Neurobiology of Disease最新文献

{"title":"Potentiation of the M1 muscarinic acetylcholine receptor normalizes neuronal activation patterns and improves apnea severity in Mecp2+/− mice","authors":"Mackenzie Smith ,&nbsp;Grace E. Dodis ,&nbsp;Amanda M. Vanderplow ,&nbsp;Sonia Gonzalez ,&nbsp;Yewon Rhee ,&nbsp;Karie Scrogin ,&nbsp;Rocco G. Gogliotti","doi":"10.1016/j.nbd.2025.106859","DOIUrl":"10.1016/j.nbd.2025.106859","url":null,"abstract":"<div><div>Rett syndrome (RTT) is a neurodevelopmental disorder that is caused by loss-of-function mutations in the <em>methyl-CpG binding protein 2</em> (<em>MeCP2</em>) gene. RTT patients experience a myriad of debilitating symptoms, which include respiratory phenotypes that are often associated with lethality. Our previous work established that expression of the M₁ muscarinic acetylcholine receptor (mAchR) is decreased in RTT autopsy samples, and that potentiation of the M₁ receptor improves apneas in a mouse model of RTT; however, the population of neurons driving this rescue is unclear. Loss of Mecp2 correlates with excessive neuronal activity in cardiorespiratory nuclei. Since M₁ is found on cholinergic interneurons, we hypothesized that M₁-potentiating compounds decrease apnea frequency by tempering brainstem hyperactivity. To test this, <em>Mecp2</em>^{<em>+/−</em>} and <em>Mecp2</em>^<em>+/+</em> mice were screened for apneas before and after administration of the M₁ positive allosteric modulator (PAM) VU0453595 (VU595). Brains from the same mice were then imaged for c-Fos, ChAT, and Syto16 using whole-brain light-sheet microscopy to establish genotype and drug-dependent activation patterns that could be correlated with VU595's efficacy on apneas. The vehicle-treated <em>Mecp2</em>^{<em>+/−</em>} brain exhibited broad hyperactivity when coupled with the phenotypic prescreen, which was significantly decreased by administration of VU595, particularly in regions known to modulate the activity of respiratory nuclei (i.e. hippocampus and striatum). Further, the extent of apnea rescue in each mouse showed a significant positive correlation with c-Fos expression in non-cholinergic neurons in the striatum, thalamus, dentate gyrus, and within the cholinergic neurons of the brainstem. These results indicate that <em>Mecp2</em>^{<em>+/−</em>} mice are prone to hyperactivity in brain regions that regulate respiration, which can be normalized through M₁ potentiation.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106859"},"PeriodicalIF":5.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tsc1 deletion in Purkinje neurons disrupts the axon initial segment, impairing excitability and cerebellar function","authors":"Samuel P. Brown ,&nbsp;Achintya K. Jena ,&nbsp;Joanna J. Osko,&nbsp;Joseph L. Ransdell","doi":"10.1016/j.nbd.2025.106856","DOIUrl":"10.1016/j.nbd.2025.106856","url":null,"abstract":"<div><div>Loss-of-function mutations in tuberous sclerosis 1 (<em>TSC1</em>) are prevalent monogenic causes of autism spectrum disorder (ASD). Selective deletion of <em>Tsc1</em> from mouse cerebellar Purkinje neurons has been shown to cause several ASD-linked behavioral impairments, which are linked to reduced Purkinje neuron repetitive firing rates. We used electrophysiology methods to investigate why Purkinje neuron-specific <em>Tsc1</em> deletion (<em>Tsc1</em>^{<em>mut/mut</em>}) impairs Purkinje neuron firing. These studies revealed a depolarized shift in action potential threshold voltage, an effect that we link to reduced expression of the fast-transient voltage-gated sodium (Nav) current in <em>Tsc1</em>^{<em>mut/mut</em>} Purkinje neurons. The reduced Nav currents in these cells was associated with diminished secondary immunofluorescence from anti-pan Nav channel labeling at Purkinje neuron axon initial segments (AIS). Anti-ankyrinG immunofluorescence was also found to be significantly reduced at the AIS of <em>Tsc1</em>^{<em>mut/mut</em>} Purkinje neurons, suggesting Tsc1 is necessary for the organization and functioning of the Purkinje neuron AIS. An analysis of the 1st and 2nd derivative of the action potential voltage-waveform supported this hypothesis, revealing spike initiation and propagation from the AIS of <em>Tsc1</em>^{<em>mut/mut</em>} Purkinje neurons is impaired compared to age-matched control Purkinje neurons. Heterozygous <em>Tsc1</em> deletion resulted in no significant changes in the firing properties of adult Purkinje neurons, and slight reductions in anti-pan Nav and anti-ankyrinG labeling at the Purkinje neuron AIS, revealing deficits in Purkinje neuron firing due to <em>Tsc1</em> haploinsufficiency are delayed compared to age-matched <em>Tsc1</em>^{<em>mut/mut</em>} Purkinje neurons. Together, these data reveal that the loss of <em>Tsc1</em> impairs Purkinje neuron firing and membrane excitability through the dysregulation of proteins essential for AIS organization and function.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106856"},"PeriodicalIF":5.1,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of efferocytosis in chronic pain —— From molecular perspective","authors":"Hu Zang,&nbsp;Xiaoyu Ji,&nbsp;Wenlong Yao,&nbsp;Li Wan,&nbsp;Chuanhan Zhang,&nbsp;Chang Zhu,&nbsp;Tongtong Liu","doi":"10.1016/j.nbd.2025.106857","DOIUrl":"10.1016/j.nbd.2025.106857","url":null,"abstract":"<div><div>The complex nature of pain pathophysiology complicates the establishment of objective diagnostic criteria and targeted treatments. The heterogeneous manifestations of pain stemming from various primary diseases contribute to the complexity and diversity of underlying mechanisms, leading to challenges in treatment efficacy and undesirable side effects. Recent evidence suggests the presence of apoptotic cells at injury sites, the distal dorsal root ganglia (DRG), spinal cord, and certain brain regions, indicating a potential link between the ineffective clearance of dead cells and debris and pain persistence. This review highlights recent research findings indicating that efferocytosis plays a significant yet often overlooked role in lesion expansion while also representing a potentially reversible impairment that could be targeted therapeutically to mitigate chronic pain progression. We examine recent advances into how efferocytosis, a process by which phagocytes clear apoptotic cells without triggering inflammation, influences pain initiation and intensity in both human diseases and animal models. This review summarizes that efferocytosis contributes to pain progression from the perspective of defective and inefficient efferocytosis and its subsequent secondary necrocytosis, cascade inflammatory response, and the shift of phenotypic plasticity and metabolism. Additionally, we investigate the roles of newly discovered genetic alterations or modifications in biological signaling pathways in pain development and chronicity, providing insights into innovative treatment strategies that modulate efferocytosis, which are promising candidates and potential avenues for further research in pain management and prevention.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106857"},"PeriodicalIF":5.1,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Essential tremor disrupts rhythmic brain networks during naturalistic movement","authors":"Timothy O. West ,&nbsp;Kenan Steidel ,&nbsp;Tjalda Flessner ,&nbsp;Alexander Calvano ,&nbsp;Deniz Kucukahmetler ,&nbsp;Mariëlle J. Stam ,&nbsp;Meaghan E. Spedden ,&nbsp;Benedikt Wahl ,&nbsp;Veikko Jousmäki ,&nbsp;John Eraifej ,&nbsp;Ashwini Oswal ,&nbsp;Tabish A. Saifee ,&nbsp;Gareth Barnes ,&nbsp;Simon F. Farmer ,&nbsp;David J. Pedrosa ,&nbsp;Hayriye Cagnan","doi":"10.1016/j.nbd.2025.106858","DOIUrl":"10.1016/j.nbd.2025.106858","url":null,"abstract":"<div><div>Essential Tremor (ET) is a very common neurological disorder characterised by involuntary rhythmic movements attributable to pathological synchronization within corticothalamic circuits. Previous work has focused on tremor in isolation, overlooking broader disturbances to motor control during naturalistic movements such as reaching. We hypothesised that ET disrupts the sequential engagement of large-scale rhythmic brain networks, leading to both tremor and deficits in motor planning and execution. To test this, we performed whole-head neuroimaging during an upper-limb reaching task using high-density electroencephalography in ET patients and healthy controls, alongside optically pumped magnetoencephalography in a smaller cohort. Key motor regions—including the supplementary motor area, premotor cortex, posterior parietal cortex, and motor cerebellum—were synchronized to tremor rhythms. Patients exhibited a 15 % increase in low beta (14–21 Hz) desynchronization over the supplementary motor area during movement, which strongly correlated with tremor severity (R² = 0.85). A novel dimensionality reduction technique revealed four distinct networks accounting for 97 % of the variance in motor-related brain-wide oscillations, with ET altering their sequential engagement. Consistent with our hypothesis, the frontoparietal beta network- normally involved in motor planning-exhibited additional desynchronization during movement execution in ET patients. This altered engagement correlated with slower movement velocities, suggesting an adaptation towards feedback-driven motor control. These findings reveal fundamental disruptions in distributed motor control networks in ET and identify novel biomarkers as targets for next-generation brain stimulation therapies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106858"},"PeriodicalIF":5.1,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing spinal circuit reorganization for targeted functional recovery after spinal cord injury","authors":"Xin Sun ,&nbsp;Lijuan Li ,&nbsp;Liyi Huang ,&nbsp;Yangan Li ,&nbsp;Lu Wang ,&nbsp;Quan Wei","doi":"10.1016/j.nbd.2025.106854","DOIUrl":"10.1016/j.nbd.2025.106854","url":null,"abstract":"<div><div>Spinal cord injury (SCI) disrupts the communication between the brain and spinal cord, resulting in the loss of motor function below the injury site. However, spontaneous structural and functional plasticity occurs in neural circuits after SCI, with unaffected synaptic inputs forming new connections and detour pathways to support recovery. The review discusses various mechanisms of circuit reorganization post-SCI, including supraspinal pathways, spinal interneurons, and spinal central pattern generators. Functional recovery may rely on maintaining a balance between excitatory and inhibitory neural activity, as well as enhancing proprioceptive input, which plays a key role in limb stability. The review emphasizes the importance of endogenous neuronal regeneration, neuromodulation therapies (such as electrical stimulation) and proprioception in SCI treatment. Future research should integrate advanced technologies such as gene targeting, imaging, and single-cell mapping to better understand the mechanisms underpinning SCI recovery, aiming to identify key neuronal subpopulations for targeted reconstruction and enhanced functional recovery. By harnessing spinal circuit reorganization, these efforts hold the potential to pave the way for more precise and effective strategies for functional recovery after SCI.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106854"},"PeriodicalIF":5.1,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulated balance of D- and L-amino acids modulating glutamatergic neurotransmission in severe spinal muscular atrophy","authors":"Amber Hassan ,&nbsp;Raffaella di Vito ,&nbsp;Tommaso Nuzzo ,&nbsp;Matteo Vidali ,&nbsp;Maria Jose Carlini ,&nbsp;Shubhi Yadav ,&nbsp;Hua Yang ,&nbsp;Adele D'Amico ,&nbsp;Xhesika Kolici ,&nbsp;Valeria Valsecchi ,&nbsp;Chiara Panicucci ,&nbsp;Giuseppe Pignataro ,&nbsp;Claudio Bruno ,&nbsp;Enrico Bertini ,&nbsp;Francesco Errico ,&nbsp;Livio Pellizzoni ,&nbsp;Alessandro Usiello","doi":"10.1016/j.nbd.2025.106849","DOIUrl":"10.1016/j.nbd.2025.106849","url":null,"abstract":"<div><div>Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by reduced expression of the survival motor neuron (SMN) protein. In addition to motor neuron survival, SMN deficiency affects the integrity and function of afferent synapses that provide glutamatergic excitatory drive essential for motor neuron firing and muscle contraction. However, it is unknown whether deficits in the metabolism of excitatory amino acids and their precursors contribute to neuronal dysfunction in SMA. To address this issue, we measured the levels of the main neuroactive D- and L-amino acids acting on glutamatergic receptors in the central nervous system of SMN∆7 mice as well as the cerebrospinal fluid (CSF) of SMA patients of varying severity before and after treatment with the SMN-inducing drug Nusinersen. Our findings reveal that SMN deficiency is associated with disruption of glutamate and serine metabolism in the CSF of severe SMA patients, including decreased concentration of L-glutamate, which is partially corrected by Nusinersen therapy. Moreover, we identify dysregulated <span>l</span>-glutamine/L-glutamate ratio as a shared neurochemical signature of altered glutamatergic synapse metabolism that implicates neuron-astrocyte dysfunction in both severe SMA patients and mouse models. Lastly, consistent with hypo-glutamatergic neurotransmission in SMA, we show that daily supplementation with the NMDA receptor co-agonist <span>d</span>-serine improves neurological deficits in SMN∆7 mice. Altogether, these findings provide direct evidence for central dysregulation of D- and L-amino acid metabolism linked to glutamatergic neurotransmission in severe SMA and have potential implications for treating this neurological disorder.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106849"},"PeriodicalIF":5.1,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards a better diagnosis and treatment of dementia: Identifying common and distinct neuropathological mechanisms in Alzheimer's and vascular dementia","authors":"Alisa Vollhardt ,&nbsp;Lutz Frölich ,&nbsp;Anna Christina Stockbauer ,&nbsp;Adrian Danek ,&nbsp;Christoph Schmitz ,&nbsp;Anna-Sophia Wahl","doi":"10.1016/j.nbd.2025.106845","DOIUrl":"10.1016/j.nbd.2025.106845","url":null,"abstract":"<div><div>Alzheimer's disease (AD) and vascular dementia (VaD) together contribute to almost 90 % of all dementia cases leading to major health challenges of our time with a substantial global socioeconomic burden. While in AD, the improved understanding of Amyloid beta (Aß) mismetabolism and tau hyperphosphorylation as pathophysiological hallmarks has led to significant clinical breakthroughs, similar advances in VaD are lacking. After comparing the clinical presentation, including risk factors, disease patterns, course of diseases and further diagnostic parameters for both forms of dementia, we highlight the importance of shared pathomechanisms found in AD and VaD: Endothelial damage, blood brain barrier (BBB) breakdown and hypoperfusion inducing oxidative stress and inflammation and thus trophic uncoupling in the neurovascular unit. A dysfunctional endothelium and BBB lead to the accumulation of neurotoxic molecules and Aß through impaired clearance, which in turn leads to neurodegeneration. In this context we discuss possible neuropathological parameters, which might serve as biomarkers and thus improve diagnostic accuracy or reveal targets for novel therapeutic strategies for both forms of dementia.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106845"},"PeriodicalIF":5.1,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An unraveled mystery: What's the role of brain sphingolipids in neurodegenerative and psychiatric disorders","authors":"Xintian Bie ,&nbsp;Maoxing Zhang ,&nbsp;Qingyu Wang ,&nbsp;Ying Wang","doi":"10.1016/j.nbd.2025.106852","DOIUrl":"10.1016/j.nbd.2025.106852","url":null,"abstract":"<div><div>Sphingolipids are a class of lipids highly expressed in brain, especially in the myelin sheath of white matter. In recent years, with the development of lipidomics, the role of brain sphingolipids in neurological disorders have raised lots of interests due to their function in neuronal signal transduction and survival. Although not thoroughly investigated, some previous studies have indicated that sphingolipids homeostasis are closely linked to the etiology and development of some neurological disorders. For example, disrupted sphingolipids level have been found in clinic patients with neurological disorders, such as neurodegeneration and psychiatric disorders. Conversely, intervention of sphingolipids metabolism by modulating activity of related enzymes also could result in pathological deficits identified in neurological disorders. Moreover, the alteration of sphingolipids catabolic pathway in the brain could be partly represented in cerebrospinal fluid and blood tissues, which show diagnostic potential for neurological disorders. Therefore, our review aims to summarize and discuss the known contents of bioactive sphingolipid metabolism with their related studies in neurodegenerative and psychiatric disorders, to help understand the potential mechanism underlying sphingolipid regulation of neural function and provide possible directions for further study. The new perspectives in this promising field will open up new therapeutic options for neurological disorders.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106852"},"PeriodicalIF":5.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143465065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycosphingolipids in neurodegeneration – Molecular mechanisms, cellular roles, and therapeutic perspectives","authors":"Andreas J. Hülsmeier","doi":"10.1016/j.nbd.2025.106851","DOIUrl":"10.1016/j.nbd.2025.106851","url":null,"abstract":"<div><div>Neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neuronal loss and pose significant global health challenges. Glycosphingolipids (GSLs), critical components of neuronal membranes, regulate signal transduction, membrane organization, neuroinflammation, and lipid raft functionality. This review explores GSL roles in neural development, differentiation, and neurogenesis, along with their dysregulation in neurodegenerative diseases. Aberrations in GSL metabolism drive key pathological features such as protein aggregation, neuroinflammation, and impaired signaling. Specific GSLs, such as GM1, GD3, and GM3, influence amyloid-beta aggregation in AD, α-synuclein stability in PD, and mutant huntingtin toxicity in HD. Therapeutic strategies targeting GSL metabolism, such as GM1 supplementation and enzyme modulation, have demonstrated potential to mitigate disease progression. Further studies using advanced lipidomics and glycomics may support biomarker identification and therapeutic advancements. This work aims to highlight the translational potential of GSL research for diagnosing and managing devastating neurodegenerative conditions.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106851"},"PeriodicalIF":5.1,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deficits in taste-guided behaviors and central processing of taste in the transgenic TDP-43Q331K mouse model of frontotemporal dementia","authors":"Camelia Yuejiao Zheng ,&nbsp;Jennifer M. Blackwell ,&nbsp;Alfredo Fontanini","doi":"10.1016/j.nbd.2025.106850","DOIUrl":"10.1016/j.nbd.2025.106850","url":null,"abstract":"<div><div>Frontotemporal dementia (FTD) is the second most prevalent form of presenile dementia. Patients with FTD show prominent chemosensory symptoms such as abnormal detection and recognition thresholds for various gustatory stimuli. The chemosensory symptoms of FTD may be related to damage of the gustatory insular cortex (GC) as the insular cortex is one of the primary targets in FTD disease progression. Little is known about how circuitry changes in GC lead to deficits in taste processing in FTD. Here we tested the hypothesis that gustatory deficits are present in a mouse model of FTD, and that they are related to abnormal patterns of neural activity in GC. We behaviorally evaluated a transgenic FTD mouse model overexpressing human TDP-43 with a Q331K mutation (TDP-43^Q331K) in a brief access test and a taste-based two alternative forced choice (2AFC) task probing the ability to discriminate sucrose/NaCl mixtures. TDP-43^Q331K mice showed abnormal sucrose consumption and an impaired ability to discriminate taste mixtures compared to non-transgenic control mice. To assess deficits in GC taste processing, we relied on electrophysiological recordings using chronically implanted tetrodes in alert TDP-43^Q331K and non-transgenic control mice. The proportion of taste-selective neurons in TDP-43^Q331K mice decreased over time compared to control mice. Similarly, encoding of chemosensory information and processing of taste palatability were impaired in TDP-43^Q331K mice compared to control mice. Overall, these results demonstrate taste-related symptoms in a mouse model of FTD and provide evidence for altered taste processing in GC of TDP-43^Q331K mice compared to control mice.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106850"},"PeriodicalIF":5.1,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143454159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}