Journal of Neuroscience最新文献

{"title":"The Temporal Organization of Learned Vocal Behavior Is Predicted by Species Rather Than Experience.","authors":"Jacob A Edwards, Moises Rivera, Sarah M N Woolley","doi":"10.1523/JNEUROSCI.0576-24.2025","DOIUrl":"10.1523/JNEUROSCI.0576-24.2025","url":null,"abstract":"<p><p>Birdsong is hierarchically organized in time, like speech and other communication behaviors. Syllables are produced in sequences to form song motifs and bouts. While syllables are copied from tutors, the factors that determine song temporal organization, including syllable sequencing (syntax), are unknown. Here, we tested the roles of learning and species genetics in song organization. We manipulated juvenile song experience and genetics in three species of estrildid finches (zebra finches, <i>Taeniopygia guttata castanotis</i>; long-tailed finches, <i>Poephila acuticauda</i>; Bengalese finches, <i>Lonchura striata</i> var. <i>domestica</i>). We analyzed the adult songs of male birds that were: (1) tutored by conspecifics; (2) untutored; (3) tutored by heterospecifics; and (4) genetic hybrids. Song macrostructure, syllable sequencing, and syllable timing were quantified and compared within and across species. Results showed that song organization was consistent within a species and differed across species, regardless of experience. Temporal features did not differ between tutored and untutored birds of the same species. The songs of birds tutored by other species were composed of heterospecific syllables produced in sequences typical of conspecific songs. The songs of genetic hybrids showed the organization of both parental species, despite the fact that only males sing. Results indicate that song organization is predicted by species rather than experience.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076207","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":"Reference Frames for Encoding of Translation and Tilt in the Caudal Cerebellar Vermis.","authors":"Félix Buron, Christophe Z Martin, Jessica X Brooks, Andrea M Green","doi":"10.1523/JNEUROSCI.0135-24.2025","DOIUrl":"10.1523/JNEUROSCI.0135-24.2025","url":null,"abstract":"<p><p>Many daily behaviors rely on estimates of our body's motion and orientation in space. Vestibular signals are essential for such estimates, but to contribute appropriately, two key computations are required. First, ambiguous motion information from otolith organs must be combined with spatially transformed rotational signals (e.g., from the canals) to distinguish head translation from tilt. Second, tilt and translation estimates must be transformed from a head- to a body-centered reference frame to correctly interpret the body's motion. Studies have shown that cells in the caudal cerebellar vermis (nodulus and ventral uvula, NU) reflect the output of the first set of computations to estimate translation and tilt. However, it remains unknown whether these estimates are encoded exclusively in head-centered coordinates or whether they reflect further transformation toward body-centered coordinates. Here, we addressed this question by examining how the 3D spatial tuning of otolith and canal signals on translation- and tilt-selective NU Purkinje cells in male rhesus monkeys varies with changes in head-re-body and body-re-gravity orientation. We show that NU cell tuning properties are consistent with head-centered otolith signal coding during translation. Furthermore, while canal signals in the NU have been transformed into a specific world-referenced rotation signal indicating reorientation relative to gravity (tilt), as needed to resolve the tilt/translation ambiguity, the resulting tilt estimates are encoded in head-centered coordinates. Our results thus suggest that body-centered motion and orientation estimates required for postural control, navigation, and reaching are computed elsewhere, either by further transforming NU outputs or via computations in other parallel pathways.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400522","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":"Retraction: Larson et al., \"The Complex PrP^c-Fyn Couples Human Oligomeric Aβ with Pathological Tau Changes in Alzheimer's Disease\".","authors":"","doi":"10.1523/JNEUROSCI.0301-25.2025","DOIUrl":"10.1523/JNEUROSCI.0301-25.2025","url":null,"abstract":"","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574488","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":"Motor preparation tracks decision boundary crossing rather than accumulated evidence in temporal decision-making.","authors":"Nir Ofir, Ayelet N Landau","doi":"10.1523/JNEUROSCI.1675-24.2025","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1675-24.2025","url":null,"abstract":"<p><p>Interval timing, the ability of animals to estimate the passage of time, is thought to involve diverse neural processes rather than a single central \"clock\" (Paton & Buonomano, 2018). Each of the different processes engaged in interval timing follows a different dynamic path, according to its specific function. For example, attention tracks anticipated events, such as offsets of intervals (Rohenkohl & Nobre, 2011), while motor processes control the timing of the behavioral output (De Lafuente et al., 2024). However, which processes are involved and how they are orchestrated over time to produce a temporal decision remains unknown. Here, we study motor preparation in the temporal bisection task, in which Human (Female and male) participants categorized intervals as \"long\" or \"short\". In contrast to typical perceptual decisions, where motor plans for all response alternatives are prepared simultaneously (Shadlen & Kiani, 2013), we find that temporal bisection decisions develop sequentially. While preparation for \"long\" responses was already underway before interval offset, no preparation was found for \"short\" responses. Furthermore, within intervals categorized as \"long\", motor preparation was stronger at interval offset for faster responses. Our findings support the two-stage model of temporal decisions, where \"long\" decisions are considered during the interval itself, while \"short\" decisions are only considered after the interval is over. Viewed from a wider perspective, our study offers methods to study the neural mechanisms of temporal decisions, by studying the multiple processes that produce them.<b>Significance Statement</b> Interval timing is thought to rely on multiple neural processes, yet little is known about which processes are involved, and how they are organized in time. We recorded the EEG of Human participants while they performed a simple temporal decision task, and focused on mu-beta activity, a signature of motor preparation. In typical non-temporal perceptual decisions, mu-beta activity reflects the accumulation of evidence. We find that in temporal decision-making, mu-beta reflects the commitment of the decision instead. This distinction stems from the uniqueness of temporal decisions, in which alternatives are considered sequentially rather than simultaneously. Studying temporal decisions as the dynamic orchestration of multiple neural processes offers a new approach to study the neural mechanisms underlying the perception of time.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607053","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":"Medial orbitofrontal, prefrontal and amygdalar circuits support dissociable component processes of risk/reward decision making.","authors":"Nicole L Jenni, Debra A Bercovici, Stan B Floresco","doi":"10.1523/JNEUROSCI.2147-24.2025","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.2147-24.2025","url":null,"abstract":"<p><p>The medial orbitofrontal cortex (mOFC) has been implicated in shaping decisions involving reward uncertainty, in part by using memories to infer future outcomes. This region is interconnected with other key systems that mediated these decisions, including the basolateral amygdala (BLA) and prelimbic (PL) region of the medial prefrontal cortex, yet the functional importance of these circuits remains unclear. The present study used chemogenetic silencing to examine the contribution of different input and output pathways of the mOFC to risk/reward decision making. Male rats were well-trained on a probabilistic discounting task where they chose between a small/certain (1 pellet) and a large/uncertain 4 pellet option, the odds for which changed systematically across a session. Suppressing activity of descending mOFC terminals in the BLA impaired adjustment in choice biases as reward probabilities change, suggesting this circuit tracks changes in relative value to support flexible reward-seeking. Inhibiting bottom-up BLA→mOFC circuits had no effect on choice. With respect to cortico-cortical circuits, inhibiting mOFC inputs to PL led to more random choice patterns, indicating this circuit promotes advantageous choice by processing context-dependent information regarding wins and losses. In comparison, PL inputs to mOFC attenuates the allure of larger yet uncertain rewards and reduces loss sensitivity, particularly early in the choice sequence. The present findings provide novel insight into the functional contribution that mOFC/BLA and PL interactions make to distinct processes that shape decision making in situations of reward uncertainty.<b>Significance Statement</b> The medial orbitofrontal cortex supports the use of reward memories to guide efficient value-based decision-making, yet the functional circuits through which it mediates this form of cognition is unclear. The present study revealed that different mOFC interactions with the BLA and the PL facilitate dissociable component processes of decisions involving risks and rewards. These findings clarify the functions of cortico-cortical and cortico-amygdalar pathways and may have implications for understanding how dysfunction in these circuits relates to aberrant decision making seen in certain psychiatric disorders.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143606988","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":"Response of neuronal populations to phase-locked stimulation: model-based predictions and validation.","authors":"Nima Mirkhani, Colin G McNamara, Gaspard Oliviers, Andrew Sharott, Benoit Duchet, Rafal Bogacz","doi":"10.1523/JNEUROSCI.2269-24.2025","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.2269-24.2025","url":null,"abstract":"<p><p>Modulation of neuronal oscillations holds promise for the treatment of neurological disorders. Nonetheless, conventional stimulation in a continuous open-loop manner can lead to side effects and suboptimal efficiency. Closed-loop strategies such as phase-locked stimulation aim to address these shortcomings by offering a more targeted modulation. While theories have been developed to understand the neural response to stimulation, their predictions have not been thoroughly tested using experimental data. Using a mechanistic coupled oscillator model, we elaborate on two key predictions describing the response to stimulation as a function of the phase and amplitude of ongoing neural activity. To investigate these predictions, we analyze electrocorticogram recordings from a previously conducted study in Parkinsonian rats, and extract the corresponding phase and response curves. We demonstrate that the amplitude response to stimulation is strongly correlated to the derivative of the phase response ([Formula: see text] > 0.8) in all animals except one, thereby validating a key model prediction. The second prediction postulates that the stimulation becomes ineffective when the network synchrony is high, a trend that appeared missing in the data. Our analysis explains this discrepancy by showing that the neural populations in Parkinsonian rats did not reach the level of synchrony for which the theory would predict ineffective stimulation. Our results highlight the potential of fine-tuning stimulation paradigms informed by mathematical models that consider both the ongoing phase and amplitude of the targeted neural oscillation.<b>Significance Statement</b> This study validates a mathematical model of coupled oscillators in predicting the response of neural activity to stimulation for the first time. Our findings also offer further insights beyond this validation. For instance, the demonstrated correlation between phase response and amplitude response is indeed a key theoretical concept within a subset of mathematical models. This prediction can bring about clinical implications in terms of predictive power for manipulation of neural activity. Additionally, while phase dependence in modulation has been previously studied, we propose a general framework for studying amplitude dependence as well. Lastly, our study reconciles the seemingly contradictory views of pathologic hypersynchrony and theoretical low synchrony in Parkinson's disease.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607055","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":"Frontostriatal Networks Undergo Functional Specialization During Adolescence that Follows a Ventral-Dorsal Gradient: Developmental Trajectories and Longitudinal Associations.","authors":"Samuel D Klein, Paul F Collins, Vanessa Lozano-Wun, Peter Grund, Monica Luciana","doi":"10.1523/JNEUROSCI.1233-23.2025","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1233-23.2025","url":null,"abstract":"<p><p>Seminal studies in animal neuroscience demonstrate that frontostriatal circuits exhibit a ventral-dorsal functional gradient to integrate neural functions related to reward processing and cognitive control. Prominent neurodevelopmental models posit that heightened reward-seeking and risk-taking during adolescence result from maturational imbalances between frontostriatal neural systems underlying reward processing and cognitive control. The present study investigated whether the development of ventral (VS) and dorsal (DS) striatal resting-state connectivity (rsFC) networks along this proposed functional gradient relates to putative imbalances between reward and executive systems posited by a dual neural systems theory of adolescent development. 163 participants aged 11-25 years (54% female, 90% white) underwent resting scans at baseline and biennially thereafter, yielding 339 scans across four assessment waves. We observed developmental increases in VS rsFC with brain areas implicated in reward processing (e.g., subgenual cingulate gyrus and medial orbitofrontal cortex) and concurrent decreases with areas implicated in executive function (e.g., ventrolateral and dorsolateral prefrontal cortices). DS rsFC exhibited the opposite pattern. More rapid developmental increases in VS rsFC with reward areas were associated with developmental improvements in reward-based decision making, whereas increases in DS rsFC with executive function areas were associated with improved executive function, though each network exhibited some crossover in function. Collectively, these findings suggest that typical adolescent neurodevelopment is characterized by a divergence in ventral and dorsal frontostriatal connectivity that may relate to developmental improvements in affective decision-making and executive function.<b>Significance Statement</b> Anatomical studies in nonhuman primates demonstrate that frontostriatal circuits are essential for integration of neural functions underlying reward processing and cognition, with human neuroimaging studies linking alterations in these circuits to psychopathology. The present study characterized the developmental trajectories of frontostriatal resting state networks from childhood to young adulthood. We demonstrate that ventral and dorsal aspects of the striatum exhibit distinct age-related changes that predicted developmental improvements in reward-related decision making and executive function. These results highlight that adolescence is characterized by distinct changes in frontostriatal networks that may relate to normative increases in risk-taking. Atypical developmental trajectories of frontostriatal networks may contribute to adolescent-onset psychopathology.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143598234","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":"Decoding the Neural Dynamics of Headed Syntactic Structure Building.","authors":"Junyuan Zhao 赵隽元, Ruimin Gao 高睿敏, Jonathan R Brennan","doi":"10.1523/JNEUROSCI.2126-24.2025","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.2126-24.2025","url":null,"abstract":"<p><p>The brain builds hierarchical phrases during language comprehension; however, the representational details and dynamics of the phrase-building process remain underspecified. This study directly probes whether the neural code of verb phrases involves reactivating the syntactic property of a key subcomponent (the \"head\" verb). To this end, we train a part-of-speech sliding-window neural decoder (verb vs. adverb) on EEG signals recorded while 30 participants (17 females) read sentences in a controlled experiment. The decoder reaches above-chance performance that is spatiotemporally consistent and generalizes to unseen data across sentence positions. Appling the decoder to held-out data yields predicted activation levels for the verbal \"head\" of a verb phrase at a distant non-head word (adverb); the critical adverb appeared either at the end of a verb phrase or at a sequentially and lexically matched position with no verb phrase boundary. There is stronger verb activation beginning at ∼600 milliseconds at the critical adverb when it appears at a verb phrase boundary; this effect is not modulated by the strength of conceptual association between the two subcomponents in the verb phrase nor does it reflect word predictability. Time-locked analyses additionally reveal a negativity waveform component and increased beta-delta inter-trial phase coherence, both previously linked to linguistic composition, in a similar time window. With a novel application of neural decoding, our findings delineate the dynamics by which the brain encodes phrasal representations by, in part, reactivating the representation of key subcomponents. We thus establish a link between cognitive accounts of phrasal representations and electrophysiological dynamics.<b>Significance Statement</b> Neuroimaging studies suggest that the brain constructs hierarchical linguistic representations. However, current evidence does not specify the details of minimal hierarchical units, namely phrases. On the other hand, theoretical consensus postulates phrases represented with properties derived from a key subcomponent, so-called the \"head\". Here, we explore the neural code of headed phrases. Leveraging advances in neural decoding, this study introduces a training-prediction pipeline to probe the activation dynamics of the phrasal head in electrophysiological recordings. Our analysis provides novel evidence regarding the neural representation of phrases that, at phrasal boundaries, the head of a phrase is reactivated and integrated into the higher-level representation. This is a fundamental step to understanding the neural bases of language comprehension at the sentence level.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574418","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":"A shared threat-anticipation circuit is dynamically engaged at different moments by certain and uncertain threat.","authors":"Brian R Cornwell, Paige R Didier, Shannon E Grogans, Allegra S Anderson, Samiha Islam, Hyung Cho Kim, Manuel Kuhn, Rachael M Tillman, Juyoen Hur, Zachary S Scott, Andrew S Fox, Kathryn A DeYoung, Jason F Smith, Alexander J Shackman","doi":"10.1523/JNEUROSCI.2113-24.2025","DOIUrl":"10.1523/JNEUROSCI.2113-24.2025","url":null,"abstract":"<p><p>Temporal dynamics play a central role in models of emotion: <i>\"fear\"</i> is widely conceptualized as a phasic response to certain-and-imminent danger, whereas <i>\"anxiety\"</i> is a sustained response to uncertain-or-distal harm. Yet the underlying neurobiology remains contentious. Leveraging a translationally relevant fMRI paradigm and theory-driven modeling approach in 220 adult humans, we demonstrate that certain- and uncertain-threat anticipation recruit a shared circuit that encompasses the central extended amygdala (EAc), periaqueductal gray, midcingulate, and anterior insula. This circuit exhibits persistently elevated activation when threat is uncertain and distal, and transient bursts of activation just before certain encounters with threat. Although there is agreement that the EAc plays a critical role in orchestrating responses to threat, confusion persists about the respective contributions of its major subdivisions, the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce). Here we used anatomical regions-of-interest to demonstrate that the BST and Ce exhibit statistically indistinguishable threat dynamics. Both regions exhibited activation dynamics that run counter to popular models, with the Ce showing sustained responses to uncertain-and-distal threat and the BST showing phasic responses to certain-and-imminent threat. For many scientists, feelings are the hallmark of fear and anxiety. Here we used an independently validated multivoxel brain 'signature' to covertly probe the moment-by-moment dynamics of anticipatory distress for the first time. Results mirrored the dynamics of neural activation. These observations provide fresh insights into the neurobiology of threat-elicited emotions and set the stage for more ambitious clinical and mechanistic research.<b>Significance statement</b> <i>\"Fear\"</i> is widely viewed as a phasic response to certain-and-imminent danger, whereas <i>\"anxiety\"</i> is a sustained response to uncertain-or-distal harm. Prior work has begun to reveal the neural systems recruited by certain and uncertain anticipated threats, but has yet to rigorously plumb the moment-by-moment dynamics anticipated by theory. Here we used a novel combination of neuroimaging techniques to demonstrate that certain and uncertain threat recruit a common threat-anticipation circuit. Activity in this circuit and covert measures of distress showed similar patterns of context-dependent dynamics, exhibiting persistent increases when anticipating uncertain-threat encounters and transient surges just before certain encounters. These observations provide fresh insights into the neurobiology of fear and anxiety, laying the groundwork for more ambitious clinical and mechanistic research.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574411","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":"Hippocampal neural stem cell exosomes promote brain resilience against the impact of tau oligomers.","authors":"Balaji Krishnan, Michela Marcatti, Anna Fracassi, Wen-Ru Zhang, Jutatip Guptarak, Kathia Johnson, Auston Grant, Rakez Kayed, Giulio Taglialatela, Maria-Adelaide Micci","doi":"10.1523/JNEUROSCI.1664-24.2025","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1664-24.2025","url":null,"abstract":"<p><p>A promising therapeutic intervention for preventing the onset and progression of Alzheimer's Disease (AD) is to protect and improve synaptic resilience, a well-established early vulnerability associated with the toxic effects of oligomers of Aβ (AβO) and Tau (TauO). We have previously reported that exosomes from hippocampal neural stem cells (NSCs) protect synapses against AβO. Here, we demonstrate how exosomes can also shield against TauO toxicity in adult mice synapses, potentially benefiting primary and secondary tauopathies. Exosomes from hippocampal NSCs (NSCexo) or mature neurons (MNexo) were delivered intracerebroventricularly to adult wildtype male mice (C57Bl6/J). After 24 hours, TauO were administered to suppress long-term potentiation (LTP) and memory, measured by electrophysiology and contextual memory deficits measured using novel object recognition (NOR) test. We also assessed TauO binding to synapses using isolated synaptosomes and cultured hippocampal neurons. Furthermore, mimics of select miRNAs present in NSCexo, were delivered ICV to mice prior to assessment of TauO-induced suppression of hippocampal LTP. Our results showed that NSC-, not MN-, derived exosomes, prevented TauO-induced memory impairment, LTP suppression, and reduced Tau accumulation and TauO internalization in synaptosomes. These findings suggest that NSC-derived exosomes can protect against synaptic dysfunction and memory deficits induced by both AβO and TauO, offering a novel therapeutic strategy for multiple neurodegenerative states.<b>Significance Statement</b> NSCexo provide an unprecedented therapeutic strategy targeting an early vulnerability driven by amyloidogenic toxic oligomers associated with multiple neurodegenerative states.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574477","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}