eNeuroPub Date : 2025-10-06DOI: 10.1523/ENEURO.0114-25.2025
Sahar Emami Naeini, Bidhan Bhandari, Breanna Hill, Nayeli Perez-Morales, Hannah M Rogers, Hesam Khodadadi, Nancy Young, Lívia Maria Maciel, Jack C Yu, David C Hess, John C Morgan, Évila Lopes Salles, Lei P Wang, Babak Baban
{"title":"Rethinking Alzheimer's: Harnessing Cannabidiol to Modulate IDO and cGAS Pathways for Neuroinflammation Control.","authors":"Sahar Emami Naeini, Bidhan Bhandari, Breanna Hill, Nayeli Perez-Morales, Hannah M Rogers, Hesam Khodadadi, Nancy Young, Lívia Maria Maciel, Jack C Yu, David C Hess, John C Morgan, Évila Lopes Salles, Lei P Wang, Babak Baban","doi":"10.1523/ENEURO.0114-25.2025","DOIUrl":"https://doi.org/10.1523/ENEURO.0114-25.2025","url":null,"abstract":"<p><p>Alzheimer's disease (AD) has traditionally been associated with amyloid-β plaques, but growing evidence underscores the role of neuroinflammation in disease progression. The autoinflammatory hypothesis of AD suggests chronic immune dysfunction contributes to neuronal damage, making immune modulation a promising therapeutic strategy.Cannabidiol (CBD), a phytocannabinoid with anti-inflammatory properties, may offer therapeutic potential. This study investigates how CBD independently influences two key neuroinflammatory regulators in AD: the Indoleamine 2,3-dioxygenase (IDO) pathway and the cyclic GMP-AMP synthase (cGAS) pathway. Though mechanistically distinct, both shape CNS immune responses. Targeting these immune-metabolic axes provides a mechanistic alternative to amyloid- or tau-based approaches by addressing upstream drivers of neuroinflammation and immune dysregulation. Using the male 5XFAD transgenic AD mouse model, we administered CBD via inhalation and assessed IDO and cGAS expression using flow cytometry, immunofluorescence, and gene expression analysis. We evaluated cytokine levels and used STRING-based bioinformatics to identify CBD-target interactions. CBD treatment significantly reduced IDO and cGAS expression, correlating with decreased pro-inflammatory cytokines, including TNF-α, IL-1β, and IFN-γ. Bioinformatics identified potential interactions between CBD and immune targets such as AKT1, TRPV1, and GPR55. These targets were prioritized based on their roles in neuroinflammatory signaling and high-confidence interactions with CBD. AKT1 regulates inflammatory signaling and cell survival, TRPV1 modulates nociception and neuroinflammation, and GPR55 influences immune cell activation. These findings support CBD as a potential monotherapy or adjunctive treatment for AD by targeting distinct neuroinflammatory pathways, including IDO and cGAS. Further studies are warranted to fully explore its therapeutic potential.<b>Significance statement</b> This study highlights the therapeutic potential of cannabidiol (CBD) in targeting neuroinflammation, a major driver of Alzheimer's disease (AD) progression. By modulating the IDO and cGAS pathways-critical regulators of CNS immune responses-CBD reduces pro-inflammatory cytokines and ameliorates immune dysfunction. These findings support the emerging autoinflammatory hypothesis of AD, which posits that chronic inflammation underlies neuronal damage. The IDO/cGAS signaling axis, located at the intersection of innate immunity and metabolic regulation, remains underexplored in AD and represents a key intervention point to disrupt neuroinflammatory loops. This study positions CBD as a promising mono- or adjunctive therapy and reinforces the need to consider multi-targeted strategies that address upstream immune mechanisms in neurodegenerative disease.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eNeuroPub Date : 2025-10-01DOI: 10.1523/ENEURO.0183-25.2025
Tiziana Pedale, Olympia Karampela, Johan Eriksson
{"title":"No Selective Attentional Shift despite Prefrontal Activation during a Working-Memory Task with Unconscious Stimuli.","authors":"Tiziana Pedale, Olympia Karampela, Johan Eriksson","doi":"10.1523/ENEURO.0183-25.2025","DOIUrl":"10.1523/ENEURO.0183-25.2025","url":null,"abstract":"<p><p>A key process for successful working memory is to prioritize task-relevant information over distraction, i.e., to control attentional deployment. Here we investigate to what extent attentional control during a delayed match-to-sample task can be achieved when to-be-remembered items were presented unconsciously together with distracting information and with a prestimulus cue that indicated whether the target was likely to appear on the left or right side of the screen. This expectation was sometimes violated (20% of trials), requiring reorienting of attention to successfully solve the task. Moreover, the cue was uninformative of the exact location of the target, which could appear on the top, middle, or bottom part of the screen. Participants performed better than chance on unconscious trials only when the cue correctly indicated target side, suggesting an inability to reorient attention when the cues were invalid. Neural activity (fMRI BOLD signal change) in medial and lateral prefrontal cortex was significant for unconscious valid-cue trials and remained significant for invalid-cue trials only in the lateral prefrontal cortex, although neither region was significantly modulated by cue validity. Parietal regions did not show significant activation for valid or invalid unconscious stimuli. Thus, even though activity in brain regions associated with cognitive control reached significant levels for unconscious stimuli, there was no evidence for adaptive deployment of selective attention based on unconscious information, which was the case for conscious stimuli. The ability to control attentional deployment appears to differ between conscious and unconscious working memory.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eNeuroPub Date : 2025-09-30DOI: 10.1523/ENEURO.0431-24.2025
Vinsea A V Singh, Vinodh G Kumar, Arpan Banerjee, Dipanjan Roy
{"title":"Prestimulus Periodic and Aperiodic Neural Activity Shapes McGurk Perception.","authors":"Vinsea A V Singh, Vinodh G Kumar, Arpan Banerjee, Dipanjan Roy","doi":"10.1523/ENEURO.0431-24.2025","DOIUrl":"https://doi.org/10.1523/ENEURO.0431-24.2025","url":null,"abstract":"<p><p>Previous studies emphasize the importance of prestimulus neural oscillations in shaping endogenous brain states that substantially impact perceptual outcomes. However, what features in such oscillations drive perception remains unknown. Furthermore, research has shown that non-oscillatory activity is also important for cognitive processing. However, their interaction prior to perceiving a multisensory stimulus remains unexplored. In this human EEG study (n=18, 10 males and 8 females), we investigated the role of prestimulus periodic power and aperiodic activity in modulating perception of the widely studied McGurk illusion on a trial-by-trial basis. Using logistic mixed-effect models, we reveal that the illusion perception is associated with reduced prestimulus alpha (8-12 Hz) and beta (15-30 Hz) power over frontal and occipital regions, increased theta (4-7 Hz) power in parietal, central, and occipital regions, and increased gamma (31-45 Hz) power across the scalp. Furthermore, lower aperiodic offset and exponent values in central, parietal, and occipital regions also predicted illusory responses. Our logistic mixed interaction models revealed that the aperiodic exponent and periodic power jointly influence the perception of upcoming McGurk stimuli. Specifically, a decrease in occipital theta and global beta power and an increase in occipital and parietal gamma power were associated with a steeper slope. We conclude that the predominant source of variations in the prestimulus state is the aperiodic activity and that fluctuations in both periodic and aperiodic activity account for inter-trial variability in the perception of the McGurk illusion.<b>Significance Statement</b> Prestimulus brain oscillations and aperiodic activity are fundamental to understanding individual perceptual and cognitive processing during multisensory speech perception. However, during multisensory integration between auditory and visual streams, how periodic and aperiodic activity sculpts inter-individual and inter-trial differences in multisensory perception remains largely unknown. In this EEG study, we discovered that lower aperiodic offset and exponent (slope) values in central, parietal, and occipital regions predicted illusory responses. Using statistical interaction models, we further show that the mechanisms of susceptibility to illusory speech perception arise from the significant interplay between aperiodic background activity and oscillatory features. This interplay between periodic and aperiodic activity accounts for inter-trial variability in the perception of the McGurk illusion.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eNeuroPub Date : 2025-09-30DOI: 10.1523/ENEURO.0291-25.2025
Kathryn K Walder-Christensen, Jack Goffinet, Alexandra L Bey, Reah Syed, Jacob Benton, Stephen D Mague, Elise Adamson, Sophia Vera, Hannah A Soliman, Sujay Kansagra, David Carlson, Kafui Dzirasa
{"title":"Sleep-wake states are encoded across emotion-regulation regions of the mouse brain.","authors":"Kathryn K Walder-Christensen, Jack Goffinet, Alexandra L Bey, Reah Syed, Jacob Benton, Stephen D Mague, Elise Adamson, Sophia Vera, Hannah A Soliman, Sujay Kansagra, David Carlson, Kafui Dzirasa","doi":"10.1523/ENEURO.0291-25.2025","DOIUrl":"https://doi.org/10.1523/ENEURO.0291-25.2025","url":null,"abstract":"<p><p>Emotional dysregulation is highly comorbid with sleep disturbances. Sleep is comprised of unique physiological states that are reflected by conserved brain oscillations. Though the role of these state-dependent oscillations in cognitive function has been well-established, less is known regarding the nature of state-dependent oscillations across brain regions that strongly contribute to emotional function. To characterize these dynamics, we recorded local field potentials simultaneously from multiple cortical and subcortical regions implicated in sleep and emotion-regulation and characterized widespread patterns of spectral power and synchrony between brain regions during sleep-wake states in male and female mice. First, we showed that single brain regions encode sleep state, albeit to various degrees of accuracy. We then identified network-based classifiers of sleep based on the combination of features from all recorded brain regions. Spectral power and synchrony from brain networks allowed for automatic, accurate and rapid discrimination of wake, non-REM sleep (NREM) and rapid eye movement (REM) sleep. When we examined the impact of commonly prescribed sleep-promoting medications on neural dynamics across these regions, we found disparate alterations to both cortical and subcortical activity across all three states. Finally, we found that a stress manipulation that disrupts circadian rhythm in male mice increased sleep fragmentation without altering the underlying average brain dynamics across sleep-wake states. Thus, we characterized state-dependent brain dynamics across regions canonically associated with emotions.<b>Significance Statement</b> Sleep and emotion regulation are known to be intertwined at the level of behavior and in neuropsychiatric illnesses. Here, we examined how brain regions involved in emotion regulation encode wake and sleep states by performing multi-site electrophysiological recordings in mice. We developed classifiers that rapidly labeled sleep-wake states from brain activity alone. We then identified how commonly prescribed sleep-inducing medications have unique impacts on brain activity throughout these emotion-regulation regions. Finally, we explored the impact of circadian rhythm disruption on sleep architecture and brain activity. Together, these data shed light on how brain regions that regulate emotion behave during sleep so that one day, treatments to improve both sleep and emotional well-being may be developed.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eNeuroPub Date : 2025-09-30DOI: 10.1523/ENEURO.0200-25.2025
Christina Sheckler, Kathleen Kish, Zion Walker, Grant Barkelew, Dakota N Crisp, Matt P Szuromi, Maria Luisa Saggio, William C Stacey
{"title":"Dynamotypes for Dummies: A toolbox, atlas, and tutorial for simulating a comprehensive range of realistic synthetic seizures.","authors":"Christina Sheckler, Kathleen Kish, Zion Walker, Grant Barkelew, Dakota N Crisp, Matt P Szuromi, Maria Luisa Saggio, William C Stacey","doi":"10.1523/ENEURO.0200-25.2025","DOIUrl":"https://doi.org/10.1523/ENEURO.0200-25.2025","url":null,"abstract":"<p><p>Epileptic seizures involve the brain transitioning from a resting state to an abnormal state of synchronized bursting, akin to a bifurcation in dynamical systems where a parameter shift triggers a qualitative change in behavior. A comprehensive model was previously developed that used dynamical equations capable of simulating 16 \"dynamotypes\" of seizures that span the full range of theoretical first-order dynamics. The current work is a tool to understand and implement this model with the goal of generating a wide range of synthetic seizures. We present a dynamical atlas of all 16 possible onset-offset bifurcation combinations, each characterized by distinct features in simulated EEG-like recordings. We include a tutorial and GUI that generates diverse simulated seizures. In addition, we include methods to add realistic noise and filtering effects to enhance their resemblance to human EEG data. This toolbox has two purposes: it is a practical, educational demonstration of the dynamical principles underlying seizure bifurcations, and it provides the algorithms necessary to produce large numbers of realistic, diverse seizure patterns that have similar noise and filtering characteristics as human EEG. This generative model can aid in training seizure detection algorithms, understanding brain dynamical behavior for clinicians, and exploring the impact of noise on EEG recordings and detection algorithms.<b>Significance Statement</b> This work contains a tutorial, atlas, and generative model for a comprehensive, realistic seizure model based upon dynamical theory. This user-friendly tool is designed to teach the theoretical principles underlying the model, as well as implement it in order to generate a wide range of simulated seizures that have the same appearance as human EEG recordings. This work is thus broadly applicable to clinicians, students, and researchers.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eNeuroPub Date : 2025-09-30DOI: 10.1523/ENEURO.0210-25.2025
Thorge Haupt, Marc Rosenkranz, Martin G Bleichner
{"title":"Neural response attenuates with decreasing inter-onset intervals between sounds in a natural soundscape.","authors":"Thorge Haupt, Marc Rosenkranz, Martin G Bleichner","doi":"10.1523/ENEURO.0210-25.2025","DOIUrl":"https://doi.org/10.1523/ENEURO.0210-25.2025","url":null,"abstract":"<p><p>Sensory attenuation of auditory evoked potentials (AEPs), particularly N1 and P2 components, has been widely demonstrated in response to simple, repetitive stimuli sequences of isolated synthetic sounds. It remains unclear, however, whether these effects generalize to complex soundscapes where temporal and acoustic features vary more broadly and dynamically. In this study, we investigated whether the inter-onset interval (IOI), the time between successive sound events, modulates AEP amplitudes in a complex auditory scene. We derived acoustic onsets from a naturalistic soundscape and applied temporal response function (TRF) analysis to EEG data recorded from normal hearing human listeners (N = 22, 16 females, 6 males). Our results showed that shorter IOIs are associated with attenuated N1 and P2 amplitudes, replicating classical adaptation effects in a naturalistic sound scape. These effects remained stable when controlling for other acoustic features such as intensity and envelope sharpness and across different TRF model specifications. Integrating IOI information into predictive modelling revealed that neural dynamics were captured more effectively than simpler onset models when training data were matched. These findings highlight the brain's sensitivity to temporal structure even in highly variable auditory environments, and show that classical lab findings generalize to naturalistic soundscapes. Our results underscore the need to include temporal features alongside acoustic ones in models of real-world auditory processing.<b>Significance Statement</b> Employing automatic onset detection in a complex, ecologically valid soundscape, we enable fine-grained analysis of temporal auditory processing. Specifically, we find that neural responses (i.e. the N1 and P2 components) 26 to sound events are attenuated when inter-onset intervals are short, replicating classic attenuation effects within a naturalistic soundscape. These findings demonstrate that temporal sensitivity in auditory processing persists even in the presence of substantial acoustic variability, which is characteristic of real-world settings.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eNeuroPub Date : 2025-09-29Print Date: 2025-09-01DOI: 10.1523/ENEURO.0487-23.2025
Kevin Ung, John F Magnotti, Brandon Kim, Jeffrey M Yau, Per F Nordmark
{"title":"Acute Loss of Tactile Input Leads to General Compensatory Changes in Eye-Hand Coordination during Object Manipulation.","authors":"Kevin Ung, John F Magnotti, Brandon Kim, Jeffrey M Yau, Per F Nordmark","doi":"10.1523/ENEURO.0487-23.2025","DOIUrl":"10.1523/ENEURO.0487-23.2025","url":null,"abstract":"<p><p>Current models of motor control emphasize the critical role of sensory feedback, as demonstrated by movement coordination deficits following sensory impairment. When both vision and touch are available for object-oriented manual behaviors, they serve distinct roles; vision guides the execution of planned movements, while touch provides more direct feedback on hand-object interactions. The impact of losing somatosensory feedback on eye-hand coordination during dexterous object manipulation tasks has not been thoroughly studied. Conceivably, vision is recruited to compensate for the feedback lost when touch is abolished based on the dexterity demands of the behavior. To investigate this, we tested healthy participants of either sex on a manual dexterity task requiring the movement of small metal pegs, both before and after the administration of digital anesthesia, which selectively abolished cutaneous sensations in the fingertips while preserving motor function. We recorded participants' gaze and hand positions. Despite loss of cutaneous feedback, participants successfully completed the pegboard task. However, they exhibited significantly longer trial times and altered force profiles. Notably, acute somatosensory loss triggered a rapid shift in visual behavior, characterized by a tighter coupling between gaze and hand positions across all task actions, even those not directly involving object manipulation. These changes, which occurred with anesthesia of the dominant and nondominant hands, were not evident with sham (saline) injections. Our findings underscore the contributions of sensory feedback to force control in service of dexterous object manipulation and reveal the nonselective nature of compensatory gaze-hand coordination processes.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12494028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eNeuroPub Date : 2025-09-29Print Date: 2025-09-01DOI: 10.1523/ENEURO.0587-24.2025
Katsuki Higo, Itsuki Ohtsuka, Sotaro Shimada
{"title":"Distinct Roles of the Premotor and Occipitotemporal Cortices in the Full-Body Illusion.","authors":"Katsuki Higo, Itsuki Ohtsuka, Sotaro Shimada","doi":"10.1523/ENEURO.0587-24.2025","DOIUrl":"10.1523/ENEURO.0587-24.2025","url":null,"abstract":"<p><p>The sense of body ownership, a core aspect of self-recognition, has been studied using illusions such as the full-body illusion. Although the premotor cortex is considered central to body ownership in first-person full-body illusions, the occipitotemporal cortex-including the temporoparietal junction (TPJ) and the extrastriate body area (EBA)-also plays a critical role in third-person full-body illusions. However, their distinct contributions to the full-body illusion remain unclear, partly due to the challenges of applying neuroimaging in such experiments. This study employed functional near-infrared spectroscopy to investigate brain activity during a third-person full-body illusion in virtual reality. Eighteen healthy human adult males participated in the study. The experiment consisted of two sessions. In Session 1, participants observed an avatar's back receiving either synchronous or asynchronous visual-tactile stimulation. In Session 2, visual stimuli alone were presented to participants after they experienced the full-body illusion to induce visuotactile discrepancies. In the synchronous condition of Session 1, we found significant deactivation in the superior and middle temporal gyri (partially including the TPJ), followed by higher activity than in the asynchronous condition in the left middle occipital gyrus (likely EBA). The left premotor cortex also showed significant activation (uncorrected), although this did not survive multiple-comparison adjustment. In Session 2, the visuotactile discrepancy induced significant left premotor activation only in the synchronous condition (FDR-corrected). These findings suggest that the occipitotemporal cortex supports receptivity to third-person full-body illusions, whereas the premotor cortex contributes to maintaining illusory body ownership by reconciling multisensory conflicts.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145052512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eNeuroPub Date : 2025-09-29Print Date: 2025-09-01DOI: 10.1523/ENEURO.0453-24.2025
Nicholas W Ringelberg, Renée E Mayfield, Julia S Lord, Graham H Diering, Alain C Burette, Benjamin D Philpot
{"title":"Cell Type-Specific Contributions of UBE3A to Angelman Syndrome Behavioral Phenotypes.","authors":"Nicholas W Ringelberg, Renée E Mayfield, Julia S Lord, Graham H Diering, Alain C Burette, Benjamin D Philpot","doi":"10.1523/ENEURO.0453-24.2025","DOIUrl":"10.1523/ENEURO.0453-24.2025","url":null,"abstract":"<p><p>Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by loss of expression of the maternal <i>UBE3A</i> allele and is characterized by a constellation of impactful neurologic symptoms. While previous work has uncovered outsized contributions of GABAergic neuron-selective <i>Ube3a</i> deletion to seizure susceptibility and electroencephalography (EEG) phenotypes in a mouse model of AS, the neuronal populations governing a broader range of behaviors have not been studied. Here, we used male and female mice to test the consequences of <i>Ube3a</i> deletion from GABAergic or glutamatergic neurons across a well-characterized battery of AS-relevant behaviors. Surprisingly, we observed deficits in numerous motor and innate behaviors in mice with glutamatergic <i>Ube3a</i> deletion and relatively few consequences of GABAergic <i>Ube3a</i> deletion. Furthermore, genetic <i>Ube3a</i> reinstatement in glutamatergic neurons rescued multiple motor and innate behaviors. When tested for sleep-wake behaviors, the selective loss of <i>Ube3a</i> from glutamatergic neurons disrupted sleep similarly to that of AS model mice (<i>Ube3a<sup>m-/p+</sup></i> ), and glutamatergic <i>Ube3a</i> reinstatement overcame the lack of active cycle \"siesta\" and decreased REM phenotypes observed in AS model mice. Altogether, this work demonstrates a major role of glutamatergic neuron UBE3A loss in mediating multiple AS behavioral features, suggesting a divergence from the circuitry underlying enhanced seizure susceptibility. Our findings imply that neuronal cell type-agnostic UBE3A reinstatement is likely required for successful AS genetic therapies-with reinstatement of UBE3A in GABAergic neurons necessary for overcoming epileptic and EEG phenotypes, and reinstatement in glutamatergic neurons necessary for overcoming most other behavioral phenotypes.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eNeuroPub Date : 2025-09-26Print Date: 2025-09-01DOI: 10.1523/ENEURO.0141-25.2025
James D O'Leary, Dhwani C Gondalia, Molly O'Brien, Miles Morlock, Gemma Haney, Bevan S Main, Mark P Burns
{"title":"Low-Cost 3D-Printed Mazes with Open-Source ML Tracking for Mouse Behavior.","authors":"James D O'Leary, Dhwani C Gondalia, Molly O'Brien, Miles Morlock, Gemma Haney, Bevan S Main, Mark P Burns","doi":"10.1523/ENEURO.0141-25.2025","DOIUrl":"10.1523/ENEURO.0141-25.2025","url":null,"abstract":"<p><p>Behavioral neuroscience research often requires substantial financial investment in specialized equipment and software, creating barriers for new investigators and limiting the flexibility of established laboratories. This study explores how 3D printing and machine learning can be combined to reduce startup and operational costs while maintaining research quality. Using 3D printing, we designed and manufactured a mouse T-maze and elevated plus maze to assess cognition and anxiety-like behaviors in male mice. These custom-built mazes demonstrated comparable efficacy with commercial alternatives while offering greater affordability, scalability, and customization. To complement the hardware, we integrated machine learning for automated tracking and analysis of mouse behavior, achieving accuracy equivalent to commercial solutions or experienced human scoring at significantly reduced cost. By combining 3D printing with machine learning, our approach significantly lowers financial barriers for new investigators and enables established research groups to allocate resources more effectively. This approach not only expands research possibilities for established labs but also lowers the barrier to entry for early-career scientists and institutions with limited funding.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":"12 9","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12468991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}