Pub Date : 2025-12-27DOI: 10.1016/j.brainres.2025.150136
Øyvind A. Høydal , Runa R.G. Notøy , Kjetil L. Høydal
With a rising prevalence of the major mood disorders, recent years have seen a growing interest in the potential therapeutic value of lifestyle practises such as exercise and thermotherapy. While the beneficial effects of exercise on mental health are now well documented, the potential benefits of thermotherapy are less studied. Similarly to exercise, passive heat- and cold exposure may induce physiological responses which counteract the pathophysiological underpinnings of mood disorders such as depression and anxiety. Thus, for prevention or treatment of mood disorders, thermotherapy could complement exercise or be a viable alternative for people with injuries or disability. Here, we first review physiological adaptations to passive heat- or cold treatment in the context of hypotheses for the pathogenesis of depression. Next, we review clinical interventions investigating effects of passive heat- or cold treatment on depressive disorder, before ending with a discussion of future directions.
{"title":"Can thermotherapy mitigate depression? A review of physiological adaptations and clinical evidence","authors":"Øyvind A. Høydal , Runa R.G. Notøy , Kjetil L. Høydal","doi":"10.1016/j.brainres.2025.150136","DOIUrl":"10.1016/j.brainres.2025.150136","url":null,"abstract":"<div><div>With a rising prevalence of the major mood disorders, recent years have seen a growing interest in the potential therapeutic value of lifestyle practises such as exercise and thermotherapy. While the beneficial effects of exercise on mental health are now well documented, the potential benefits of thermotherapy<!--> <!-->are less studied. Similarly to exercise, passive heat- and cold exposure may induce physiological responses which counteract the pathophysiological underpinnings of mood disorders such as depression and anxiety. Thus, for prevention or treatment of mood disorders, thermotherapy could complement exercise or be a viable alternative for people with injuries or disability. Here, we first review physiological adaptations to passive heat- or cold treatment in the context of hypotheses for the<!--> <!-->pathogenesis of depression. Next, we review clinical interventions investigating effects of passive heat- or cold treatment on depressive disorder, before ending with a discussion of future directions.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1873 ","pages":"Article 150136"},"PeriodicalIF":2.6,"publicationDate":"2025-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neurodegenerative disorders—including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis—are increasingly understood to have origins in early neurodevelopmental disturbances. This review examines how genetic, epigenetic, and environmental factors impact brain development during critical periods, predisposing individuals to neurodegeneration later in life. Prenatal and early-life exposures such as maternal stress, malnutrition, infection, and environmental toxins can alter key developmental processes, leading to long-term vulnerability. Mechanistic pathways linking early-life disruptions to neurodegenerative outcomes include persistent mitochondrial dysfunction, chronic neuroinflammation, increased oxidative stress, and aberrant synaptic pruning, all of which contribute to progressive neuronal damage and dysfunction. The gut-brain axis is also discussed as a key intermediary, where early microbiota dysbiosis alters neuroimmune signaling and inflammatory responses, modulating susceptibility to age-related neurological disorders. In this context, the review highlights emerging molecular and imaging biomarkers capable of detecting subtle neurodevelopmental deviations that may precede clinical symptoms by decades. The paper emphasizes the need for early-life interventions, including maternal nutritional optimization, management of prenatal stress, and microbiome-targeted strategies, as potential tools to reduce long-term neurological risk. Furthermore, it proposes the integration of precision medicine approaches aimed at individualized risk assessment and therapeutic targeting of developmental pathways. Adopting a lifespan perspective, this review argues for a paradigm shift from reactive to preventive strategies in neurology. Understanding the developmental roots of neurodegeneration opens new avenues for research and intervention, enabling resilience and reducing disease burden through early diagnostics and tailored therapeutics across the lifespan.
{"title":"Neurodevelopmental origins of neurodegeneration: a lifespan perspective on brain vulnerability","authors":"Spandana Rajendra Kopalli , Nasir Vadia , Pooja Varma , Swati Mishra , Neha Joshi , Pooja Bansal , Shaker Al-Hasnaawei , Ashish Singh Chauhan , Hardik Jain , Deepak Nathiya , Anita Devi , Hanish Singh Jayasingh Chellammal , Priyanka Gupta , Pranay Wal , Sushruta Koppula","doi":"10.1016/j.brainres.2025.150134","DOIUrl":"10.1016/j.brainres.2025.150134","url":null,"abstract":"<div><div>Neurodegenerative disorders—including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis—are increasingly understood to have origins in early neurodevelopmental disturbances. This review examines how genetic, epigenetic, and environmental factors impact brain development during critical periods, predisposing individuals to neurodegeneration later in life. Prenatal and early-life exposures such as maternal stress, malnutrition, infection, and environmental toxins can alter key developmental processes, leading to long-term vulnerability. Mechanistic pathways linking early-life disruptions to neurodegenerative outcomes include persistent mitochondrial dysfunction, chronic neuroinflammation, increased oxidative stress, and aberrant synaptic pruning, all of which contribute to progressive neuronal damage and dysfunction. The gut-brain axis is also discussed as a key intermediary, where early microbiota dysbiosis alters neuroimmune signaling and inflammatory responses, modulating susceptibility to age-related neurological disorders. In this context, the review highlights emerging molecular and imaging biomarkers capable of detecting subtle neurodevelopmental deviations that may precede clinical symptoms by decades. The paper emphasizes the need for early-life interventions, including maternal nutritional optimization, management of prenatal stress, and microbiome-targeted strategies, as potential tools to reduce long-term neurological risk. Furthermore, it proposes the integration of precision medicine approaches aimed at individualized risk assessment and therapeutic targeting of developmental pathways. Adopting a lifespan perspective, this review argues for a paradigm shift from reactive to preventive strategies in neurology. Understanding the developmental roots of neurodegeneration opens new avenues for research and intervention, enabling resilience and reducing disease burden through early diagnostics and tailored therapeutics across the lifespan.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1873 ","pages":"Article 150134"},"PeriodicalIF":2.6,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145848897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-24DOI: 10.1016/j.brainres.2025.150135
Cinthia Coria-Lucero , Mariana Lopez , Sandra Gomez-Mejiba , Dario Ramirez , María Belén Delsouc , Marilina Casais , Richard Alba , Jorge Leporatti , Silvia Delgado , Ana Cecilia Anzulovich , Lorena Navigatore-Fonzo
Alzheimer’s dementia (AD) is a neurodegenerative disorder that causes memory loss and dementia in older adults. The neuropathological hallmarks of AD include amyloid plaques, neurofibrillary tangles, oxidative damage, neuroinflammation, synaptic loss and neuronal cell death. The accumulation of Aβ in the brain plays a key role in the pathogenesis of AD. Elevated levels of Aβ causes an increase in oxidative damage and neuroinflammation both are considered key factors in the progression of AD. Also patients with Alzheimer’s show alterations in their circadian rhythms. Our objectives were (a) to analyze whether inflammation and cognition-related factors exhibit a day-night variation, (b) to verify whether antioxidant enzymes expression and activity exhibit a daily rhythm in the rat temporal cortex and (c) to evaluate the effects of an intracerebroventricular injection of Aβ-amyloid (1–42) aggregates on those temporal profiles. Four-month old males Holtzman rats were used in this study. Groups were defined as: 1) control 2) Aβ-injected. Rats were maintained under 12 h-Light:12 h-Dark conditions with food ad-libitum. Our results showed temporal patterns of nitrites, iNOS, catalase and glutathione peroxidase expression and activity, as well as Rc3 and Gap-43 mRNA, in the rat temporal cortex. An i.c.v. injection of Aβ abolishes the temporal pattern of Rc3 and Gap-43 mRNA. Also increased the rhythm’s mesor of NO and iNOS levels, reduced the mesor of CAT activity rhythms, and changed the phase of GPx activity patterns. These alterations in the temporal patterns of inflammation and redox status-related factors would affect cellular clock activity and consequently cognitive performance.
{"title":"Daily temporal organization of inflammation and cognition-related factors and antioxidant enzymes are modified by an intracerebroventricular injection of amyloid-beta peptide (1–42) aggregates in the rat temporal cortex","authors":"Cinthia Coria-Lucero , Mariana Lopez , Sandra Gomez-Mejiba , Dario Ramirez , María Belén Delsouc , Marilina Casais , Richard Alba , Jorge Leporatti , Silvia Delgado , Ana Cecilia Anzulovich , Lorena Navigatore-Fonzo","doi":"10.1016/j.brainres.2025.150135","DOIUrl":"10.1016/j.brainres.2025.150135","url":null,"abstract":"<div><div>Alzheimer’s dementia (AD) is a neurodegenerative disorder that causes memory loss and dementia in older adults. The neuropathological hallmarks of AD include amyloid plaques, neurofibrillary tangles, oxidative damage, neuroinflammation, synaptic loss and neuronal cell death. The accumulation of Aβ in the brain plays a key role in the pathogenesis of AD. Elevated levels of Aβ causes an increase in oxidative damage and neuroinflammation both are considered key factors in the progression of AD. Also patients with Alzheimer’s show alterations in their circadian rhythms. Our objectives were (a) to analyze whether inflammation and cognition-related factors exhibit a day-night variation, (b) to verify whether antioxidant enzymes expression and activity exhibit a daily rhythm in the rat temporal cortex and (c) to evaluate the effects of an intracerebroventricular injection of Aβ-amyloid (1–42) aggregates on those temporal profiles. Four-month old males Holtzman rats were used in this study. Groups were defined as: 1) control 2) Aβ-injected. Rats were maintained under 12 h-Light:12 h-Dark conditions with food ad-libitum. Our results showed temporal patterns of nitrites, iNOS, catalase and glutathione peroxidase expression and activity, as well as Rc3 and Gap-43 mRNA, in the rat temporal cortex. An i.c.v. injection of Aβ abolishes the temporal pattern of Rc3 and Gap-43 mRNA. Also increased the rhythm’s mesor of NO and iNOS levels, reduced the mesor of CAT activity rhythms, and changed the phase of GPx activity patterns. These alterations in the temporal patterns of inflammation and redox status-related factors would affect cellular clock activity and consequently cognitive performance.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1874 ","pages":"Article 150135"},"PeriodicalIF":2.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1016/j.brainres.2025.150133
Zhi Wen , Yuan-Zhi He , Zhan-Xiang Hu , Xin Huang , Bao-jun Xie
Parkinson’s disease (PD) is characterized by widespread motor and non-motor impairments; however, the temporal dynamics underlying these functional disruptions remain unclear. The intrinsic neural timescale (INT), a novel neuroimaging metric that reflects the capacity of brain regions to integrate information over time, provides new insights into cortical hierarchy and dysfunction. In this study, we examined voxel-wise and network-level alterations in INT among PD patients using resting-state fMRI and integrated their molecular correlates with transcriptomic data from the Allen Human Brain Atlas and PET-derived neurotransmitter receptor maps. Our analysis revealed localized reductions in INT in the left insula, Rolandic operculum, and middle temporal gyrus in PD, while large-scale network hierarchies remained preserved. Partial least squares regression analysis indicated that changes in INT were significantly associated with spatial gene expression gradients, particularly those involving immune-metabolic stress and synaptic maintenance. Furthermore, cell-type enrichment analysis identified excitatory and inhibitory neurons as key cellular contributors. Notably, INT alterations correlated with cortical GABAA receptor density, suggesting a role for inhibitory neurotransmission in temporal integration deficits. These findings highlight a multiscale pathophysiological framework linking functional brain dynamics, molecular architecture, and neurochemical modulation in PD.
{"title":"Molecular and neurochemical underpinnings of altered intrinsic neural timescales in Parkinson’s disease: a multimodal imaging and transcriptomics study","authors":"Zhi Wen , Yuan-Zhi He , Zhan-Xiang Hu , Xin Huang , Bao-jun Xie","doi":"10.1016/j.brainres.2025.150133","DOIUrl":"10.1016/j.brainres.2025.150133","url":null,"abstract":"<div><div>Parkinson’s disease (PD) is characterized by widespread motor and non-motor impairments; however, the temporal dynamics underlying these functional disruptions remain unclear. The intrinsic neural timescale (INT), a novel neuroimaging metric that reflects the capacity of brain regions to integrate information over time, provides new insights into cortical hierarchy and dysfunction. In this study, we examined voxel-wise and network-level alterations in INT among PD patients using resting-state fMRI and integrated their molecular correlates with transcriptomic data from the Allen Human Brain Atlas and PET-derived neurotransmitter receptor maps. Our analysis revealed localized reductions in INT in the left insula, Rolandic operculum, and middle temporal gyrus in PD, while large-scale network hierarchies remained preserved. Partial least squares regression analysis indicated that changes in INT were significantly associated with spatial gene expression gradients, particularly those involving immune-metabolic stress and synaptic maintenance. Furthermore, cell-type enrichment analysis identified excitatory and inhibitory neurons as key cellular contributors. Notably, INT alterations correlated with cortical GABAA receptor density, suggesting a role for inhibitory neurotransmission in temporal integration deficits. These findings highlight a multiscale pathophysiological framework linking functional brain dynamics, molecular architecture, and neurochemical modulation in PD.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1873 ","pages":"Article 150133"},"PeriodicalIF":2.6,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-21DOI: 10.1016/j.brainres.2025.150120
Desmond Agboada , Roman Rethwilm , Manuel Kuder , Wolfgang Mack , Wolfgang Seiberl
Background
Conventional TMS devices are limited in the number of variations of pulse parameters they produce, which limits the extension of TMS application. Recently, however, successful attempts have been made to introduce next-generation (next-gen) TMS devices with adjustable pulse parameters. Although research using these devices is still in its infancy, a systematic synthesis of the direction of results is valuable to identify the current progress and some limitations of these technologies which can guide further studies in the field.
Objective
This review aims to investigate the influence of pulse parameters (width, shape, and current direction) of next-gen TMS devices on corticospinal excitability and the induction of neuroplasticity.
Methods
Using the PRISMA method of reporting systematic reviews, we searched major biomedical databases − PubMed (n = 84), Web of Science (n = 141), Scopus (n = 111) and APA PsychInfo (n = 27) for literature, with 21 studies included in this review.
Results
Compared to conventional TMS devices, next-generation TMS devices were more efficient in many neurophysiological measurements. For plasticity inducing protocols, both inhibitory and facilitatory protocols showed enhanced respective inhibitory and excitatory after-effects with increasing pulse width. The new near-rectangular pulse shape moreover induced stronger inhibitory after-effects compared to conventional pulses.
Conclusions
Next-generation devices expand the parameter space of TMS. Further studies are however needed to explore the full potential of these next-gen devices, especially in non-motor brain regions.
Significance
Next-gen TMS devices do hold a promise in the optimization of the neuromodulatory effects of TMS.
{"title":"A systematic review of the effect of pulse parameters of next-generation TMS devices on corticospinal excitability and neuroplasticity","authors":"Desmond Agboada , Roman Rethwilm , Manuel Kuder , Wolfgang Mack , Wolfgang Seiberl","doi":"10.1016/j.brainres.2025.150120","DOIUrl":"10.1016/j.brainres.2025.150120","url":null,"abstract":"<div><h3>Background</h3><div>Conventional TMS devices are limited in the number of variations of pulse parameters they produce, which limits the extension of TMS application. Recently, however, successful attempts have been made to introduce next-generation (next-gen) TMS devices with adjustable pulse parameters. Although research using these devices is still in its infancy, a systematic synthesis of the direction of results is valuable to identify the current progress and some limitations of these technologies which can guide further studies in the field.</div></div><div><h3>Objective</h3><div>This review aims to investigate the influence of pulse parameters (width, shape, and current direction) of next-gen TMS devices on corticospinal excitability and the induction of neuroplasticity.</div></div><div><h3>Methods</h3><div>Using the PRISMA method of reporting systematic reviews, we searched major biomedical databases − PubMed (n = 84), Web of Science (n = 141), Scopus (n = 111) and APA PsychInfo (n = 27) for literature, with 21 studies included in this review.</div></div><div><h3>Results</h3><div>Compared to conventional TMS devices, next-generation TMS devices were more efficient in many neurophysiological measurements. For plasticity inducing protocols, both inhibitory and facilitatory protocols showed enhanced respective inhibitory and excitatory after-effects with increasing pulse width. The new near-rectangular pulse shape moreover induced stronger inhibitory after-effects compared to conventional pulses.</div></div><div><h3>Conclusions</h3><div>Next-generation devices expand the parameter space of TMS. Further studies are however needed to explore the full potential of these next-gen devices, especially in non-motor brain regions.</div></div><div><h3>Significance</h3><div>Next-gen TMS devices do hold a promise in the optimization of the neuromodulatory effects of TMS.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1873 ","pages":"Article 150120"},"PeriodicalIF":2.6,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145817731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-20DOI: 10.1016/j.brainres.2025.150122
Zina Li , Jichan Nian , Shuiyan Li , Zhiqing Deng , Hang Wu , Haili Zhong , Xiyan Huang , Pengmin Qin , Jinhui Wang , Qiuyou Xie , Juan Chen
The Minimally Conscious State (MCS) is a condition in which a patient, following a brain injury, exhibits minimal yet definite behavioral evidence of awareness, representing a crucial transitional state between unconsciousness and the full emergence of consciousness. Assessing preserved cognitive function, particularly visual function, is crucial for diagnosis and rehabilitation, given that vision is the primary source of sensory input. While MCS patients consistently exhibit visual behaviors, such as sustained fixation or pursuit eye movements, previous neuroimaging studies have treated the visual network as a monolith, leaving it unclear which part of their visual cortical neural networks is affected or preserved. Here, we investigated the visual neural network of patients, encompassing 38 visual cortical subregions, from the primary visual cortex (V1), which processes low-level features (e.g., contrast, orientation), to higher-level visual regions that mediate object recognition and visual attention. Threshold-free network-based statistical analysis revealed that inter-hemispheric connectivity is significantly decreased, while intra-hemispheric connectivity is largely preserved in the visual network of MCS patients. Graph-based analysis showed a longer characteristic path length in them, indicating impaired global integration. Nodal analysis revealed that the primary visual cortex (V1) is a more critical hub for information transfer, while the middle and high-level visual areas are less essential in MCS patients than in HCs. These findings provide a detailed characterization of the functional connectivity and topological properties of the visual cortical network in MCS patients, offering crucial insights for stimulus selection when using visual stimulation in rehabilitation and for assessing other cognitive functions.
{"title":"Functional connectivity and graphical topological properties of the visual cortical network of minimally conscious state (MCS) patients","authors":"Zina Li , Jichan Nian , Shuiyan Li , Zhiqing Deng , Hang Wu , Haili Zhong , Xiyan Huang , Pengmin Qin , Jinhui Wang , Qiuyou Xie , Juan Chen","doi":"10.1016/j.brainres.2025.150122","DOIUrl":"10.1016/j.brainres.2025.150122","url":null,"abstract":"<div><div>The Minimally Conscious State (MCS) is a condition in which a patient, following a brain injury, exhibits minimal yet definite behavioral evidence of awareness, representing a crucial transitional state between unconsciousness and the full emergence of consciousness. Assessing preserved cognitive function, particularly visual function, is crucial for diagnosis and rehabilitation, given that vision is the primary source of sensory input. While MCS patients consistently exhibit visual behaviors, such as sustained fixation or pursuit eye movements, previous neuroimaging studies have treated the visual network as a monolith, leaving it unclear which part of their visual cortical neural networks is affected or preserved. Here, we investigated the visual neural network of patients, encompassing 38 visual cortical subregions, from the primary visual cortex (V1), which processes low-level features (e.g., contrast, orientation), to higher-level visual regions that mediate object recognition and visual attention. Threshold-free network-based statistical analysis revealed that inter-hemispheric connectivity is significantly decreased, while intra-hemispheric connectivity is largely preserved in the visual network of MCS patients. Graph-based analysis showed a longer characteristic path length in them, indicating impaired global integration. Nodal analysis revealed that the primary visual cortex (V1) is a more critical hub for information transfer, while the middle and high-level visual areas are less essential in MCS patients than in HCs. These findings provide a detailed characterization of the functional connectivity and topological properties of the visual cortical network in MCS patients, offering crucial insights for stimulus selection when using visual stimulation in rehabilitation and for assessing other cognitive functions.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1873 ","pages":"Article 150122"},"PeriodicalIF":2.6,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145808867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leucine-rich repeat neuronal protein 3 (LRRN3) is a multifunctional transmembrane protein with a crucial role in intracellular signal transduction. It is expressed at high levels in neurons. LRRN3 expression has been shown to be associated with Parkinson’s disease (PD) and aging. It is involved in regulating cellular energy metabolism. However, the specific mechanism involved remains undetermined. In this study, we investigated whether LRRN3 can regulate the expression of the key glycolytic enzymes HK2 and LDHA as well as lactate levels. We also studied the expression of the apoptosis-related regulatory factors Bax and Bcl-2 and the mitochondrial structure. We found that LRRN3 can inhibit the expression of HK2 and LDHA and reduce lactate levels in PD models. LRRN3 rescued apoptotic cells, reversed mitochondrial structure damage, and alleviated motor deficits in PD mice. When glycolysis was inhibited in mice treated with 2-deoxy-D-glucose, apoptosis, mitochondrial structure damage, and motor deficits were reversed. Mechanistically, LRRN3 targets and inhibits glycolytic enzymes to enhance lactate homeostasis, ultimately exerting a protective effect on dopaminergic (DA) neurons. Our data indicate that LRRN3 can protect DA neurons by suppressing glycolysis. It holds promise as a potential therapeutic target for PD.
{"title":"LRRN3 protects dopaminergic neurons by inhibiting glycolysis in Parkinson’s disease","authors":"Jinzhao Gao, Kunpeng Qin, Wenke Xian, Jiwen Ren, Anmu Xie, Binghui Hou","doi":"10.1016/j.brainres.2025.150119","DOIUrl":"10.1016/j.brainres.2025.150119","url":null,"abstract":"<div><div>Leucine-rich repeat neuronal protein 3 (LRRN3) is a multifunctional transmembrane protein with a crucial role in intracellular signal transduction. It is expressed at high levels in neurons. LRRN3 expression has been shown to be associated with Parkinson’s disease (PD) and aging. It is involved in regulating cellular energy metabolism. However, the specific mechanism involved remains undetermined. In this study, we investigated whether LRRN3 can regulate the expression of the key glycolytic enzymes HK2 and LDHA as well as lactate levels. We also studied the expression of the apoptosis-related regulatory factors Bax and Bcl-2 and the mitochondrial structure. We found that LRRN3 can inhibit the expression of HK2 and LDHA and reduce lactate levels in PD models. LRRN3 rescued apoptotic cells, reversed mitochondrial structure damage, and alleviated motor deficits in PD mice. When glycolysis was inhibited in mice treated with 2-deoxy-D-glucose, apoptosis, mitochondrial structure damage, and motor deficits were reversed. Mechanistically, LRRN3 targets and inhibits glycolytic enzymes to enhance lactate homeostasis, ultimately exerting a protective effect on dopaminergic (DA) neurons. Our data indicate that LRRN3 can protect DA neurons by suppressing glycolysis. It holds promise as a potential therapeutic target for PD.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1873 ","pages":"Article 150119"},"PeriodicalIF":2.6,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145789794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1016/j.brainres.2025.150118
Andrew M. Victoria , Haley E. Capeci , Jade A. Steber , Hailey M. Donald , Piper L. Rennerfeldt , Jeffrey P. Cheng , Eleni H. Moschonas , Corina O. Bondi , Anthony E. Kline
Environmental enrichment (EE) promotes neurobehavioral recovery after traumatic brain injury (TBI). However, most preclinical studies initiate EE immediately after injury, which contrasts with delayed rehabilitation in the clinic. To better model clinical practice, we delayed the onset of EE and administered amantadine (AMT), which exhibits indirect dopaminergic effects, acutely as a therapeutic bridge. We hypothesized that this temporally sequenced combination therapy would improve neurobehavioral outcomes more than either treatment alone. Post-natal day 21 male rats received a controlled cortical impact or sham surgery and housed in standard (STD) conditions. Beginning 24 h post-surgery, daily intraperitoneal injections of AMT (20 mg/kg) or saline vehicle (VEH; 1 mL/kg) were provided for 7 days (bridge phase). On post-operative day 8, a subset transitioned to abbreviated EE (6 h/day). Vestibulomotor (beam-balance), cognition (spatial learning/memory), and affect (shock probe defensive burying) were assessed on days 8–12, 14–20, and 23, respectively. Hippocampal neuron survival was quantified on day 24. EE, regardless of AMT or VEH treatment, and AMT in STD housing, improved motor and cognitive outcomes versus VEH + STD (p < 0.05). Additionally, AMT + EE outperformed VEH + EE in spatial learning and improved memory retention relative to AMT + STD (p < 0.05). All treatment groups engaged quicker with the shock probe and increased burying behavior compared to VEH + STD. Additionally, the AMT + EE group spent more time burying the probe than the AMT + STD and VEH + EE groups (p < 0.05) and did not differ from SHAM controls (p > 0.05). Both EE groups had more CA3 neurons compared to the STD-housed groups (p < 0.05), while no difference in CA1 neurons was observed among the groups (p > 0.05). Overall, these findings reveal that acute AMT treatment augments the efficacy of delayed and abbreviated EE, particularly in cognitive and affective domains, which support the hypothesis. This temporally staged combination therapy may more accurately model clinical care and lead to greater improvement after TBI.
{"title":"Bridging the gap: Acute amantadine augments the neurorehabilitative efficacy of delayed and abbreviated environmental enrichment in a pediatric traumatic brain injury model","authors":"Andrew M. Victoria , Haley E. Capeci , Jade A. Steber , Hailey M. Donald , Piper L. Rennerfeldt , Jeffrey P. Cheng , Eleni H. Moschonas , Corina O. Bondi , Anthony E. Kline","doi":"10.1016/j.brainres.2025.150118","DOIUrl":"10.1016/j.brainres.2025.150118","url":null,"abstract":"<div><div>Environmental enrichment (EE) promotes neurobehavioral recovery after traumatic brain injury (TBI). However, most preclinical studies initiate EE immediately after injury, which contrasts with delayed rehabilitation in the clinic. To better model clinical practice, we delayed the onset of EE and administered amantadine (AMT), which exhibits indirect dopaminergic effects, acutely as a therapeutic bridge. We hypothesized that this temporally sequenced combination therapy would improve neurobehavioral outcomes more than either treatment alone. Post-natal day 21 male rats received a controlled cortical impact or sham surgery and housed in standard (STD) conditions. Beginning 24 h post-surgery, daily intraperitoneal injections of AMT (20 mg/kg) or saline vehicle (VEH; 1 mL/kg) were provided for 7 days (bridge phase). On post-operative day 8, a subset transitioned to abbreviated EE (6 h/day). Vestibulomotor (beam-balance), cognition (spatial learning/memory), and affect (shock probe defensive burying) were assessed on days 8–12, 14–20, and 23, respectively. Hippocampal neuron survival was quantified on day 24. EE, regardless of AMT or VEH treatment, and AMT in STD housing, improved motor and cognitive outcomes versus VEH + STD (<em>p</em> < 0.05). Additionally, AMT + EE outperformed VEH + EE in spatial learning and improved memory retention relative to AMT + STD (<em>p</em> < 0.05). All treatment groups engaged quicker with the shock probe and increased burying behavior compared to VEH + STD. Additionally, the AMT + EE group spent more time burying the probe than the AMT + STD and VEH + EE groups (<em>p</em> < 0.05) and did not differ from SHAM controls (<em>p</em> > 0.05). Both EE groups had more CA3 neurons compared to the STD-housed groups (<em>p</em> < 0.05), while no difference in CA1 neurons was observed among the groups (<em>p</em> > 0.05). Overall, these findings reveal that acute AMT treatment augments the efficacy of delayed and abbreviated EE, particularly in cognitive and affective domains, which support the hypothesis. This temporally staged combination therapy may more accurately model clinical care and lead to greater improvement after TBI.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1873 ","pages":"Article 150118"},"PeriodicalIF":2.6,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.brainres.2025.150115
Caiti-Erin Talty , Susan F. Murphy , Pamela J. VandeVord
Traumatic brain injury (TBI) is a leading cause of disability worldwide, with approximately 50 % of individuals with mild TBI experiencing persistent, debilitating symptoms. Clinical findings have demonstrated that females are more likely than males to develop chronic symptoms and tend to report greater symptom severity. Despite this, the pathophysiological mechanisms underlying these sex-specific chronic outcomes remain poorly understood. Using a clinically-relevant preclinical model of closed-head controlled impact in adult female rats, we examined affective-like behavior alterations up to twelve weeks post-injury. Injured animals exhibited early increases in risk-taking and disinhibition behaviors, followed by decreased social novelty preference and evidence of increased grooming behavior at eight weeks. Glutamatergic protein expression was measured in the frontal cortex and hippocampus at twelve weeks to assess glutamatergic alterations associated with chronic behavioral outcomes. TBI resulted in elevated expression of N-methyl-D-aspartate receptor subunits GluN1, GluN2A, and GluN2B, along with a decreased GluN2A:GluN2B ratio in the frontal cortex. Additionally, glutamate transporters GLT-1 and GLAST were upregulated in the hippocampus and frontal cortex, respectively. Together, these findings demonstrated that females exhibited dynamic behavioral changes accompanied by region-specific upregulation of glutamatergic signaling proteins. Further investigations are warranted to investigate circuit-level glutamatergic dysfunction and its potential role as a mechanistic driver of chronic TBI-related deficits in females.
外伤性脑损伤（TBI）是世界范围内致残的主要原因，大约50%的轻度TBI患者会出现持续的、使人衰弱的症状。临床研究结果表明，女性比男性更容易出现慢性症状，而且往往报告的症状更严重。尽管如此，这些性别特异性慢性结果的病理生理机制仍然知之甚少。使用与临床相关的成年雌性大鼠闭头控制撞击的临床前模型，我们检查了损伤后12周的情感样行为改变。受伤的动物表现出冒险行为和去抑制行为的早期增加，随后是社会新奇偏好的减少和8周时梳理行为的增加。在12周时测量额叶皮层和海马体中的谷氨酸能蛋白表达，以评估与慢性行为结果相关的谷氨酸能改变。脑外伤导致n -甲基- d -天冬氨酸受体亚基GluN1、GluN2A和GluN2B的表达升高，GluN2A:GluN2B比值降低。此外，海马和额叶皮层的谷氨酸转运体GLT-1和GLAST分别上调。总之，这些发现表明，雌性表现出动态的行为变化，并伴有区域特异性的谷氨酸信号蛋白上调。有必要进一步研究回路水平的谷氨酸能功能障碍及其作为女性慢性创伤性脑损伤相关缺陷的机制驱动因素的潜在作用。
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Pub Date : 2025-12-17DOI: 10.1016/j.brainres.2025.150116
You-hai Hua , Xin-yue Huang , Jing-jing Ma , Jin Wu , Zeng-hui Zhou
Objective
Neuroinflammation driven by microglial hyperactivation plays a critical role in Parkinson’s disease (PD). Ezetimibe, a cholesterol absorption inhibitor widely used for hyperlipidemia, has recently been implicated in neuroprotection. However, its impact on microglial activation in PD remains poorly understood. This study aimed to investigate the therapeutic potential and mechanisms of ezetimibe in modulating microglial activation in PD model.
Methods
Network pharmacology was employed to predict ezetimibe targets in PD, followed by validation in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Protein–protein interaction (PPI) analysis and Gene Ontology (GO) enrichment were used to identify relevant pathways. Molecular docking assessed ezetimibe-TLR4 binding. The effects of ezetimibe on pro-inflammatory mediator production, TLR4/JNK signaling, and microglia-induced dopaminergic neurotoxicity were evaluated using western blotting, qPCR, ELISA, and BV2–SH-SY5Y co-culture assays.
Results
Network pharmacology identified 53 common targets between ezetimibe and PD, with TLR4, TNF, and IL-1β as hub genes enriched in inflammatory processes. In BV2 cells, ezetimibe markedly reduced LPS-induced expression and secretion of iNOS, COX-2, Nitric oxide (NO), and IL-6 at both protein and transcriptional levels. Molecular docking revealed a strong binding affinity of ezetimibe to TLR4, although ezetimibe did not alter the basal expression of TLR4. Mechanistically, ezetimibe pretreatment suppressed LPS-induced JNK phosphorylation and AP-1 transcriptional activity, key downstream events of TLR4 activation. Consistently, pharmacological inhibition of TLR4 with TLR4-IN-C34 did not produce additional anti-inflammatory effects, confirming that ezetimibe acts through the TLR4 signaling pathway. Moreover, conditioned medium from ezetimibe-pretreated BV2 cells significantly reduced SH-SY5Y neuronal death, as indicated by decreased PI staining, LDH release, CCK8 assay, tyrosine hydroxylase (TH) protein levels and caspase-3 activation.
Conclusion
Ezetimibe suppresses microglial activation by targeting the TLR4/JNK pathway, thereby alleviating dopaminergic neuronal death. These findings highlight ezetimibe as a promising candidate for repurposing in PD therapy.
目的：由小胶质细胞过度激活驱动的神经炎症在帕金森病（PD）中起关键作用。依折替米贝是一种广泛用于高脂血症的胆固醇吸收抑制剂，最近被认为与神经保护有关。然而，其对PD中小胶质细胞激活的影响仍然知之甚少。本研究旨在探讨依折麦布调节PD模型小胶质细胞活化的治疗潜力和机制。方法采用网络药理学方法预测依zetimibe在PD中的靶点，然后在脂多糖（LPS）刺激的BV2小胶质细胞中进行验证。通过蛋白-蛋白相互作用（PPI）分析和基因本体（GO）富集来确定相关途径。分子对接评估ezetimibe-TLR4结合。采用western blotting、qPCR、ELISA和BV2-SH-SY5Y共培养试验评估依泽替米贝对促炎介质产生、TLR4/JNK信号传导和小胶质细胞诱导的多巴胺能神经毒性的影响。结果网络药理学鉴定了依zetimibe和PD之间的53个共同靶点，其中TLR4、TNF和IL-1β是炎症过程中富集的中心基因。在BV2细胞中，依zetimibe在蛋白和转录水平上显著降低lps诱导的iNOS、COX-2、一氧化氮（NO）和IL-6的表达和分泌。分子对接显示ezetimibe与TLR4有很强的结合亲和力，尽管ezetimibe没有改变TLR4的基础表达。在机制上，依zetimibe预处理抑制了lps诱导的JNK磷酸化和AP-1转录活性，这是TLR4激活的关键下游事件。与此一致的是，TLR4- in - c34对TLR4的药理学抑制并未产生额外的抗炎作用，证实依折麦贝是通过TLR4信号通路起作用的。此外，ezetimibe预处理BV2细胞的条件培养基显著降低了SH-SY5Y神经元的死亡，PI染色、LDH释放、CCK8检测、酪氨酸羟化酶（TH）蛋白水平和caspase-3激活均有所降低。结论依折替米贝通过TLR4/JNK通路抑制小胶质细胞的激活，从而减轻多巴胺能神经元的死亡。这些发现突出了依折麦布在帕金森病治疗中的应用前景。
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