Scholarly Works, School of Neuroscience

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Blood Pressure Variability (BPV) as a Novel Digital Biomarker of Multisystem Risk and Diagnostic Insight: Measurement, Mechanisms, and Emerging Artificial Intelligence Methods
Pugalenthi, Lakshmi Sree; Senapati, Sidhartha Gautam; Gohri, Jay; Anam, Hema Latha; Madan, Hritik; Arora, Adi; Arora, Avni; Lee, Jieun; Yerrapragada, Gayathri; Elangovan, Poonguzhali; Shariff, Mohammed Naveed; Natarajan, Thangeswaran; Janarthanan, Jayarajasekaran; Agarwal, Shreshta; Karuppiah, Shiva Sankari; Sood, Divyanshi; Rapolu, Swetha; Iyer, Vivek N.; Helgeson, Scott A.; Arunachalam, Shivaram P. (MDPI, 2026-01-30)
Hypertension has been traditionally known to be highlighted by mean blood pressure; however, emerging evidence exhibits that blood pressure variability (BPV), including short-term, day-to-day, and visit-to-visit fluctuations can have an implication across multiple body systems. Elevated BPV reflects repetitive hemodynamic stress, affecting the physiologic hemostasis contributing to vascular injury and end organ damage. This narrative review is a compilation of recent evidence on the prognostic value of BPV, explained by pathophysiology, various devices with its measurement approaches, and, essentially, the clinical implication of BPV and the use of such devices utilizing artificial intelligence. A comprehensive literature search across PubMed, Cochrane Library, Scopus, and Web of Science were conducted, focusing on observational studies, cohorts, randomized trials, and meta-analyses. Higher BPV has been associated with an increased risk of cardiovascular mortality, stroke, coronary events, and heart failure, the progression of chronic kidney disease, cognitive decline, and preeclampsia, among other end organ damage, despite mean blood pressure. The various pathophysiologic mechanisms include autonomic dysregulation, arterial stiffness, endothelial dysfunction, circadian rhythm alteration, and systemic inflammation, which result in vascular remodeling and multisystem damage. Antihypertensive medications such as calcium channel blockers and renin–angiotensin–aldosterone system inhibitors seem to reduce BPV; randomized trials have not specifically investigated their BPV-reducing effects. The aim of this review is to highlight that BPV is a dynamic marker of multisystem risk, and question how various AI-based devices can aid continuous BPV monitoring and patient specific risk stratification.
Venezuelan Equine Encephalitis Virus Antagonizes the cGAS-STING Pathway
Heath, Brittany N.; Akhrymuk, Maryna; Jamiu, Abdullahi T.; Akhrymuk, Ivan; Pickrell, Alicia M.; Kehn-Hall, Kylene (MDPI, 2026-02-10)
Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne pathogen causing low mortality but high morbidity in humans, with 4–14% cases exhibiting neurological complications. While the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) pathway is canonically associated with double-stranded DNA (dsDNA) detection, it has been shown to respond to RNA viruses and subsequently limit viral pathogenesis. Several viruses antagonize this signaling cascade, underscoring the importance that cGAS–STING plays in host immunity. Previous studies regarding single-stranded RNA viruses revealed that cGAS–STING limits viral replication in Old World alphavirus chikungunya virus infections, but little is known about New World alphaviruses such as VEEV. Here, we investigate the impact that STING activation has on VEEV infection as a potential prophylactic and therapeutic intervention. VEEV infection alone did not induce STING phosphorylation at Ser366, but interferon-stimulated genes (ISGs) were upregulated during the late phase of infection. Loss of STING through siRNA showed a partial dependency on STING for ISG transcription, suggesting that STING activation may occur through a noncanonical process. Priming of the STING pathway prior to infection was found to be critical in limiting viral replication; however, targeting STING activation post-infection abrogated the antiviral effects that dsDNA had on VEEV. VEEV suppressed STING phosphorylation in a multiplicity of infection (MOI)-dependent manner with the most robust pSTING (Ser366) inhibition observed at an MOI of 10. Collectively, our results suggest that VEEV antagonizes canonical STING activation.
Octopamine and tyramine dynamics predict learning rate phenotypes during associative conditioning in honey bees
Sands, Lester P.; Lei, Hong; Batten, Seth R.; Hartle, Alec; Lohrenz, Terry; Barbosa, Leonardo; Bang, Dan; Dayan, Peter; Howe, William M.; Smith, Brian H.; Montague, P. Read (American Association for the Advancement of Science, 2026-02-13)
Biogenic amines are fundamental for physiological homeostasis and behavioral control in both vertebrates and invertebrates. Monoamine neurotransmitters released in target brain regions conjointly regulate adaptive learning and plasticity. However, our understanding of these multianalyte mechanisms remains nascent, in part due to limitations in measurement technology. Here, during associative conditioning in honey bees, we concurrently tracked subsecond fluctuations in octopamine, tyramine, dopamine, and serotonin in the antennal lobe, where plasticity influences odorant representations. By repeatedly pairing an odorant with subsequent sucrose delivery, we observed individual differences in the conditioned response to odor, which occurred after a variable number of pairings (learners) or not at all (non-learners). The distinction between learners and non-learners was reflected in neurotransmitter responses across experimental conditions. The speed of learning, the number of pairings prior to a proboscis extension reflex, could be predicted from monoamine opponent signaling (octopamine-tyramine), from both the first presentation of the odorant alone, prior to any pairing with sucrose, and the first conditioned response to the odorant, coming after a number of sucrose pairings. These results suggest that monoamine signaling phenotypes may relate directly to the now widely reported socially relevant genetic differences in honey bee learning.
Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh syndrome mice
Biswas, Sahitya Ranjan; Tomsick, Porter L.; Kelly, Colin; Lester, Brooke A.; Milner, Julia P.; Henry, Sara N.; Soto, Yairis; Brindley, Samantha; Defoor, Nicole; Morton, Paul D.; Pickrell, Alicia M. (Springer Nature, 2025-12)
Leigh syndrome (LS) is a complex, genetic mitochondrial disorder defined by neurodegenerative phenotypes with pediatric manifestation. However, recent clinical studies report behavioral phenotypes in human LS patients that are more reminiscent of neurodevelopmental delays. To determine if disruptions in epochs of rapid brain growth during infancy precede the hallmark brain lesions that arise during childhood, we evaluated neural and glial precursor cellular dynamics in a mouse model of LS. Loss of Complex I significantly impacted neural stem cell proliferation, neuronal and oligodendroglial progeny, lineage progression, and displayed overt differences in specific brain regions across postnatal development. Our findings show that these disruptions in all categories occur specifically within the subventricular zone and corpus callosum prior to the age when these mice experience neurodegeneration. Given that LS is considered a neurodegenerative disease, we propose that there are neurodevelopmental signatures predating classic diagnosis in LS.
Chronic intermittent ethanol produces nociception through endocannabinoid-independent mechanisms in mice
Miliano, Cristina; Dong, Yuyang; Proffit, Mckenzie; Cabanas, Natalia Corvalan; Natividad, Luis A.; Buczynski, Matthew W.; Gregus, Ann M. (Pergamon-Elsevier, 2025-10-01)
Alcohol use disorder (AUD) affects millions of people and represents a significant health and economic burden. Pain is a frequently under-treated aspect of hyperkatifeia during alcohol withdrawal, yet to date no drugs have received FDA approval for the treatment of this indication in AUD patients. This study aims to evaluate the potential of targeting bioactive lipid signaling pathways as a therapeutic approach for treating alcohol withdrawal-related pain hypersensitivity. We utilized a chronic intermittent ethanol (CIE) vapor exposure model in C57BL/6J mice of both sexes to establish alcohol dependence and demonstrated that CIE produced robust tactile allodynia and thermal hyperalgesia during withdrawal that was independent of prior blood alcohol levels. Next, we evaluated four drugs for their efficacy in reversing tactile allodynia during abstinence from CIE using a cross-over treatment design that included FDA-approved naltrexone as well as commercially available inhibitors targeting the inflammatory lipid signaling enzymes fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), and 15-Lipoxygenase (LOX). None of these compounds produced significant therapeutic benefit in reversing established CIE-induced tactile allodynia, despite attenuating pain-like behaviors at these doses in other chronic pain models. Additionally, we assessed plasma endocannabinoid levels in both sexes during withdrawal. We found that there was an inherent sex difference in the endogenous anti-inflammatory endocannabinoid tone in naive mice and that CIE treatment affected endocannabinoids levels in female mice only. These findings underscore the need to better understand the underlying causes of AUD-induced allodynia and to develop novel therapeutic approaches to mitigate pain hypersensitivity in AUD patients.
Medial prefrontal cortical neurotransmitters reactive to relapse-promoting and relapse-suppressing cues in male rats trained to self-administer cocaine or alcohol
Nedelescu, Hermina; Miliano, Cristina; Wagner, Grant E.; Carroll, Ayla M.; De Ness, Genna L.; Kerr, Tony M.; Owusu Mensah, Richard Nana Abankwah; Koya, Eisuke; Gregus, Ann M.; Weiss, Friedbert; Buczynski, Matthew W.; Suto, Nobuyoshi (Elsevier, 2026-03-01)
Environmental cues signaling drug availability ( S +) vs. omission (S-) each recruit specific prefrontal cortical neurons to promote vs. suppress drug seeking in rats, suggesting similarly cue-specific neurotransmission regulates such behavior. We here determined extracellular neurotransmitter fluctuations in the infralimbic (IL) and prelimbic (PL) cortices of rats reactive to S + vs. S-. For this, male rats were trained to recognize both S + and S- within the context of either cocaine or alcohol self-administration and then subjected to S + vs. S- cue-tests during which animals engaged in active drug seeking vs. suppression of this behavior. In cocaine-trained rats, serotonin, taurine and adenosine in PL were preferentially modulated during the S + (vs. S-) cue-test, while glutamate in PL was preferentially modulated during the S- (vs. S +) cue-test. In alcohol-trained rats, γ-aminobutyric acid (GABA) in IL was preferentially modulated during the S + cue-test, while histamine in PL as well as glutamate and dopamine in IL were preferentially modulated during the S- cue-test. In summary, prefrontal neurotransmissions reactive to drug discriminative cues are dependent on cue types ( S + vs. S-), brain regions (IL vs. PL) and drugs used for cue-conditioning (cocaine vs. alcohol), thereby suggesting cocaine- and alcohol-seeking are each regulated by distinct neurochemical processes.
Phenelzine-based probes reveal Secernin-3 is involved in thermal nociception
Bustin, Katelyn; Shishikura, Kyosuke; Chen, Irene; Zongtao, Lin; McKnight, Nate; Chang, Yuxuan; Wang, Xie; Li, Jing Jing; Arellano, Eric; Pei, Liming; Morton, Paul D.; Gregus, Ann M.; Buczynski, Matthew W.; Matthews, Megan L. (Elsevier, 2023-02-03)
Chemical platforms that facilitate both the identification and elucidation of new areas for therapeutic development are necessary but lacking. Activity-based protein profiling (ABPP) leverages active site-directed chemical probes as target discovery tools that resolve activity from expression and immediately marry the targets identified with lead compounds for drug design. However, this approach has traditionally focused on predictable and intrinsic enzyme functionality. Here, we applied our activity-based proteomics discovery platform to map non-encoded and post-translationally acquired enzyme functionalities (e.g. cofactors) in vivo using chemical probes that exploit the nucleophilic hydrazine pharmacophores found in a classic antidepressant drug (e.g. phenelzine, Nardil ® ). We show the probes are in vivo active and can map proteome-wide tissue-specific target engagement of the drug. In addition to engaging targets (flavoenzymes monoamine oxidase A/B) that are associated with the known therapeutic mechanism as well as several other members of the flavoenzyme family, the probes captured the previously discovered N -terminal glyoxylyl (Glox) group of Secernin-3 (SCRN3) in vivo through a divergent mechanism, indicating this functional feature has biochemical activity in the brain. SCRN3 protein is ubiquitously expressed in the brain, yet gene expression is regulated by inflammatory stimuli. In an inflammatory pain mouse model, behavioral assessment of nociception showed Scrn3 male knockout mice selectively exhibited impaired thermal nociceptive sensitivity. Our study provides a guided workflow to entangle molecular (off)targets and pharmacological mechanisms for therapeutic development.
12/15-lipoxygenases mediate toll-like receptor 4-dependent nociplastic pain hypersensitivity in female mice
Miliano, Cristina; Chen, Irene; Brown, Brieann; Murdaugh, Laura B.; Dong, Yuyang; Eddinger, Kelly A.; Geng, Shuo; Li, Liwu; Yaksh, Tony L.; Burton, Michael D.; Buczynski, Matthew W.; Gregus, Ann M. (Lippincott Williams & Wilkins, 2025-12)
Chronic nociplastic pain syndromes are characterized by sensitization of peripheral and central nervous systems and exhibit increased incidence in women. However, nonsteroidal anti-inflammatory drugs are ineffective in mitigating nociplastic pain, and current prescription treatments, such as opioids, anticonvulsants, and antidepressants, provide limited therapeutic benefit for these indications. In the current work, we extended previous studies in rats of central Toll-like receptor 4-dependent pain hypersensitivity to male and female C57BL/6N mice, uncovering an unexpected hyperalgesic phenotype in female mice following intrathecal (IT) lipopolysaccharide (LPS). In contrast to previous reports in female C57BL/6J mice, female C57BL/6N mice displayed tactile and cold allodynia, grip force deficits, and a modest increase in locomotor activity in response to IT LPS. Congruent with our previous observations in male rats, LPS released spinal 12/15-lipoxygenase (12/15-LOX) metabolites (12/15-LMs) in female C57BL/6N mice. Likewise, 12/15-LOX enzymes are basally expressed in multiple tissues and cell types relevant to nociceptive transmission. Systemic inhibition of 12/15-LOX in female C57BL/6N mice with selective inhibitors ML355 (targeting 12-LOX-p) or ML351 (targeting 15-LOX-1) completely reversed allodynia and grip force deficits. 12/15-LMs also produce tactile allodynia when administered spinally (IT) or peripherally (paw intraplantar) at a subthreshold dose in a hyperalgesic priming model, similar to others' observations with a subthreshold dose of the cyclooxygenase metabolite prostaglandin E2. Collectively, these data suggest that 12/15-LOX enzymes contribute to peripheral and central pain hypersensitivity in rodents, with potential translatability as druggable targets across sexes and species using multiple reflexive and functional outcome measures.
Alcohol use disorder-associated pain: clinical and preclinical evidence
Dong, Yuyang; Buczynski, Matthew W.; Gregus, Ann M. (Elsevier, 2025-12)
Alcohol Use Disorder (AUD) affects millions of people globally and is characterized by cycles of intoxication, withdrawal, and relapse. Convergent clinical and preclinical evidence strongly support the conclusion that AUD precipitates chronic pain marked by mechanical and thermal hypersensitivity, yet currently available FDA-approved therapeutics do not effectively manage AUD-associated pain. This review synthesizes clinical and preclinical evidence on AUD-associated pain, highlighting known phenomena of allodynia and hyperalgesia as well as small and/or large fiber neuropathy in patient subpopulations along with preclinical acute and chronic alcohol exposure paradigm-specific nociceptive phenotypes in rodents. Herein, we provide detailed descriptions and interpretations of outcome measures for different sensory modalities typically utilized in clinical and/or preclinical studies of nociception. We examine how these endpoints vary in rodent models according to the type of alcohol exposure paradigm with regard to route of administration, chronicity, and contingency (forced, voluntary, or combined). Finally, we summarize the prominent molecular mechanisms that have been proposed to mediate alcohol withdrawal-induced pain-like behaviors. While major advances have been made in treatment of AUD, critical gaps in understanding of human pain phenotypes due to lack of quantitative endpoints in clinical trials impede further advancement in refining preclinical models to recapitulate these features. Patient phenotype-driven preclinical models will increase cross-species translational potential for interrogating mechanistic underpinnings and thereby inform future drug discovery campaigns for treatment of AUD-associated pain.
Perinatal citalopram exposure alters the gut composition and microbial metabolic profiles of Sprague-Dawley rat dams and female offspring but not male offspring
Kropp, Dawson R.; Glover, Matthew E.; Samanta, Rupabali; Unroe, Keaton A.; Clinton, Sarah M.; Hodes, Georgia E. (2025-12-03)
Background: Selective serotonin reuptake inhibitors are widely prescribed during pregnancy. Their main route of administration is through the gut. However, their impact on the maternal and offspring gut microbiome and microbial metabolic pathways remains poorly understood. This study used metagenomic shotgun sequencing to examine the effects of perinatal citalopram exposure in rat dams and their offspring on gut composition and downstream metabolic pathways. Methods: We treated pregnant and nursing rat dams with either citalopram or vehicle (water). Their feces were collected, DNA from these samples was extracted and then sequenced using shotgun metagenomic sequencing. The BioBakery suite of microbiome analysis tools was utilized in tandem with RStudio to analyze the gut composition and microbial metabolic pathways of the rat dams and their offspring. Results: Pregnant and nursing dams treated with citalopram exhibited marked shifts in microbial community structure, including phylum-level alterations in Proteobacteria and Defferibacteria. Citalopram treated dams displayed significantly altered beta diversity. Species level alterations due to treatment were composed of five significantly altered microbes, two of which belong to the Proteobacteria phylum. These changes were highly diverse and were not congruent with microbe-level alterations observed in offspring. Alpha diversity of microbial metabolic pathways was compared using the Gini-Simpson index, which was significantly increased in dams suggesting greater metabolic functional diversity with age. Female offspring perinatally exposed to citalopram showed significant changes in gut beta diversity, with seven significant alterations at the microbe level. These microbial shifts were accompanied by twenty-one significantly altered microbial metabolic pathways. In contrast, male offspring showed no significant differences in microbial composition or beta diversity and only minor metabolic changes. Conclusions: These findings demonstrate that maternal citalopram exposure during pregnancy and lactation has lasting, sex-specific impacts on the offspring’s gut microbiome and microbial metabolic pathways. The pronounced alterations in female, but not male offspring, suggest that host sex may be a critical determinant in the developmental response to citalopram exposure. This work underscores the value of metagenomic approaches in uncovering complex host-microbiome interactions and highlights the need to consider offspring sex in evaluating the safety and long-term effects of antidepressant use during pregnancy.
Reductions in protein degradation in the retrosplenial cortex regulate contextual fear memory formation in a sex-independent manner
Turner, Meagan; Ball, Olivia; Ray, W. Keith; Helm, Richard F.; Jarome, Timothy J. (Elsevier, 2025-12-16)
The retrosplenial cortex (RSC), which serves as a hub to connect the hippocampus and amygdala with other cortical regions, has been shown to play a role in the formation of contextual fear memories. However, the molecular mechanisms by which the RSC forms memories and whether sex differences exist within these mechanisms remain largely unknown. Increases in ubiquitin–proteasome-mediated protein degradation have been shown to be sex-dependently involved in the formation of contextual fear memories in multiple brain regions, including the hippocampus and amygdala. To date, whether increases in protein degradation are needed in the RSC for memory formation in either sex has yet to be examined. Here, we found that proteasome function in the RSC decreases after contextual fear conditioning in both male and female rats. Consistent with this, increasing proteasome activity in the RSC via CRISPR-dCas9-mediated upregulation of Psmd14 impaired contextual fear memory in a mixed sex cohort. Interestingly, proteomic analysis of degradation-specific lysine-48 (K48) polyubiquitination in the RSC of fear-conditioned rats showed largely distinct protein degradation targets and impacted pathways across the sexes. This suggests that despite the shared need for reductions in protein degradation, males and females are using this mechanism in different ways to form the same memory. Together, these data demonstrate that reductions in protein degradation in the RSC are critical for contextual fear memory formation in both males and females and indicate that the molecular changes in the RSC during memory formation may be distinct from those of other more commonly studied brain regions.
Chronic variable stress leads to sex specific gut microbiome alterations in mice
Kropp, Dawson R.; Rainville, Jennifer R.; Glover, Matthew E.; Tsyglakova, Mariya; Samanta, Rupabali; Hage, Tamer R.; Carlson, Audrey E.; Clinton, Sarah M.; Hodes, Georgia E. (Elsevier, 2024-05)
Stress has been implicated in the incidence and severity of psychiatric and gastrointestinal disorders. The immune system is capable of modulating the activity and composition of the gut following stress and vice versa. In this study we sought to examine the sequential relationship between immune signaling and microbiome composition occurring in male and female mice over time using a variable stress paradigm. Tissue was collected prior to, during, and after the stress paradigm from the same mice. Cytokines from plasma and brain were quantified using a multiplexed cytokine assay. Fecal samples were collected at the same timepoints and 16S rRNA amplicon sequencing was performed to determine the relative abundance of microbiota residing in the guts of stressed and control mice. We found sex differences in the response of the gut microbiota to stress following 28 days of chronic variable stress but not 6 days of sub-chronic variable stress. Immune activation was quantified in the nucleus accumbens immediately following Sub-chronic variable when alterations of gut composition had not yet occurred. In both sexes, 28 days of stress induced significant changes in the proportion of Erysipelotrichaceae and Lactobacillaceae, but in opposite directions for male and female mice. Alterations to the gut microbiome in both sexes were associated with changes in cytokines related to eosinophilic immune activity. Our use of an animal stress model reveals the immune mechanisms that may underly changes in gut microbiome composition during and after stress. This study reveals potential drug targets and microbiota of interest for the intervention of stress related conditions.
Integrating neuroscience and immunology core concepts to develop a neuroimmunology curriculum
Shah, Aparna P.; Leininger, Elizabeth C.; Pandey, Sumali (Frontiers, 2025-03-19)
Training students in interdisciplinary thinking is critical for the future of scientific discovery and problem-solving more generally. Therefore, students must have early opportunities to grapple with knowns and unknowns at the frontiers of interdisciplinary inquiry. Neuroimmunology challenges students to think at the intersection of two rapidly evolving fields, neuroscience and immunology. As these disciplines focus on complex systems, their intersection represents a unique opportunity for students to witness the nature and process of interdisciplinary collaboration and synthesis. However, the fast pace of research and specialized knowledge in both disciplines present challenges for instructors interested in teaching the subject to undergraduate students. In this article, we share and describe a curriculum developed using a backward-design approach to analyze core concepts in both neuroscience and immunology, which were articulated by disciplinary experts in collaboration with their respective education communities. We determine overlaps between these conceptual frameworks, identify key prerequisite knowledge, and suggest example activities to introduce neuroimmunology to undergraduate students. This curriculum may be used for an entire course, or modified into shorter units that instructors can use within diverse educational contexts. We hope that this effort will encourage instructors to adopt neuroimmunology into their curricula, provide a roadmap to forge other such interdisciplinary educational collaborations, and prepare students to develop creative solutions to current and future societal problems.
Meningeal vascular Aβ deposition associates with cerebral hypoperfusion and compensatory collateral remodeling
Kaloss, Alexandra M.; Browning, Jack L.; Li, Jiangtao; Pan, Yuhang; Watsen, Sachi; Sontheimer, Harald; Theus, Michelle H.; Olsen, Michelle L. (2025-11-13)
Background: Global reductions in cerebral blood flow (CBF) are among the earliest and most consistent abnormalities observed in Alzheimer’s disease (AD), preceding both cortical plaque formation and cognitive decline. While the pial arterial network—a critical supplier of intracortical perfusion—has been overlooked in this context, it may play a pivotal role in early vascular pathology. Here, we report extensive cerebral amyloid angiopathy (CAA) within the pial artery and arteriole network in the J20 (PDGF-APPSw, Ind) mouse model of AD. Methods: Using premortem delivery of Methoxy-XO4 to label Aβ, and arterial vascular labeling, we assessed Aβ burden on the pial artery/arteriole network and cerebral blood flow in aged male and female WT and J20 AD mice. Results: We show that 12-month-old J20 mice exhibit significant Aβ deposition across major leptomeningeal arteries (ACA, MCA) and pial collaterals, with ~ 40% vessel coverage in males and ~ 20% in females—substantially exceeding Aβ levels in cortical or hippocampal vessels. This vascular Aβ burden was accompanied by compensatory enlargement and increased tortuosity of pial collateral vessels. Yet, despite this apparent remodeling, CBF was reduced by ~ 15% in J20 mice, and this decline was significantly associated with leptomeningeal CAA burden. Conclusions: This is the first study to comprehensively characterize meningeal arterial Aβ accumulation in a preclinical model of vascular AD, mirroring recent observations in early-stage human disease. Our findings implicate meningeal CAA as a potential driver of early CBF disruption and suggest that pial collateral remodeling may reflect a compensatory response to vascular insufficiency. Moreover, we identify robust sex differences in CAA burden, paralleling sex-specific patterns of parenchymal Aβ pathology in humans. These results highlight the leptomeningeal vasculature as a novel and understudied locus for early AD pathology and a potential therapeutic target to preserve cerebrovascular integrity.
Astrocytes require perineuronal nets to maintain synaptic homeostasis in mice
Tewari, Bhanu P.; Woo, AnnaLin M.; Prim, Courtney E.; Chaunsali, Lata; Patel, Dipan C.; Kimbrough, Ian F.; Engel, Kaliroi; Browning, Jack L.; Campbell, Susan L.; Sontheimer, Harald (Nature Portfolio, 2024-08-01)
Perineuronal nets (PNNs) are densely packed extracellular matrices that cover the cell body of fast-spiking inhibitory neurons. PNNs stabilize synapses inhibiting synaptic plasticity. Here we show that synaptic terminals of fast-spiking interneurons localize to holes in the PNNs in the adult mouse somatosensory cortex. Approximately 95% of holes in the PNNs contain synapses and astrocytic processes expressing Kir4.1, glutamate and GABA transporters. Hence, holes in the PNNs contain tripartite synapses. In the adult mouse brain, PNN degradation causes an expanded astrocytic coverage of the neuronal somata without altering the axon terminals. The loss of PNNs impairs astrocytic transmitter and potassium uptake, resulting in the spillage of glutamate into the extrasynaptic space. Our data show that PNNs and astrocytes cooperate to contain synaptically released signals in physiological conditions. Their combined action is altered in mouse models of Alzheimer's disease and epilepsy where PNNs are disrupted. Perineuronal nets stabilize synapses inhibiting synaptic plasticity. Here, the authors show that perineuronal nets act as a diffusion barrier facilitating astrocytic clearance of synaptically released ions and neurotransmitters.
Expression and localization of the neuropeptide Y-Y4 receptor in the chick spleen: mRNA upregulation by high ambient temperature
Nishimura, Haruka; Elhussiny, Mohamed Z.; Ouchi, Yoshimitsu; Haraguchi, Shogo; Itoh, Taichi Q.; Gilbert, Elizabeth R.; Cline, Mark A.; Nishimura, Shotaro; Hosaka, Yoshinao Z.; Takahashi, Eiki; Cockrem, John F.; Bungo, Takashi; Chowdhury, Vishwajit S. (Elsevier, 2024-10-01)
High ambient temperatures (HT) can increase diencephalic neuropeptide Y (NPY) expression, and central injection of NPY attenuates heat stress responses while inducing an antioxidative state in the chick spleen. However, there is a lack of knowledge about NPY receptor expression, and its regulation by HT, in the chick spleen. In the current study, male chicks were used to measure the expression of NPY receptors in the spleen and other immune organs under acute (30 vs. 40 f 1 degrees C for 3 h) or chronic (30 vs. 40 f 1 degrees C for 3 h/day for 3 days) exposure to HT and in response to central injection of NPY (47 pmol, 188 pmol, or 1 nmol). We found that NPYY4 receptor mRNA was expressed in the spleen, but not in other immune organs studied. Immunofluorescence staining revealed that NPY-Y4 receptors were localized in the splenic pulp. Furthermore, NPY-Y4 receptor mRNA increased in the chick spleen under both acute and chronic exposure to HT. Central NPY at two dose levels (47 and 188 pmol) and a higher dose (1 nmol) did not increase splenic NPY-Y4 receptor mRNA expression or splenic epinephrine under HT (35 f 1 degrees C), and significantly increased 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations under HT (40 f 1 degrees C). In conclusion, increased expression of NPY-Y4 receptor mRNA in the spleen under HT suggest that Y4 receptor may play physiological roles in response to HT in male chicks.
Age-related dysregulation of proteasome-independent K63 polyubiquitination in the hippocampus and amygdala
Bae, Yeeun; Venkat, Harshini; Preveza, Natalie; Ray, W. Keith; Helm, Richard F.; Jarome, Timothy J. (Pergamon-Elsevier, 2025-08-06)
Cognitive decline with aging is a complex process involving multiple brain regions and molecular mechanisms. While the role of the canonical protein degradation function of the ubiquitin–proteasome system (UPS) has been well studied in the context of aging and age-associated memory loss, the non-proteolytic functions of ubiquitin activity remain poorly understood. Here, we investigated the role of lysine-63 (K63) polyubiquitination, the most abundant form of proteasome-independent ubiquitination, in aged rats, focusing on the hippocampus and amygdala, two brain regions reported to have cellular and molecular alterations with age that are associated with age-related memory loss. Using an unbiased proteomic approach, we observed a significant increase of K63 polyubiquitination in the hippocampus across the lifespan. Reducing K63 polyubiquitination in the hippocampus of aged male rats using the CRISPR-dCas13 RNA editing system enhanced contextual fear memory, while similar manipulations in middle-aged rats, which typically have normal memory, had no effect, emphasizing the age-dependent role of K63 polyubiquitination in memory formation. Conversely, the amygdala showed a consistent reduction of K63 polyubiquitination protein targets across the lifespan, and further reductions of K63 polyubiquitination improved memory retention in aged, but not middle-aged, male rats. Together, our findings reveal the dynamic and region-specific functions of K63 polyubiquitination in the brain aging process, providing novel insights into its contribution to age-associated memory decline.
Increased DNA methylation of Igf2 in the male hippocampus regulates age-related deficits in synaptic plasticity and memory
Kincaid, Shannon; Stickling, Courtney P.; Farrell, Kayla; Bae, Yeeun; Patrick, Morgan B.; Bhanot, Gitali; Cummings, Adam; Abraham, Jennifer; Alisesky, Abby; Ferrara, Nicole; Rosenkranz, J. Amiel; Jarome, Timothy J. (Elsevier, 2025-10-01)
The aging process is characterized by a general decline in cognitive abilities, which affects nearly 33 % of U.S. adults over the age of 70 and is a risk factor for the development of dementia and Alzheimer's disease. Numerous studies have reported increased neuroinflammation and impaired synaptic plasticity and memory with age in the hippocampus, a major brain region involved in the formation and storage of most memories. However, much remains unknown about the mechanisms that contribute to age-related deficits in synaptic plasticity and memory. The Insulin-like growth factor 2 (Igf2) is a genomic imprinted gene that is expressed from a single allele in all species. Though IGF2 has been shown to be important in development, synaptic plasticity, and memory formation in the hippocampus and administration of IGF2 can improve memory late in life, whether changes in regulation of this gene contribute to age-related memory decline have yet to be explored. Here, we show that aged (24 months) male rats have increased CpG-site specific promoter methylation and reduced expression of Igf2 in the hippocampus relative to young adult (3 months) and middle-aged (12 months) rats. Importantly, CRISPR-dCas9 mediated increase of DNA 5-hydroxymethylation, an active transcriptional mark, of the Igf2 promoter in the hippocampus improved memory and long-term potentiation in aged, but not middle-aged, rats. These data indicate that increased DNA methylation of Igf2 in the hippocampus contributes to age-related deficits in synaptic plasticity and memory.

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