sleep architecture was reorganized: stage composition shifted toward NREM at the expense of REM, transitions between REM and NREM increased, bout durations shortened, and spectral power shifted toward slower activity, with higher gamma and lower alpha/theta/beta at multiple time points. These results identify microglial P2Y12 signaling as a temporal organizer that links microglial structural dynamics to perivascular fluid exchange and to sleep-wake organization. Disruption of this pathway alters the phase and stability of glymphatic and sleep rhythms, suggesting a neuroimmune target for conditions with circadian misalignment, sleep fragmentation, or impaired metabolic clearance.
HTRA1 and brain disorders: A balancing act across neurodegeneration and repair.
Hjæresen S, Gramkow ET, Zhang M … +1 more , Fex Svenningsen Å
Prog Neurobiol · 2026 Jun · PMID 41932381 · Publisher ↗
High temperature requirement protein A1 (HTRA1) is a trypsin-like serine protease increasingly recognized as a central regulator of brain homeostasis. HTRA1 is broadly expressed in the brain, where it regulates proteosta...
High temperature requirement protein A1 (HTRA1) is a trypsin-like serine protease increasingly recognized as a central regulator of brain homeostasis. HTRA1 is broadly expressed in the brain, where it regulates proteostasis, extracellular matrix (ECM) remodeling, and important signaling pathways such as TGF-β, Wnt, and Notch. These functions are essential for maintaining blood-brain barrier integrity, supporting tissue repair, and restraining inflammation. HTRA1 is a double-edged sword, as both insufficient and excessive activity can lead to neurodegenerative and vascular pathology. Reduced HTRA1 levels are linked to ECM accumulation and vascular fibrosis, while elevated activity contributes to tissue breakdown, inflammation, and impaired repair. This dual role is implicated in a range of disorders, including cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, small vessel disease, age-related macular degeneration, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. We review recent insights into HTRA1's interactions with ApoE and tau, its roles in lipid and cytoskeletal regulation, and its modulation by inhibitors such as Macrophage Migration Inhibitory Factor. Finally, we explore its biomarker potential and therapeutic targeting strategies. Understanding the mechanisms behind HTRA1's shift from protective to pathological is crucial for developing targeted therapies that preserve its beneficial roles.
Corrigendum to "Cortical hyperexcitability drives dying forward amyotrophic lateral sclerosis symptoms and pathology in mice"[Prog. Neurobiol. 252 (2025) 102809].
Haidar M, Viden A, Daniel C … +17 more , Cuic B, Wang T, Rosier M, Tomas D, Mills SA, Govier-Cole A, Djouma E, Perera ND, Luikinga S, Rytova V, Barton SK, Gonsalvez DG, Palmer LM, McLean C, Kiernan MC, Vucic S, Turner BJ
Prog Neurobiol · 2026 May · PMID 41904090 · Publisher ↗
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Normative modeling of brain function abnormalities in complex pathology requires a whole-brain approach.
Kobbersmed JRL, Gohil C, Marquand A … +1 more , Vidaurre D
Prog Neurobiol · 2026 May · PMID 41856310 · Publisher ↗
Many brain diseases and disorders lack objective measures of brain function as indicators of pathology. The search for brain function biomarkers is complicated by the fact that these conditions are often heterogeneous an...
Many brain diseases and disorders lack objective measures of brain function as indicators of pathology. The search for brain function biomarkers is complicated by the fact that these conditions are often heterogeneous and described as a spectrum from normal to abnormal rather than a sick-healthy dichotomy. Normative modeling addresses these challenges by characterizing the normal variation of brain function given sex and age and identifying abnormalities as deviations from this norm. Focusing on functional connectivity (FC) as a way to capture the network properties of the brain's activity, we here argue that the pathological effects of neurological or psychiatric disease lie at the systemic level, and that whole-brain normative models are more suitable to capture individual variations associated to these complex conditions than existing localized approaches that analyze one connection at a time. To be able to capture the whole-brain effects of disease, we thus propose Functional Connectivity Integrative Normative Modeling (FUNCOIN) as a novel whole-brain approach to normative modeling of FC. Using FUNCOIN and UK Biobank resting-state fMRI data from 46,000 healthy subjects across training and testing sets, we found that subjects with bipolar disorder and Parkinson's disease were significantly, and substantially, more likely than healthy subjects to exhibit abnormal FC patterns, which was not seen in localized models. Subjects with bipolar disorder divided into two distinct subgroups characterized by different brain function deviations. In Parkinson's disease subjects, abnormal FC patterns were significant even on scans up to 8 years before diagnosis.
Human induced pluripotent stem cell-based models for studying neural repair.
Agrawal M, Desai M, Ghumra S … +2 more , Bhorkar Y, Sahoo PK
Prog Neurobiol · 2026 May · PMID 41856309 · Publisher ↗
Injuries and degenerative diseases of the human nervous system result in irreversible functional loss, reflecting the limited regenerative capacity of the central nervous system and the slow repair rate of the peripheral...
Injuries and degenerative diseases of the human nervous system result in irreversible functional loss, reflecting the limited regenerative capacity of the central nervous system and the slow repair rate of the peripheral nervous system. Progress has been hindered by the lack of human-relevant experimental models that accurately capture the cellular diversity, long axonal architecture, and species-specific regulatory mechanisms underlying neural injury and repair. Human induced pluripotent stem cells (iPSCs) have emerged as a transformative platform to bridge this gap, enabling the generation of diverse neuronal and glial subtypes, reconstruction of complex neural circuits, and modeling of injury and regeneration in a human-specific context. In this review, we discuss the recent advances in the use of human iPSC-derived systems to study neural repair, spanning two-dimensional cultures, three-dimensional organoids and assembloids, microengineered axon injury platforms, and in vivo transplantation models. We highlight how these approaches have revealed key intracellular regulators of neurite growth, clarified the impact of disease-associated mutations on axonal integrity, and enabled high-throughput screening of neuroprotective and pro-regenerative compounds. We further discuss the role of iPSC-derived glial cells, Schwann cells, and neuromuscular junction models in elucidating axon-glia interactions, remyelination, and circuit-level repair mechanisms. Together, human iPSC-based models offer unprecedented insight into the cellular and molecular determinants of human neural regeneration, thereby overcoming the limitations of animal systems. While challenges remain in standardization, maturation, and clinical translation, these platforms are redefining regenerative neuroscience and hold promise for the development of patient-specific therapies aimed at restoring function after nervous system injury.
Spinal motoneuron excitability is homeostatically regulated through β-adrenergic neuromodulation in wild-type and presymptomatic SOD1 mice.
Antonucci S, Caron G, Dikwella N … +12 more , Krishnamurthy SS, Harster A, Wasicki B, Zarrin H, Tahanis A, Heuvel FO, Danner SM, Ludolph AC, Grycz K, Bączyk M, Zytnicki D, Roselli F
Prog Neurobiol · 2026 May · PMID 41812870 · Full text
Homeostatic feedback loops are essential to stabilize the activity of neurons and neuronal networks. It has been hypothesized that, in the context of Amyotrophic Lateral Sclerosis (ALS), an excessive gain in feedback loo...
Homeostatic feedback loops are essential to stabilize the activity of neurons and neuronal networks. It has been hypothesized that, in the context of Amyotrophic Lateral Sclerosis (ALS), an excessive gain in feedback loops might hyper- or hypo-excite motoneurons (MNs) and contribute to the pathogenesis. Here, we investigated how the neuromodulation of MN intrinsic properties is homeostatically controlled in presymptomatic adult SOD1(G93A) mice and in the age-matched control WT mice. First, we determined that Adrb2 and Adrb3 adrenergic receptors, which are Gs-coupled receptors and subject to tight and robust feedback loops, are specifically expressed in spinal MNs of both SOD1 and WT mice at P45. We then demonstrated that these receptors elicit a so-far overlooked neuromodulation of the electrical properties of MNs, in particular the frequency-current gain, a crucial determinant of excitability. These electrical properties are homeostatically regulated following receptor engagement, which triggers ion channel transcriptional changes and downregulates those receptors. These homeostatic feedbacks are not dysregulated in presymptomatic SOD1 mice, and they set the MN excitability upon β-adrenergic neuromodulation.
The VGLUT3 positive neurons of the median raphe region promote long-term spatial memory through time-dependent mechanisms.
Fazekas CL, Török B, Szabó A … +5 more , Correia P, Chaves T, Fabre V, Daumas S, Zelena D
Prog Neurobiol · 2026 May · PMID 41802696 · Publisher ↗
Episodic memory and related forms of learning depend critically on the hippocampus, whose activity is regulated by brainstem inputs that remain incompletely understood. The midbrain median raphe region (MRR) is a key reg...
Episodic memory and related forms of learning depend critically on the hippocampus, whose activity is regulated by brainstem inputs that remain incompletely understood. The midbrain median raphe region (MRR) is a key regulator of forebrain circuits and, while classically recognised as serotonergic, many of its neurons also release glutamate. Notably, a subset of MRR neurons projecting to the hippocampus expresses the vesicular glutamate transporter type 3 (VGLUT3), suggesting a glutamatergic contribution. Moreover, electrophysiological data indicate that these MRR-VGLUT3 + neurons influence hippocampal oscillations and therefore, hippocampus-dependent learning and memory. Our goal was to investigate the role of MRR-VGLUT3 + neurons in hippocampus-dependent learning and memory. Using VGLUT3-Cre mice of both sexes, we employed adeno-associated viral vectors to selectively activate MRR-VGLUT3 + neurons during the water maze task, a known hippocampus-dependent behavioural paradigm. Neuronal excitation was achieved by chemogenetics (DREADDs) or, to probe temporally restricted effects, by optogenetics (Channelrhodopsin2) during the spatial reference memory phase. Given the involvement of MRR and VGLUT3 + neurons in locomotion and anxiety-like behaviours, open field and elevated plus maze assays were also performed but yield inconclusive results. We found that chronic chemogenetic excitation did not alter learning but enhanced long-term memory performance, a finding replicated in an independent cohort. In contrast, acute optogenetic excitation had no effect, suggesting that MRR-VGLUT3 + neurons may contribute to memory related processes in a temporally specific manner.
Multiplexed changes in synaptic transmission underlie stress-induced reduction of persistent firing in the parietal cortex.
Proddutur A, Rindner DJ, Azouz G … +2 more , Beier KT, Lur G
Prog Neurobiol · 2026 May · PMID 41763383 · Full text
Repeated exposure to stress disrupts cognitive processes, including attention and working memory. A key mechanism supporting these functions is the ability of neurons to sustain action potential firing, even after a stim...
Repeated exposure to stress disrupts cognitive processes, including attention and working memory. A key mechanism supporting these functions is the ability of neurons to sustain action potential firing, even after a stimulus is no longer present. How stress impacts this persistent neuronal activity is currently unknown. We found that repeated exposure to multiple concurrent stressors during adolescence (aRMS) impedes the ability of layer 5 pyramidal neurons (L5 PNs) in the posterior parietal cortex (PPC) to produce persistent firing. To determine the mechanisms underlying this effect, we complemented computational modelling with whole-cell patch clamp electrophysiology in acute brain slices from male mice. Our model predicted that altered intrinsic excitability, reduced local connectivity, diminished glutamatergic transmission, or enhanced inhibition could explain diminished persistent activity. In ex vivo experiments, we found minimal effect of aRMS on excitability and recurrent connectivity. However, stress exposure altered the properties of excitatory connections between L5 PNs, specifically affecting decay kinetics and short-term synaptic dynamics. In addition, aRMS increased inhibitory tone in the PPC, altering both GABAa and GABAb receptor-mediated responses. Incorporating the observed physiological changes into our network model, we found that no single parameter was sufficient alone to reproduce the stress-induced reduction in persistent firing. Rather, a combination of altered excitatory and inhibitory synaptic transmission was necessary to impact sustained activity. These data suggest that a multitude of converging changes in neural and circuit function underpin the effects of stress on cognitive processes.
The reading brain - Transforming vision into language.
Ghuman AS, Fiez JA, Boring MJ
Prog Neurobiol · 2026 May · PMID 41724370 · Publisher ↗
Reading is built upon transformations that map representations of written words to their pronunciations, names, and meanings. However, unlike many other visual skills, literacy is unique to humans and has only become wid...
Reading is built upon transformations that map representations of written words to their pronunciations, names, and meanings. However, unlike many other visual skills, literacy is unique to humans and has only become widespread in the past few hundred years, therefore neural circuits that underly reading cannot have evolved for reading. Thus, scientists have long debated the nature of the neural re-tuning of visual networks that must occur to support these transformations in a highly skilled manner. A key node of the reading brain, the visual word form area (VWFA), lies where circuits that underpin key aspects of visuolinguistic transformations diverge from earlier visual processing in ventral occipitotemporal cortex. Furthermore, different reading deficits co-occur with parallel deficits in these visuolinguistic transformations. Evidence suggests that as literacy is acquired during development, preexisting visuolinguistic circuits that support representational transformations compatible with reading become tuned for understanding written words. This model implies that the VWFA is where it is because reading requires functional capacities that are parallel to those needed to recognize and name objects on one hand and those needed for multimodal integration during speech/language comprehension on the other. The VWFA is at a key location that gets input from earlier visual regions and has lateral connectivity into the auditory-visual speech and language network and ventral connectivity into visual naming circuits. We review neurophysiological, neuroanatomical, and neurodevelopmental evidence that support a model in which literacy emerges from the specialization of preexisting circuits that have the natural capacities for vision to linguistic transformations needed to acquire and facilitate fluent reading.
Divergent hippocampal output via covariant local and long-range neuronal structure.
Campbell RE, Zhang MY, Merryweather DN … +1 more , Cembrowski MS
Prog Neurobiol · 2026 Apr · PMID 41720209 · Publisher ↗
Understanding the brain's structural architecture and organizational logic is essential for interpreting brain function. Morphological properties are well-known to discretely separate distinct types of cells and influenc...
Understanding the brain's structural architecture and organizational logic is essential for interpreting brain function. Morphological properties are well-known to discretely separate distinct types of cells and influence their respective computations, but whether finer-scale morphological differences within narrowly-defined cell types can govern disparate computations remains unknown. Here, we address this question by focusing on long-range projection neurons of the subiculum, the primary output cells of the hippocampus. We used high-resolution whole-brain neuronal reconstructions to concomitantly examine local and long-range neuronal architecture, as well as computational modeling to identify how projection-specific morphology shapes circuit computation. Our results reveal that subiculum projection neurons have a high degree of "matched complexity" between dendritic and axonal patterning, and that this dendritic-axonal covariation can lead to projection-specific input-output operations. Extending this work with viral circuit tracing, we further illustrate that subiculum neurons embedded within different long-range circuits exhibit spatially distinct local dendritic domains, suggesting these projection streams also receive fundamentally distinct types of input. This covariance of single-cell dendritic morphology with long-range neural targets illustrates a new form of organizational logic for hippocampal circuits, and likely plays a key role in driving distinct computations across hippocampal output pathways.
Multiple neural networks from cognition to motivation of prosocial behaviour in rodents: Potential mechanism between empathy and autism spectrum disorder.
Lv C, Song D, Ni J … +2 more , Qing H, Quan Z
Prog Neurobiol · 2026 Apr · PMID 41655884 · Publisher ↗
Prosocial behaviour, as a facet of social behaviour across species, entails voluntary actions that benefit others, including helping and comforting behaviours. To explain how external sensory information is integrated to...
Prosocial behaviour, as a facet of social behaviour across species, entails voluntary actions that benefit others, including helping and comforting behaviours. To explain how external sensory information is integrated to generate motivation and ultimately govern prosocial action, we organize its emergence into three interacting components: a social orientation process centered on the superior colliculus (SC), which selects and evaluates social cues and calibrates attention and arousal; a framework formed by the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC), which transforms perceived distress into internal representations, forming empathic memory that guides subsequent behavior; and neuromodulatory systems (e.g., oxytocin and dopamine) together with projections linking the insular cortex (IC), thalamus, and ventral tegmental area (VTA), that compose social motivation, assign value to prosocial acts and promote helping. Evidence across these processes suggests alignment and potential generalisation in autism spectrum disorder (ASD), which is marked by atypical attention to social signals and diminished responsiveness to social reward. We define prosocial neural network mapping as the characterisation of interregional projections and their neuromodulatory regulation to explain how social information is organised and transformed, offering new insights into circuit-level pathology in ASD and helping identify therapeutic targets aimed at restoring social salience and enhancing social motivation.
ABCA7 deficiency exacerbates glutamate excitotoxicity in Alzheimer's disease mice - A new pharmacological target for Glu-related neurotoxicity.
Górska AM, Santos-García I, Kvasnička A … +4 more , Dobešová D, Friedecký D, Gildenblat J, Pahnke J
Prog Neurobiol · 2026 Apr · PMID 41651103 · Publisher ↗
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 f...
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. 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.
Molecular mechanisms of age-related vulnerability to traumatic brain injury.
Joshi P, Vemuganti R
Prog Neurobiol · 2026 Mar · PMID 41620071 · Full text
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 molecul...
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.
Mixed-selective organization of reach and grasp in the primate fronto-parietal network.
Fathian A, Lehmann SJ, Michaels JA … +1 more , Scherberger H
Prog Neurobiol · 2026 Mar · PMID 41620070 · Publisher ↗
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 premo...
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.
The flexible synapse - How mossy fiber architecture adapts to changing needs.
Bruentgens F, Schmitz D, Orlando M
Prog Neurobiol · 2026 Mar · PMID 41587599 · Publisher ↗
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 leadin...
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.
Sustained inhibitory dysfunction in complement component C1qa-deficient mice underlies epilepsy and comorbidities.
Righes Marafiga J, Vu T, Bowlus J … +1 more , Baraban SC
Prog Neurobiol · 2026 Mar · PMID 41544964 · Publisher ↗
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 ci...
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.
Orthogonal neural geometry of orientation, spatial frequency, and ocular dominance in macaque V1.
Wang X, Zhang SH, Tang SM … +1 more , Yu C
Prog Neurobiol · 2026 Mar · PMID 41478519 · Publisher ↗
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...
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.
Prefrontal cortex interneurons and their contributions to attention, working memory, and adaptive behavior.
Boroujeni KB, Balaram P, Tiesinga P … +1 more , Womelsdorf T
Prog Neurobiol · 2026 Mar · PMID 41478518 · Full text
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 i...
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 'eType' interneurons are recruited during attention, learning, and working memory tasks. In nonhuman primate PFC, eType 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.
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