Pub Date : 2025-11-12DOI: 10.1016/j.bbi.2025.106172
Ellie B. Decker Ramirez, Jesse R. Schank
Alcohol use disorder (AUD) continues to negatively impact millions of men and women in the United States each year, and current available treatments for AUD lack widespread efficacy. Major depressive disorder (MDD) is the most common comorbid condition with AUD and is also often treatment resistant. Many studies have found a relationship of immune modulators with both alcohol use and depression. There are many sex differences within the immune system that may contribute to both AUD and MDD, as well as to sex differences in their prevalence and presentation. Examining these mechanisms may offer more effective treatment options. The following review focuses on immune signaling mechanisms, including pattern recognition receptors and proinflammatory cytokines, which have been strongly associated with alcohol use and MDD. Within the context of these signaling systems, we will further discuss known sex differences in their function that may contribute to behavioral outcomes.
{"title":"Sex differences in inflammatory mechanisms related to alcohol use disorder and depression","authors":"Ellie B. Decker Ramirez, Jesse R. Schank","doi":"10.1016/j.bbi.2025.106172","DOIUrl":"10.1016/j.bbi.2025.106172","url":null,"abstract":"<div><div>Alcohol use disorder (AUD) continues to negatively impact millions of men and women in the United States each year, and current available treatments for AUD lack widespread efficacy. Major depressive disorder (MDD) is the most common comorbid condition with AUD and is also often treatment resistant. Many studies have found a relationship of immune modulators with both alcohol use and depression. There are many sex differences within the immune system that may contribute to both AUD and MDD, as well as to sex differences in their prevalence and presentation. Examining these mechanisms may offer more effective treatment options. The following review focuses on immune signaling mechanisms, including pattern recognition receptors and proinflammatory cytokines, which have been strongly associated with alcohol use and MDD. Within the context of these signaling systems, we will further discuss known sex differences in their function that may contribute to behavioral outcomes.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"131 ","pages":"Article 106172"},"PeriodicalIF":7.6,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145522993","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}
Pub Date : 2025-11-12DOI: 10.1016/j.bbi.2025.106176
Ruo-lan Yuan , Sha-sha Wang , Pei-yi Li , Yuan Ruan , Jia-qi He , Run Zhou , Wen-fei Wang , Yu-tong Jiang , Jun-rui Ye , Ye Peng , Wen-bin He , Shi-feng Chu , Zhao Zhang , Nai-hong Chen
Background
Long COVID has emerged as a global health concern, with depression being one of its most debilitating and poorly understood manifestations. Despite evidence pointing to the role of neuroinflammation and astrocyte-mediated disruptions in brain function, the mechanistic details remain elusive.
Methods
SARS-CoV-2 spike receptor-binding domain (RBD) was microinjected into the medial prefrontal cortex (mPFC) to mimic cerebral infection, and the depressive-like behaviors, functional connectivity, and neuronal excitability were recorded for a 16-day period. Immunofluorescence, RNA sequencing, and ELISA were used to evaluate astrocytic gap junctions and inflammation. Gap junction intercellular communication (GJIC) dysfunction was confirmed by transfer of lucifer yellow (LY), cyclic adenosine monophosphate (cAMP), and cyclic GMP-AMP (cGAMP). We also investigated the role of Cx43 using conditional knockout mice, Gap 27-treated mice, and Cx43-knockdown astrocytes. Astrocytic Cx43 overexpression and celecoxib treatment were tested as a potential therapeutic to rescue Cx43 function.
Results
Mice microinjected with RBD into the mPFC exhibited significant depressive-like behaviors, decreased neuronal excitability, and disrupted functional connectivity, accompanied by a marked reduction in astrocytic Cx43 expression and impaired GJIC. Functional assays, including Lucifer Yellow, cAMP, and cGAMP transfer, confirmed compromised gap junction activity, which was further associated with enhanced astrocytic type I interferon responses and cGAS-STING pathway activation. Conditional knockout of Cx43 in astrocytes or pharmacological inhibition of GJIC mimicked the depressive-like phenotypes induced by RBD. Importantly, Astrocytic Cx43 overexpression and celecoxib treatment restored GJIC, and effectively alleviated depressive-like behaviors in RBD-injected mice.
Conclusions
Astrocytic Cx43-mediated GJIC as a promising therapeutic strategy for managing depression in long COVID.
{"title":"SARS-CoV-2 spike protein induces depressive-like behaviors by disrupting astrocytic Cx43-mediated gap junction intercellular communication","authors":"Ruo-lan Yuan , Sha-sha Wang , Pei-yi Li , Yuan Ruan , Jia-qi He , Run Zhou , Wen-fei Wang , Yu-tong Jiang , Jun-rui Ye , Ye Peng , Wen-bin He , Shi-feng Chu , Zhao Zhang , Nai-hong Chen","doi":"10.1016/j.bbi.2025.106176","DOIUrl":"10.1016/j.bbi.2025.106176","url":null,"abstract":"<div><h3>Background</h3><div>Long COVID has emerged as a global health concern, with depression being one of its most debilitating and poorly understood manifestations. Despite evidence pointing to the role of neuroinflammation and astrocyte-mediated disruptions in brain function, the mechanistic details remain elusive.</div></div><div><h3>Methods</h3><div>SARS-CoV-2 spike receptor-binding domain (RBD) was microinjected into the medial prefrontal cortex (mPFC) to mimic cerebral infection, and the depressive-like behaviors, functional connectivity, and neuronal excitability were recorded for a 16-day period. Immunofluorescence, RNA sequencing, and ELISA were used to evaluate astrocytic gap junctions and inflammation. Gap junction intercellular communication (GJIC) dysfunction was confirmed by transfer of lucifer yellow (LY), cyclic adenosine monophosphate (cAMP), and cyclic GMP-AMP (cGAMP). We also investigated the role of Cx43 using conditional knockout mice, Gap 27-treated mice, and Cx43-knockdown astrocytes. Astrocytic Cx43 overexpression and celecoxib treatment were tested as a potential therapeutic to rescue Cx43 function.</div></div><div><h3>Results</h3><div>Mice microinjected with RBD into the mPFC exhibited significant depressive-like behaviors, decreased neuronal excitability, and disrupted functional connectivity, accompanied by a marked reduction in astrocytic Cx43 expression and impaired GJIC. Functional assays, including Lucifer Yellow, cAMP, and cGAMP transfer, confirmed compromised gap junction activity, which was further associated with enhanced astrocytic type I interferon responses and cGAS-STING pathway activation. Conditional knockout of Cx43 in astrocytes or pharmacological inhibition of GJIC mimicked the depressive-like phenotypes induced by RBD. Importantly, Astrocytic Cx43 overexpression and celecoxib treatment restored GJIC, and effectively alleviated depressive-like behaviors in RBD-injected mice.</div></div><div><h3>Conclusions</h3><div>Astrocytic Cx43-mediated GJIC as a promising therapeutic strategy for managing depression in long COVID.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"131 ","pages":"Article 106176"},"PeriodicalIF":7.6,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145522970","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}
Pub Date : 2025-11-11DOI: 10.1016/j.bbi.2025.106175
Inés Martínez Sánchez , Whee-Soo Kim , Connie Heather , Susanne Nylén , Mikhail G. Shapiro , Rochellys Diaz Heijtz
Broad-spectrum β-lactam antibiotics, such as ampicillin, disrupt the commensal gut microbiota and reduce its diversity. However, their potential short-term impact on the translocation of bacterial peptidoglycan (PGN) fragments to the brain and subsequent effects on brain function remain unexplored. In this study, we investigate the effects of a clinically relevant dose of ampicillin on PGN translocation into the brain, gene expression, brain functional connectivity, and social behavior in young adult mice. PGN translocation and gene expression were analyzed at 24-, 48-, and 72-h time points, while behavior, functional connectivity, and gut microbiota were analyzed at 72 h post-exposure. We find that ampicillin increases region-specific PGN translocation into the brain, which correlates with variations in the gene expression levels of PGN transporters and receptors in naïve animals. Antibiotic-treated mice exhibit impaired sociability and social recognition at 72 h post-exposure, which correlate with changes in the expression of synaptic (Syp, Ppp1r9b, Dlg4) and immune (Trem-2) genes in both the prefrontal cortex and striatum, along with disrupted brain functional connectivity. Furthermore, antibiotic-treated mice show an increase in the relative abundance of Gram-negative bacteria at 72 h post-exposure. Mice treated with iE-DAP, a unique PGN fragment from Gram-negative bacteria, exhibit key antibiotic-induced behavioral and molecular traits. Similar to antibiotic-treated mice, iE-DAP-exposed mice show impaired social recognition while maintaining normal motor activity, and reduced expression of synaptic-related genes in the prefrontal cortex and striatum. These findings provide novel insights into the neurobiological mechanisms underlying antibiotic-induced behavioral and functional disruptions and highlight the potential risks to brain health associated with repeated antibiotic use.
{"title":"Short-term β-lactam antibiotic exposure promotes peptidoglycan translocation to the brain and impairs functional connectivity and social recognition in mice","authors":"Inés Martínez Sánchez , Whee-Soo Kim , Connie Heather , Susanne Nylén , Mikhail G. Shapiro , Rochellys Diaz Heijtz","doi":"10.1016/j.bbi.2025.106175","DOIUrl":"10.1016/j.bbi.2025.106175","url":null,"abstract":"<div><div>Broad-spectrum β-lactam antibiotics, such as ampicillin, disrupt the commensal gut microbiota and reduce its diversity. However, their potential short-term impact on the translocation of bacterial peptidoglycan (PGN) fragments to the brain and subsequent effects on brain function remain unexplored. In this study, we investigate the effects of a clinically relevant dose of ampicillin on PGN translocation into the brain, gene expression, brain functional connectivity, and social behavior in young adult mice. PGN translocation and gene expression were analyzed at 24-, 48-, and 72-h time points, while behavior, functional connectivity, and gut microbiota were analyzed at 72 h post-exposure. We find that ampicillin increases region-specific PGN translocation into the brain, which correlates with variations in the gene expression levels of PGN transporters and receptors in naïve animals. Antibiotic-treated mice exhibit impaired sociability and social recognition at 72 h post-exposure, which correlate with changes in the expression of synaptic (<em>Syp</em>, <em>Ppp1r9b</em>, <em>Dlg4</em>) and immune (<em>Trem-2</em>) genes in both the prefrontal cortex and striatum, along with disrupted brain functional connectivity. Furthermore, antibiotic-treated mice show an increase in the relative abundance of Gram-negative bacteria at 72 h post-exposure. Mice treated with iE-DAP, a unique PGN fragment from Gram-negative bacteria, exhibit key antibiotic-induced behavioral and molecular traits. Similar to antibiotic-treated mice, iE-DAP-exposed mice show impaired social recognition while maintaining normal motor activity, and reduced expression of synaptic-related genes in the prefrontal cortex and striatum. These findings provide novel insights into the neurobiological mechanisms underlying antibiotic-induced behavioral and functional disruptions and highlight the potential risks to brain health associated with repeated antibiotic use.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"131 ","pages":"Article 106175"},"PeriodicalIF":7.6,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145511694","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}
Pub Date : 2025-11-11DOI: 10.1016/j.bbi.2025.106178
Samuelle A.S. Delcy , Anthony Farrugia , Ian A. Diaz Nieves , Carleigh A. O’Brien , Frederick C. Bennett , Akiva S. Cohen
Traumatic brain injury (TBI) affects over 69 million people every year, and mild traumatic brain injury (mTBI) accounts for 70–90 % of cases. TBI has two components: i) primary injury − direct damage to the tissue from the mechanical impact and ii) secondary injury − additional or extended damage to the tissue from the ensuing biochemical and physiological processes such as neuroinflammation. Neuroinflammation triggered in part by activated microglia, determines whether the post-injury outcome is recovery or long-term neurodegeneration. Microglia, key components of the neuroinflammatory process, release cytokines such as TNF-α, which affect neuronal activity. Our study investigated the effects of acute microglia depletion on hippocampal neurophysiology in male mice (7–10 days after mTBI), a time window that allows us to target sub-acute microglial responses post-injury. An additional objective of the study was to determine if the pro-inflammatory cytokine TNF-α contributed to the injury-induced network excitability shifts in the hippocampal circuitry. We demonstrate that depleting microglia with PLX-3397 treatment for 7–10 days after mTBI restores network excitability in hippocampal area CA1 and the dentate gyrus (DG). Furthermore, treatments with thalidomide and etanercept show that TNF-α plays a role in altering the network excitability after mTBI. These findings provide new insights into the physiological changes after injury and highlight potential targets for future interventions to specifically address the detrimental effects of chronic inflammation.
{"title":"Microglia depletion improves hippocampal circuit function after mild traumatic brain injury in male mice","authors":"Samuelle A.S. Delcy , Anthony Farrugia , Ian A. Diaz Nieves , Carleigh A. O’Brien , Frederick C. Bennett , Akiva S. Cohen","doi":"10.1016/j.bbi.2025.106178","DOIUrl":"10.1016/j.bbi.2025.106178","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) affects over 69 million people every year, and mild traumatic brain injury (mTBI) accounts for 70–90 % of cases. TBI has two components: i) primary injury − direct damage to the tissue from the mechanical impact and ii) secondary injury − additional or extended damage to the tissue from the ensuing biochemical and physiological processes such as neuroinflammation. Neuroinflammation triggered in part by activated microglia, determines whether the post-injury outcome is recovery or long-term neurodegeneration. Microglia, key components of the neuroinflammatory process, release cytokines such as TNF-α, which affect neuronal activity. Our study investigated the effects of acute microglia depletion on hippocampal neurophysiology in male mice (7–10 days after mTBI), a time window that allows us to target sub-acute microglial responses post-injury. An additional objective of the study was to determine if the pro-inflammatory cytokine TNF-α contributed to the injury-induced network excitability shifts in the hippocampal circuitry. We demonstrate that depleting microglia with PLX-3397 treatment for 7–10 days after mTBI restores network excitability in hippocampal area CA1 and the dentate gyrus (DG). Furthermore, treatments with thalidomide and etanercept show that TNF-α plays a role in altering the network excitability after mTBI. These findings provide new insights into the physiological changes after injury and highlight potential targets for future interventions to specifically address the detrimental effects of chronic inflammation.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"131 ","pages":"Article 106178"},"PeriodicalIF":7.6,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145511660","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}
Pub Date : 2025-11-10DOI: 10.1016/j.bbi.2025.106179
Elena Di Martino , Davide Vacondio , Luis Enrique Arroyo-García , Michele Bedin , Luigi Balasco , Isabella Schmeh , Melanie Pieber , Anne-Kristin Kukla , Takeo Mukai , Shunichiro Tsuji , Xing-Mei Zhang , Ronny Wickström , Klas Blomgren , Robert A. Harris , Ulrika Ådén
Neonatal hypoxic-ischemia (HI) represents a major cause of brain injury in the perinatal period. Post-ischemic neuroinflammation plays a key role in HI pathophysiology and is characterized by the infiltration of peripheral immune cells in support of resident microglia.
To investigate the effects of peripheral macrophages as a possible treatment for HI, 10-day old CX3CXR1GFP/+/CCR2RFP/+ mice were subjected to electrocoagulation of the right carotid artery and 1 hour hypoxia with 10 % oxygen. CCR2RFP/+ cell migration to the brain was assessed by flow cytometry 1, 3, 5, 7, 10 and 14 days after HI, and a biphasic infiltration pattern was identified. Five days post-surgery injured and sham pups received an intraperitoneal administration of bone marrow-derived macrophages (BMDMs) previously polarized into M0 or M2 states in vitro. Open field, beam walk and rotarod behavioral tests were performed 3 weeks after HI, and brains were then collected to assess injury extent. Injured mice treated with M2 cells showed significant functional recovery and reduced brain atrophy specifically in males. In contrast, treatment with M0 cells led to a significant worsening of behavioral performances and a greater brain injury specifically in females if compared to HI mice receiving PBS.
To further define BMDM plasticity in a post-ischemic environment, M0 and M2 cells were co-cultured in vitro with hippocampal organotypic slices previously subjected to oxygen-glucose deprivation. After 48 h, M2 cells showed significant downregulation of Il1b, Cd68 and Tnfa, while significant upregulation of Il1b, Il6 and Ccl2 was observed in M0 cells, suggesting their switch into a M1 pro-inflammatory polarization state.
Overall, these results suggest the therapeutic potential of M2 BMDMs for neonatal HI.
{"title":"Delayed adoptive transfer of bone marrow-derived macrophages modulates post-ischemic inflammation in a model of neonatal hypoxia-ischemia","authors":"Elena Di Martino , Davide Vacondio , Luis Enrique Arroyo-García , Michele Bedin , Luigi Balasco , Isabella Schmeh , Melanie Pieber , Anne-Kristin Kukla , Takeo Mukai , Shunichiro Tsuji , Xing-Mei Zhang , Ronny Wickström , Klas Blomgren , Robert A. Harris , Ulrika Ådén","doi":"10.1016/j.bbi.2025.106179","DOIUrl":"10.1016/j.bbi.2025.106179","url":null,"abstract":"<div><div>Neonatal hypoxic-ischemia (HI) represents a major cause of brain injury in the perinatal period. Post-ischemic neuroinflammation plays a key role in HI pathophysiology and is characterized by the infiltration of peripheral immune cells in support of resident microglia.</div><div>To investigate the effects of peripheral macrophages as a possible treatment for HI, 10-day old CX3CXR1<sup>GFP/+</sup>/CCR2<sup>RFP/+</sup> mice were subjected to electrocoagulation of the right carotid artery and 1 hour hypoxia with 10 % oxygen. CCR2<sup>RFP/+</sup> cell migration to the brain was assessed by flow cytometry 1, 3, 5, 7, 10 and 14 days after HI, and a biphasic infiltration pattern was identified. Five days post-surgery injured and sham pups received an intraperitoneal administration of bone marrow-derived macrophages (BMDMs) previously polarized into M0 or M2 states <em>in vitro</em>. Open field, beam walk and rotarod behavioral tests were performed 3 weeks after HI, and brains were then collected to assess injury extent. Injured mice treated with M2 cells showed significant functional recovery and reduced brain atrophy specifically in males. In contrast, treatment with M0 cells led to a significant worsening of behavioral performances and a greater brain injury specifically in females if compared to HI mice receiving PBS.</div><div>To further define BMDM plasticity in a post-ischemic environment, M0 and M2 cells were co-cultured <em>in vitro</em> with hippocampal organotypic slices previously subjected to oxygen-glucose deprivation. After 48 h, M2 cells showed significant downregulation of <em>Il1b</em>, <em>Cd68</em> and <em>Tnfa</em>, while significant upregulation of <em>Il1b</em>, <em>Il6</em> and <em>Ccl2</em> was observed in M0 cells, suggesting their switch into a M1 pro-inflammatory polarization state.</div><div>Overall, these results suggest the therapeutic potential of M2 BMDMs for neonatal HI.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"131 ","pages":"Article 106179"},"PeriodicalIF":7.6,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145502102","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}
Pub Date : 2025-11-10DOI: 10.1016/j.bbi.2025.106168
Srivaishnavi Loganathan , Menghan Sun , Catalina Argandona Lopez , Jasmine Wangui , Aynur Shirmamedova , Autumn Johnson , Pearl Louie , Zachary Pelland , Raquia Alize-Hunt , Xiaolei Zhu , Dani Smith , Amanda M. Brown
The neurological complications of HIV or NeuroHIV, representing a spectrum of disorders in people living with HIV, are characterized by memory impairments and cognitive decline. Osteopontin/secreted phosphoprotein 1 (OPN/SPP1), a multifunctional cytokine-like protein secreted by multiple cell types in and outside the central nervous system (CNS), is highly elevated in NeuroHIV and other well-known neurodegenerative disorders. Additionally, previous neuroimaging studies have demonstrated a role for OPN in regulating neuroinflammatory signaling. However, the potential links between CNS-specific functions of OPN and behavior remain unclear. In this study, we used NSG immunodeficient mice (hu-mice) engrafted as neonates with HIV-susceptible human CD34 + hematopoietic stem cells (HSCs) to test the hypotheses that chronic viral infection impairs cognitive function and that systemic disruption of OPN expression can ameliorate the resulting behavioral deficits. We found that HIV-infected hu-mice treated with inhibitory OPN-aptamers to knock down OPN exhibited altered exploratory and anxiety-related behavior compared to uninfected animals. A synergistic relationship between HIV and OPN impaired cognitive performance in an object recognition memory task that was not observed in uninfected mice. The knockdown of OPN expression alleviated this recognition deficit. Interestingly, only the HIV-infected OPN knockdown group showed a marked reduction in motivation/self-care related behavior. Additionally, we found reduced OPN expression in cells located in the midbrain ventral tegmental area of HIV-infected mice, demonstrating for the first time, the systemic delivery of functional aptamers to the brain. Notably, there were no significant differences in OPN levels in similarly treated uninfected mice. Notably, a decrease in tyrosine hydroxylase (TH) expression in midbrain dopaminergic neurons of OPN knockdown compared to OPN wildtype mice, irrespective of HIV infection status was foundsuggests a potential gene expression regulatory link between OPN and TH. These findings highlight the multifaceted role of OPN in HIV-associated neurobehavioral dysfunction, suggesting context-dependent contributions to both cognitive and apathy-based processes.
{"title":"Osteopontin knockdown reverses HIV-induced cognitive deficits and influences motivation-related behavior","authors":"Srivaishnavi Loganathan , Menghan Sun , Catalina Argandona Lopez , Jasmine Wangui , Aynur Shirmamedova , Autumn Johnson , Pearl Louie , Zachary Pelland , Raquia Alize-Hunt , Xiaolei Zhu , Dani Smith , Amanda M. Brown","doi":"10.1016/j.bbi.2025.106168","DOIUrl":"10.1016/j.bbi.2025.106168","url":null,"abstract":"<div><div>The neurological complications of HIV or NeuroHIV, representing a spectrum of disorders in people living with HIV, are characterized by memory impairments and cognitive decline. Osteopontin/secreted phosphoprotein 1 (OPN/SPP1), a multifunctional cytokine-like protein secreted by multiple cell types in and outside the central nervous system (CNS), is highly elevated in NeuroHIV and other well-known neurodegenerative disorders. Additionally, previous neuroimaging studies have demonstrated a role for OPN in regulating neuroinflammatory signaling. However, the potential links between CNS-specific functions of OPN and behavior remain unclear. In this study, we used NSG immunodeficient mice (hu-mice) engrafted as neonates with HIV-susceptible human CD34 + hematopoietic stem cells (HSCs) to test the hypotheses that chronic viral infection impairs cognitive function and that systemic disruption of OPN expression can ameliorate the resulting behavioral deficits. We found that HIV-infected hu-mice treated with inhibitory OPN-aptamers to knock down OPN exhibited altered exploratory and anxiety-related behavior compared to uninfected animals. A synergistic relationship between HIV and OPN impaired cognitive performance in an object recognition memory task that was not observed in uninfected mice. The knockdown of OPN expression alleviated this recognition deficit. Interestingly, only the HIV-infected OPN knockdown group showed a marked reduction in motivation/self-care related behavior. Additionally, we found reduced OPN expression in cells located in the midbrain ventral tegmental area of HIV-infected mice, demonstrating for the first time, the systemic delivery of functional aptamers to the brain. Notably, there were no significant differences in OPN levels in similarly treated uninfected mice. Notably, a decrease in tyrosine hydroxylase (TH) expression in midbrain dopaminergic neurons of OPN knockdown compared to OPN wildtype mice, irrespective of HIV infection status was foundsuggests a potential gene expression regulatory link between OPN and TH. These findings highlight the multifaceted role of OPN in HIV-associated neurobehavioral dysfunction, suggesting context-dependent contributions to both cognitive and apathy-based processes.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"131 ","pages":"Article 106168"},"PeriodicalIF":7.6,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145502147","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}
Pub Date : 2025-11-05DOI: 10.1016/j.bbi.2025.106166
Maureen W. Groer
{"title":"Dry mouth and red hot: Cytokines and neuroendocrine responses to psychological stress","authors":"Maureen W. Groer","doi":"10.1016/j.bbi.2025.106166","DOIUrl":"10.1016/j.bbi.2025.106166","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"131 ","pages":"Article 106166"},"PeriodicalIF":7.6,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145470856","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}
Pub Date : 2025-11-05DOI: 10.1016/j.bbi.2025.106171
Bin Zhou , Hanying Ma , Yunxiao Li , Ting He , Xiaping Yao , Bifeng Liu , Jiahe Guo , Jiaping Zhang , Huiliang Zhang
Depression is one of the most prevalent mental health diseases, which is characterized by functional or structural changes of neurons. Cancer-induced depression (CID) can bring more serious medical burden. Exosomes have been implicated in cancer progression and depressive disorders; however, their specific role in CID remains unclear. To investigate the role of exosomes in CID, exosomes derived from 4T1 breast cancer cells were extracted using microfluidic chips-based isolation method. Behavioral assessments were performed to explore the effects of intranasal exosomal myeloid differentiation factor 88 (MYD88) on depressive-like behaviors in mice. Additionally, the effects of exosomal MYD88 on neuronal structure and function were researched by Golgi staining, sholl analysis and electrophysiological recordings. Exosomes from 4T1 breast cancer cells induced depressive-like symptoms and altered neuronal structure and function in the medial prefrontal cortex (mPFC) by upregulating MYD88 levels. Conversely, exosomes with reduced MYD88 content did not produce these depressive-like symptoms, suggesting a critical role for MYD88 in the observed effects. Exosomal MYD88 contributes to the development of breast cancer-induced depression. These findings highlight the potential of targeting exosomal pathways, particularly MYD88, as a therapeutic strategy for managing depression in cancer patients.
{"title":"Exosomal MYD88 isolated from 4T1 breast cancer cells using microfluidic chips promotes depressive-like behavior through neural remodeling in the mPFC","authors":"Bin Zhou , Hanying Ma , Yunxiao Li , Ting He , Xiaping Yao , Bifeng Liu , Jiahe Guo , Jiaping Zhang , Huiliang Zhang","doi":"10.1016/j.bbi.2025.106171","DOIUrl":"10.1016/j.bbi.2025.106171","url":null,"abstract":"<div><div>Depression is one of the most prevalent mental health diseases, which is characterized by functional or structural changes of neurons. Cancer-induced depression (CID) can bring more serious medical burden. Exosomes have been implicated in cancer progression and depressive disorders; however, their specific role in CID remains unclear. To investigate the role of exosomes in CID, exosomes derived from 4T1 breast cancer cells were extracted using microfluidic chips-based isolation method. Behavioral assessments were performed to explore the effects of intranasal exosomal myeloid differentiation factor 88 (MYD88) on depressive-like behaviors in mice. Additionally, the effects of exosomal MYD88 on neuronal structure and function were researched by Golgi staining, sholl analysis and electrophysiological recordings. Exosomes from 4T1 breast cancer cells induced depressive-like symptoms and altered neuronal structure and function in the medial prefrontal cortex (mPFC) by upregulating MYD88 levels. Conversely, exosomes with reduced MYD88 content did not produce these depressive-like symptoms, suggesting a critical role for MYD88 in the observed effects. Exosomal MYD88 contributes to the development of breast cancer-induced depression. These findings highlight the potential of targeting exosomal pathways, particularly MYD88, as a therapeutic strategy for managing depression in cancer patients.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"131 ","pages":"Article 106171"},"PeriodicalIF":7.6,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457514","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}
Pub Date : 2025-11-04DOI: 10.1016/j.bbi.2025.106169
Jessica Schiele , Pei-Ling Tsai , Georg Ernst , Cleo Blank , Sina Beck , Tamara Schimmele , Elisabeth Burth , Dorothea Gebauer , Christopher A. Lowry , Reiner Noschka , Dominik Langgartner , Steffen Stenger , Melanie Haffner-Luntzer , David A. Slattery , Stefan O. Reber
The prenatal period is a vulnerable phase for the offspring’s development in utero and ex utero. Accordingly, negative environmental influences such as chronic maternal stress pose a major risk factor for the offspring to develop a variety of mental and physical disorders later in life. Many of these pathologies are accompanied by an over-reactive immune system and chronic low-grade inflammation, and prospective human and mechanistic animal studies strengthen the idea that an exaggerated immune (re)activity plays a causal role in their pathogenesis. In line with the latter, we have shown in mice that repeated administrations with heat-inactivated preparations of different immunoregulatory nontuberculous mycobacteria (NTM), such as M. vaccae NCTC 11659 and the closely related strain M. vaccae ATCC 15483T promote immunoregulation and stress protection. In the current study, we extend these findings by showing that repeatedly administering M. vaccae ATCC 15483T via the intragastric (i.g.) route to female mice prior to mating protected their male offspring against the negative consequences of prenatal stress (PS) exposure (i.e., restraint stress combined with daily alternating social instability from embryonic days 4 to 16) on the immune and musculoskeletal system. In detail, while male offspring of PS vs. noPS mothers in the vehicle (i.e., borate-buffered saline, BBS) group showed an increased splenic IgG expression, lipopolysaccharide (LPS) reactivity of isolated spleen cells and chemotactic activity of isolated white blood cells (WBCs), as well as a reduced femoral bone volume/total volume (BV/TV), trabecular tissue mineral density (TbTMD), trabecular thickness (TbTh) and trabecular number (TbN), these effects were absent in male offspring of the M. vaccae ATCC 15483T group. The protective effects of M. vaccae ATCC 15483T on female offspring are harder to interpret, as the latter were not as reliably affected by PS. Collectively, our findings indicate that repeated i.g. administration of M. vaccae ATCC 15483T in an intergenerational manner is protective against the negative consequences of PS on the immune and musculoskeletal system.
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