Transcranial near-infrared stimulation alleviates stress-induced depressive-like behaviors by restoring prefrontal neurometabolic and synaptic pathways

Transcranial near-infrared stimulation alleviates stress-induced depressive-like behaviors by restoring prefrontal neurometabolic and synaptic pathways | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Transcranial near-infrared stimulation alleviates stress-induced depressive-like behaviors by restoring prefrontal neurometabolic and synaptic pathways Yuping Wang, tingting Zhang, Yan Zhang, Na Pan, Shimin Hu, Ye Ren, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8835227/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 11 You are reading this latest preprint version Abstract Depression is associated with disrupted neural energy metabolism and synaptic dysfunction. Transcranial near-infrared (tNIR) stimulation is a promising non-invasive intervention, but optimal parameters and cellular mechanisms remain unclear. Here, we compared pulsed tNIR delivered at 10 Hz, 100 Hz, or 1000 Hz targeting the prefrontal cortex (PFC) in a chronic restraint stress (CRS) rat model and profiled PFC nuclei using single-nucleus RNA sequencing. Behavioral assays showed that 100 Hz tNIR, but not 10 Hz or 1000 Hz, robustly alleviated depressive-like and anxiety-like behaviors. Transcriptomic analyses further showed that CRS induced widespread dysregulation of mitochondrial and membrane-related gene networks, which were selectively normalized by 100 Hz tNIR. At the cell-type level, tNIR reversed stress-induced mitochondrial respiratory gene upregulation in both excitatory and inhibitory neurons, and restored pathways related to synaptic organization, neuronal excitability, and lipid/sterol homeostasis in excitatory neuron. Coordinated transcriptional reversals were also observed in glial populations. Consistently, 100 Hz tNIR increased activation of glutamatergic neurons in the medial PFC. Together, these results identify 100 Hz as an effective stimulation frequency and link its antidepressant effects to normalization of stress related neurometabolic pathways and enhanced glutamatergic activation in the PFC. Biological sciences/Neuroscience Health sciences/Diseases/Psychiatric disorders/Depression Full Text Additional Declarations The authors have declared there is NO conflict of interest to disclose Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: revise 12 May, 2026 Reviewer # 3 agreed at journal 07 Apr, 2026 Review # 2 received at journal 05 Apr, 2026 Review # 1 received at journal 28 Mar, 2026 Reviewer # 2 agreed at journal 23 Mar, 2026 Reviewer # 1 agreed at journal 08 Mar, 2026 Reviewers invited by journal 05 Mar, 2026 Editor assigned by journal 25 Feb, 2026 Submission checks completed at journal 25 Feb, 2026 First submitted to journal 24 Feb, 2026 Unknown event 11 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8835227","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":601042028,"identity":"9eec4a80-eb2f-4dd6-bf0d-6ceacd3728c2","order_by":0,"name":"Yuping 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Transcranial near-infrared (tNIR) stimulation is a promising non-invasive intervention, but optimal parameters and cellular mechanisms remain unclear. Here, we compared pulsed tNIR delivered at 10 Hz, 100 Hz, or 1000 Hz targeting the prefrontal cortex (PFC) in a chronic restraint stress (CRS) rat model and profiled PFC nuclei using single-nucleus RNA sequencing. Behavioral assays showed that 100 Hz tNIR, but not 10 Hz or 1000 Hz, robustly alleviated depressive-like and anxiety-like behaviors. Transcriptomic analyses further showed that CRS induced widespread dysregulation of mitochondrial and membrane-related gene networks, which were selectively normalized by 100 Hz tNIR. At the cell-type level, tNIR reversed stress-induced mitochondrial respiratory gene upregulation in both excitatory and inhibitory neurons, and restored pathways related to synaptic organization, neuronal excitability, and lipid/sterol homeostasis in excitatory neuron. 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