Post-operative cognitive dysfunction (POCD) is the persistent form of post-operative delirium, a noticeable deterioration in cognitive abilities that occurs abruptly following surgery. POCD has been largely associated with older individuals, posing an increased risk for the development of Alzheimer’s disease (AD). Emerging evidence suggests that pre-operative lifestyle factors, including exercise, may influence susceptibility to POCD and AD. It is known that laparotomy (exploratory abdominal surgery) combined with opioid treatment (for pain management) in aged rats produces memory impairments lasting at least 8 weeks, alongside region specific mitochondrial dysfunction. Thus, the purpose of this study was to utilize an acute bout of exercise to mitigate POCD in a mouse model of AD. Mice underwent 3 weeks of voluntary wheel running prior to surgery and morphine. Laparotomies were performed on 3xTg-AD mice at 9 months old followed by 7 days of morphine administration (2mg/kg, i.p., based on our previous work in rats). A battery of cognitive behavioral tests were performed 2 weeks post-surgery. Our findings demonstrated that exercise ameliorated impairments in prefrontal cortex-dependent executive function and hippocampal-dependent memory assessed by nesting and the contextual fear test, respectively. The behavioral improvements were accompanied by a notable decrease in amyloid beta (AB42) in the hippocampus of the exercise + morphine-treated mice compared to sedentary controls, as measured by an ELISA assay. We then examined mitochondrial function in freshly isolated mitochondria from hippocampus using the Seahorse Analyzer XFe96. Exercise + morphine-treated mice demonstrated a significant increase in basal and maximal respiration compared to the sedentary + morphine-treated mice, indicating a rescue in mitochondrial function. In conclusion, in 3xTg-AD mice, a pre-operative bout of exercise reduced post-operative cognitive deficits, attenuated AD-related pathology, and restored mitochondrial function. These findings suggest that exercise may serve as a non-pharmacological strategy to mitigate POCD, potentially through preservation of mitochondrial health. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

BACKGROUND:Aging increases vulnerability to cognitive decline, and ultraprocessed diets high in saturated fat may accelerate this trajectory. Although short-term high-fat diet (HFD) exposure is known to impair memory in aged animals, the specific stages of memory most susceptible to short-term HFD remain unclear. METHODS:This study examined how short-term HFD influences anterograde consolidation, retrograde consolidation, and retrieval of long-term fear memory in aged rats. Male F344 × BN F1 rats (22-24 months) consumed chow or three days of HFD provided at distinct times relative to contextual and cued fear conditioning to isolate each memory phase. Importantly, this brief HFD protocol minimizes metabolic disturbances typically produced by longer-term diet manipulation, allowing us to isolate the effects of macronutrient composition on memory processes. RESULTS:Three days of HFD before or immediately after conditioning significantly impaired contextual and cued fear memory, reflecting disrupted anterograde and retrograde consolidation. In contrast, three days of HFD before retrieval had no effect on memory performance. CONCLUSION:These findings demonstrate that short-term consumption of ultraprocessed HFD selectively impairs consolidation while sparing retrieval of hippocampal- and amygdala-dependent memory in aging. These findings are important because identifying the specific memory processes that are disrupted, rather than global memory dysfunction, helps narrow mechanistic targets and informs the development of more precise interventions to mitigate diet-related cognitive decline in aging.

Postoperative cognitive dysfunction (POCD) is a common and persistent complication in aging individuals following surgery, particularly when opioids are used for perioperative pain management. Although opioids are widely administered in the perioperative setting, the mechanisms by which they contribute to long-term cognitive impairment remain poorly understood. Here, using an aged rat model of surgery with perioperative morphine administration, we investigated how synaptic, axonal, and mitochondrial abnormalities contribute to persistent hippocampal memory deficits, and evaluated therapeutic strategies targeting neuroinflammation and mitochondrial dysfunction. We found that these memory impairments were not attributable to systemic illness or gross dendritic degeneration. Instead, surgery and morphine-treated animals exhibited selective reductions in dendritic spine subtypes associated with synaptic stability, impaired late-phase long-term potentiation, and blunted experience-dependent upregulation of the AMPA receptor subunit GluA1. These synaptic alterations were accompanied by elevated circulating neurofilament light chain (Nf-L), indicating sustained axonal perturbation. Surgery and morphine treatment also produced persistent hippocampal mitochondrial dysfunction, characterized by impaired oxidative phosphorylation, reduced respiratory reserve capacity, and increased DNA oxidation. These effects were not observed in liver tissue, arguing against a widespread mitochondrial deficit. Pharmacological inhibition of central TLR4 signaling at the time of surgery, which previously rescued the memory deficit, attenuated oxidative stress and partially restored mitochondrial function, implicating early neuroinflammatory signaling in the development of long-term mitochondrial impairment. Finally, targeted mitochondrial rejuvenation with SS-31 four weeks post-surgery robustly rescued hippocampal-dependent memory and normalized mitochondrial respiratory function despite persistently elevated DNA oxidation and Nf-L. Together these findings identify sustained hippocampal mitochondrial dysfunction as a key mechanistic substrate underlying long-term cognitive deficits following surgery and morphine exposure in aged rats, and highlight mitochondrial bioenergetics as a promising therapeutic target for POCD.

A growing body of literature has identified periodontal disease among the modifiable risk factors for Alzheimer's disease (AD), but the mechanisms underlying this relationship is unknown. This study investigated this relationship using a ligature-induced preclinical periodontitis (Pd) model in non-transgenic (non-Tg) and 3xTg-AD mice. We found that ligature placement caused significant alveolar bone loss, with 3xTg-AD mice exhibiting exacerbated bone loss, suggesting AD-related genetic risk may amplify disease progression. Pd induced robust local inflammatory gene expression in both genotypes, but 3xTg-AD mice indicated a dysregulated immune response. Cognitive deficits were observed only in Pd-afflicted 3xTg-AD mice, specifically in hippocampus-mediated spatial memory and perirhinal cortex-mediated object recognition memory, while non-Tg mice remained unaffected. Neuroinflammatory responses varied by brain region, with the hippocampus and prefrontal cortex (PFC) showing the most pronounced changes. In these regions, 3xTg-AD mice exhibited significantly altered cytokine gene expression compared to non-Tg mice, particularly at later time points. Synaptic markers revealed vulnerabilities in 3xTg-AD mice, including reduced baseline Syp expression and dysregulated Synpo post-ligature. Pd transiently reduced glutamate receptor gene expression in both genotypes, with non-Tg mice showing persistent changes, potentially linked to preserved memory. Pd also accelerated amyloid-β (Aβ) deposition and sustained neurodegeneration in 3xTg-AD mice. Overall, this study shows that combining Pd and AD-related genetic risk exacerbates inflammation, cognitive impairment, synaptic dysfunction, Aβ pathology, and neurodegeneration. Neither insult alone was sufficient to produce these effects, highlighting the synergistic impact. These findings emphasize the need to explore anti-inflammatory interventions and downstream mechanisms to mitigate the confluence of these diseases.

Obesity and metabolic syndrome are major public health concerns linked to cognitive decline with aging. Prior work from our lab has demonstrated that short-term high fat diet (HFD) rapidly impairs memory function via a neuroinflammatory mechanism. However, the degree to which these rapid inflammatory changes are unique to the brain is unknown. Moreover, deviations in gut microbiome composition have been associated with obesity and cognitive impairment, but how diet and aging interact to impact the gut microbiome, or how rapidly these changes occur, is less clear. Thus, our study investigated the impact of HFD after two distinct consumption durations: 3 months (to model diet-induced obesity) or 3 days (to detect the rapid changes occurring with HFD) on memory function, anxiety-like behavior, central and peripheral inflammation, and gut microbiome profile in young and aged rats. Our data indicated that both short-term and long-term HFD consumption impaired memory function and increased anxiety-like behavior in aged, but not young adult, rats. These behavioral changes were accompanied by pro- and anti-inflammatory cytokine dysregulation in the hippocampus and amygdala of aged HFD-fed rats at both time points. However, changes to fasting glucose, insulin, and inflammation in peripheral tissues such as the distal colon and visceral adipose tissue were increased in young and aged rats only after long-term, but not short-term, HFD consumption. Furthermore, while subtle HFD-induced changes to the gut microbiome did occur rapidly, robust age-specific effects were only present following long-term HFD consumption. Overall, these data suggest that HFD-evoked neuroinflammation, memory impairment, and anxiety-like behavior in aging develop quicker than, and separately from the peripheral hallmarks of diet-induced obesity.

For more than 40 years, Dr. Steven F. Maier has shaped the field of psychoneuroimmunology through innovative research, influential mentorship, and dedicated service to the scientific community. As he concludes his tenure as Associate Editor of Brain, Behavior, and Immunity, this tribute reflects on his most transformative scientific contributions-from conceptualizing learned helplessness to uncovering the neural and immune mechanisms linking stress to disease vulnerability. Drawing from our experiences as longtime mentees and later colleagues, we also share reflections on his unique mentoring style, unwavering commitment to scientific rigor, and enduring influence on the field.

Long COVID (LC) following SARS-CoV-2 infection affects millions of individuals world-wide and manifests with a variety of symptoms including cognitive dysfunction also known as "brain fog". This is characterized by difficulties in executive functions, planning, decision-making, working memory, impairments in complex attention, loss of ability to learn new skills and perform sophisticated brain tasks. No effective treatment options currently exist for LC-related cognitive dysfunction. Here, we use the IntelliCage, which is an automated tracking system of cognitive functions, following SARS-CoV-2 infection in mice, measuring the ability of each mouse within a group to perform tasks that mimic complex human behaviors, such as planning, decision-making, cognitive flexibility, and working memory. Artificial intelligence and machine learning analyses of the tracking data classified LC mice into distinct behavioral categories from non-infected control mice, permitting precise identification and quantification of complex cognitive dysfunction in a controlled, replicable manner. Importantly, we find that brains from LC mice with cognitive dysfunction exhibit transcriptomic alterations similar to those observed in humans suffering from LC-related cognitive impairments, including altered expression of genes involved in learning, executive functions, synaptic functions, neurotransmitters and memory. Together, our findings establish a validated murine model and an automated unbiased approach to study LC-related cognitive dysfunction for the first time, and providing a valuable tool for screening potential treatments and therapeutic interventions.

Aging is associated with a priming of microglia such that they are hypersensitive to further immune challenges. As such high-fat diet during aging can have detrimental effects on cognition that is not seen in the young. However, conflicting findings also suggest that obesity may protect against cognitive decline during aging. Given this uncertainty we aimed here to examine the role of microglia in high-fat, high-sucrose diet (HFSD)-induced changes in cognitive performance in the aging brain. We hypothesised that 8 weeks of HFSD-feeding would alter microglia and the inflammatory milieu in aging and worsen aging-related cognitive deficits in a microglia-dependent manner. We found that both aging and HFSD reduced hippocampal neuron numbers and open field exploration; they also impaired recognition memory. However, the aging-related deficits occurred in the absence of a pro-inflammatory response and the deficits in memory performance persisted after depletion of microglia in the Cx3cr1-Dtr knock-in rat. Our data suggest that mechanisms additional to the acute microglial contribution play a role in aging- and HFSD-associated memory dysfunction.

Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by profound memory impairments, synaptic loss, neuroinflammation, and hallmark pathological markers. High-fat diet (HFD) consumption increases the risk of developing AD even after controlling for metabolic syndrome, pointing to a role of the diet itself in increasing risk. In AD, the complement system, an arm of the immune system which normally tags redundant or damaged synapses for pruning, becomes pathologically overactivated leading to tagging of healthy synapses. While the unhealthy diet to AD link is strong, the underlying mechanisms are not well understood in part due to confounding variables associated with long-term HFD which can independently influence the brain. Therefore, we experimented with a short-term diet regimen to isolate the diet’s impact on brain function without causing obesity. This project investigated the effect of short-term HFD on 1) memory, 2) neuroinflammation including complement, 3) AD pathology markers, 4) synaptic markers, and 5) in vitro microglial synaptic phagocytosis in the 3xTg-AD mouse model. Following the consumption of either standard chow or HFD, 3xTg-AD and non-Tg mice were tested for memory impairments. In a separate cohort of mice, levels of hippocampal inflammatory markers, complement proteins, AD pathology markers, and synaptic markers were measured. For the last set of experiments, BV2 microglial phagocytosis of synapses was evaluated. Synaptoneurosomes isolated from the hippocampus of 3xTg-AD mice fed chow or HFD were incubated with equal numbers of BV2 microglia. The number of BV2 microglia that phagocytosed synaptoneurosomes was tracked over time with a live-cell imaging assay. Finally, we incubated BV2 microglia with a complement receptor inhibitor (NIF) and repeated the assay. Behavioral analysis showed 3xTg-AD mice had significantly impaired long-term contextual and cued fear memory compared to non-Tg mice that was further impaired by HFD. HFD significantly increased inflammatory markers and complement expression while decreasing synaptic marker expression only in 3xTg-AD mice without altering AD pathology markers. Synaptoneurosomes from HFD-fed 3xTg-AD mice were phagocytosed at a significantly higher rate than those from chow-fed mice, suggesting the synapses were altered by HFD. The complement receptor inhibitor blocked this effect in a dose-dependent manner, demonstrating the HFD-mediated increase in phagocytosis was complement dependent. This study indicates HFD consumption increases neuroinflammation and over-activates the complement cascade in 3xTg-AD mice, resulting in poorer memory. The in vitro data point to complement as a potential mechanistic culprit and therapeutic target underlying HFD’s influence in increasing cognitive vulnerability to AD.

Dr. Ruth Barrientos is an associate professor (with tenure) in the Institute for Behavioral Medicine Research and the Department of Psychiatry and Behavioral Health in the College of Medicine at The Ohio State University. She currently serves as associate editor of Brain, Behavior, and Immunity, the flagship journal for the Psychoneuroimmunology Research Society. Her research aims to uncover the vulnerabilities associated with the aging brain that make it more susceptible to inflammatory challenges resulting in memory dysfunction, ranging from mild cognitive impairments to Alzheimer's Disease; and to discover interventions to improve these vulnerabilities and prevent memory degradation. We conducted an interview with Dr. Barrientos, asking questions about her life and scientific career and finished up with selected questions from the Proust Questionnaire.

Neuroinflammation and accumulation of Amyloid Beta (Aβ) accompanied by deterioration of special memory are hallmarks of Alzheimer's disease (AD). Effective preventative and treatment options for AD are still needed. Microglia in AD brains are characterized by elevated levels of microRNA-17 (miR-17), which is accompanied by defective autophagy, Aβ accumulation, and increased inflammatory cytokine production. However, the effect of targeting miR-17 on AD pathology and memory loss is not clear. To specifically inhibit miR-17 in microglia, we generated mannose-coated lipid nanoparticles (MLNPs) enclosing miR-17 antagomir (Anti-17 MLNPs), which are targeted to mannose receptors readily expressed on microglia. We used a 5XFAD mouse model (AD) that recapitulates many AD-related phenotypes observed in humans. Our results show that Anti-17 MLNPs, delivered to 5XFAD mice by intra-cisterna magna injection, specifically deliver Anti-17 to microglia. Anti-17 MLNPs downregulated miR-17 expression in microglia but not in neurons, astrocytes, and oligodendrocytes. Anti-17 MLNPs attenuated inflammation, improved autophagy, and reduced Aβ burdens in the brains. Additionally, Anti-17 MLNPs reduced the deterioration in spatial memory and decreased anxiety-like behavior in 5XFAD mice. Therefore, targeting miR-17 using MLNPs is a viable strategy to prevent several AD pathologies. This selective targeting strategy delivers specific agents to microglia without the adverse off-target effects on other cell types. Additionally, this approach can be used to deliver other molecules to microglia and other immune cells in other organs.

The consumption of diets high in saturated fatty acids and/or refined carbohydrates are associated with neuroinflammation, cognitive dysfunction, and neurodegenerative disease. In contrast, diets high in polyunsaturated fatty acids are associated with anti-inflammatory and neuroprotective effects. We have previously shown that high fat diet (HFD) consumption increases saturated fatty acids and decreases polyunsaturated fatty acids in the hippocampus. We have further shown that HFD elicits exaggerated neuroinflammation and reduced synaptic elements, and results in robust memory deficits in aged rats. Here, we examined the impact of palmitate, an abundant dietary saturated fat, on a variety of cellular responses in BV2 microglia and HippoE-14 neurons, and the extent to which the omega-3 fatty acid, docosahexaenoic acid (DHA), would buffer against these responses. Our data demonstrate that DHA pretreatment prevents or partially attenuates palmitate-induced alterations in proinflammatory, endoplasmic reticulum stress, and mitochondrial damage-associated gene expression in both cell types. Furthermore, we show that synaptoneurosomes isolated from aged, HFD-fed mice are engulfed by BV2 microglia at a faster rate than synaptoneurosomes isolated from aged, chow-fed mice, suggesting HFD alters signaling at synapses to hasten their engulfment by microglia. Consistent with this notion, we found modest increases in complement proteins and a decrease in CD47 protein expression on synaptoneurosomes isolated from the hippocampus of aged, HFD-fed mice. Interestingly, palmitate reduced BV2 microglial phagocytosis, but only of synaptoneurosomes isolated from chow-fed mice, an effect that was prevented by DHA pretreatment. Lastly, we measured the impact of palmitate and DHA on mitochondrial function in both microglial and neuronal cell models using the Seahorse XFe96 Analyzer. These data indicate that DHA pretreatment does not mitigate palmitate-induced reductions in mitochondrial respiration in BV2 microglia and HippoE-14 neurons, suggesting DHA may be acting downstream of mitochondrial function to exert its protective effects. Together, this study provides evidence that DHA can ameliorate the negative impact of palmitate on a variety of cellular functions in microglia- and neuron-like cells.

Global populations are increasingly consuming diets high in saturated fats and refined carbohydrates, and such diets have been well-associated with heightened inflammation and neurological dysfunction. Notably, older individuals are particularly vulnerable to the impact of unhealthy diet on cognition, even after a single meal, and pre-clinical rodent studies have demonstrated that short-term consumption of high-fat diet (HFD) induces marked increases in neuroinflammation and cognitive impairment. Unfortunately though, to date, most studies on the topic of nutrition and cognition, especially in aging, have been performed only in male rodents. This is especially concerning given that older females are more vulnerable to develop certain memory deficits and/or severe memory-related pathologies than males. Thus, the aim of the present study was to determine the extent to which short-term HFD consumption impacts memory function and neuroinflammation in female rats. Young adult (3 months) and aged (20–22 months) female rats were fed HFD for 3 days. Using contextual fear conditioning, we found that HFD had no effect on long-term contextual memory (hippocampus-dependent) at either age, but impaired long-term auditory-cued memory (amygdala-dependent) regardless of age. Gene expression of Il-1β was markedly dysregulated in the amygdala, but not hippocampus, of both young and aged rats after 3 days of HFD. Interestingly, modulation of IL-1 signaling via central administration of the IL-1 receptor antagonist (which we have previously demonstrated to be protective in males) had no impact on memory function following the HFD in females. Investigation of the memory-associated gene Pacap and its receptor Pac1r revealed differential effects of HFD on their expression in the hippocampus and amygdala. Specifically, HFD induced increased expression of Pacap and Pac1r in the hippocampus, whereas decreased Pacap was observed in the amygdala. Collectively, these data suggest that both young adult and aged female rats are vulnerable to amygdala-dependent (but not hippocampus-dependent) memory impairments following short-term HFD consumption, and identify potential mechanisms related to IL-1β and PACAP signaling in these differential effects. Notably, these findings are strikingly different than those previously reported in male rats using the same diet regimen and behavioral paradigms, and highlight the importance of examining potential sex differences in the context of neuroimmune-associated cognitive dysfunction.

Post-operative cognitive dysfunction (POCD) is an abrupt decline in neurocognitive function arising shortly after surgery and persisting for weeks to months, increasing the risk of dementia diagnosis. Advanced age, obesity, and comorbidities linked to high-fat diet (HFD) consumption such as diabetes and hypertension have been identified as risk factors for POCD, although underlying mechanisms remain unclear. We have previously shown that surgery alone, or 3-days of HFD can each evoke sufficient neuroinflammation to cause memory deficits in aged, but not young rats. The aim of the present study was to determine if HFD consumption before surgery would potentiate and prolong the subsequent neuroinflammatory response and memory deficits, and if so, to determine the extent to which these effects depend on activation of the innate immune receptor TLR4, which both insults are known to stimulate. Young-adult (3mo) & aged (24mo) male F344xBN F1 rats were fed standard chow or HFD for 3-days immediately before sham surgery or laparotomy. In aged rats, the combination of HFD and surgery caused persistent deficits in contextual memory and cued-fear memory, though it was determined that HFD alone was sufficient to cause the long-lasting cued-fear memory deficits. In young adult rats, HFD + surgery caused only cued-fear memory deficits. Elevated proinflammatory gene expression in the hippocampus of both young and aged rats that received HFD + surgery persisted for at least 3-weeks after surgery. In a separate experiment, rats were administered the TLR4-specific antagonist, LPS-RS, immediately before HFD onset, which ameliorated the HFD + surgery-associated neuroinflammation and memory deficits. Similarly, dietary DHA supplementation for 4 weeks prior to HFD onset blunted the neuroinflammatory response to surgery and prevented development of persistent memory deficits. These results suggest that HFD 1) increases risk of persistent POCD-associated memory impairments following surgery in male rats in 2) a TLR4-dependent manner, which 3) can be targeted by DHA supplementation to mitigate development of persistent POCD.

It is poorly understood how solid peripheral tumors affect brain neuroimmune responses despite the various brain-mediated side effects and higher rates of infection reported in cancer patients. We hypothesized that chronic low-grade peripheral tumor-induced inflammation conditions microglia to drive suppression of neuroinflammatory responses to a subsequent peripheral immune challenge. Here, Balb/c murine mammary tumors attenuated the microglial inflammatory gene expression responses to lipopolysaccharide (LPS) and live Escherichia coli (E. coli) challenges and the fatigue response to an E. coli infection. In contrast, the inflammatory gene expression in response to LPS or a toll-like receptor 2 agonist of Percoll-enriched primary microglia cultures was comparable between tumor-bearing and -free mice, as were the neuroinflammatory and sickness behavioral responses to an intracerebroventricular interleukin (IL)-1β injection. These data led to the hypothesis that Balb/c mammary tumors blunt the neuroinflammatory responses to an immune challenge via a mechanism involving tumor suppression of the peripheral humoral response. Balb/c mammary tumors modestly attenuated select circulating cytokine responses to LPS and E. coli challenges. Further, a second mammary tumor/mouse strain model (E0771 tumors in C57Bl/6 mice) displayed mildly elevated inflammatory responses to an immune challenge. Taken together, these data indicate that tumor-induced suppression of neuroinflammation and sickness behaviors may be driven by a blunted microglial phenotype, partly because of an attenuated peripheral signal to the brain, which may contribute to infection responses and behavioral side effects reported in cancer patients. Finally, these neuroimmune effects likely vary based on tumor type and/or host immune phenotype.

Background: Basic research and clinical trials universally demonstrate the benefits of exercise for cognitive function.In recent studies, we determined that a period of initial exercise also creates and maintains a molecular memory window for exercise benefits on cognitive function in male and female mice where a brief, 2-day exercise session following a break can also re-engage cognitive benefits, re-facilitate long-term potentiation, and allow for learning under insufficient, subthreshold training conditions.Here, we build on these exercise parameters to begin to define a mechanism responsible for maintaining cognitive benefits underlying this molecular memory window by initial exercise and driving long-term memory formation.Methods: We utilized RNA-sequencing to uncover genes in the dorsal hippocampus that are differentially expressed under conditions where exercise benefits are maintained throughout sedentary delay periods and enable the formation of long-term memory and synaptic plasticity.Specifically, adult male mice underwent 14 days of initial exercise, received a sedentary delay period (0-2 weeks), and a brief 2-day period of reactivating exercise, followed by 3 min inadequate, subthreshold training in an object location memory (OLM) task and hippocampus was dissected during the consolidation window, 1 hour after training.Those parameters were then used to examine hippocampal longterm potentiation (LTP) using theta burst stimulation in the schaffer collateral pathway.To assess how exercise modulates epigenetic regulation of genes up-regulated only under conditions where exercise enabled the formation of long-term memory and synaptic plasticity, histone modifications were examined at Acvr1c and Bdnf IV promoters using chromatin immunoprecipitation (ChIP-qPCR).To examine the role of Acvr1c, a gene coding for a type 1 activin A membrane receptor kinase of the TGF-β family of signaling molecules, in hippocampus-dependent long term memory formation and synaptic plasticity, we used intrahippocampal delivery of AAV1-ACVR1C point mutant constructs that either enhance or disrupt function.Next, sedentary mice were trained using either a subthreshold (3 min) or standard (10 min) OLM task and memory was tested the following day.The same mice from behavioral studies were used to assess the impact of Acvr1c manipulation on hippocampal LTP.Given misregulation of the TGF-β pathway that occurs with age and in AD patients, we examine whether Acvr1c declines with age in mouse and human hippocampus (Genotype-Tissue Expression Project).Dorsal hippocampus was obtained from 3 and 20 mo.female and male C57BL/6J mice and processed for RT-qPCR.Additionally, Acvr1c transcripts per million (TPM) values from RNA-Seq data set obtained through the MODEL-AD consortium were analyzed from 4, 8 and 12 mo.C57BL/6J and 5xFAD female and male mice.We next aimed to determine whether enhancing ACVR1C through virus-mediated overexpression of wildtype ACVR1C would regulate long-term memory formation and synaptic plasticity in aging 18 mo.and 12 and 18 mo.Alzheimer's Disease (AD) mouse hippocampus and ameliorate impairments.Results: We demonstrate that specific exercise patterns transform insufficient, subthreshold training into long-term memory (Group: (F(6,64) = 8.13, P < 0.0001; Tukey test: P < 0.001, 14D vs. Sed) and synaptic plasticity (Group: (F(6,89) = 22.22,P < 0.0001; Tukey test: P < 0.0001) in adult mice compared to sedentary, effects which can be maintained and re-engaged with brief 2-day re-introduction to exercise following a sedentary delay (Behavior: Tukey test: P < 0.05, LTP: P < 0.0001, 2-day re-introduction vs sedentary).We identify a small number of genes whose expression correlate with conditions in which exercise facilitates long-term memory formation.Among these genes we found Acvr1c and Bdnf.We find that exercise, in any amount, alleviates epigenetic repression at the Acvr1c (Group (F(5,49) = 9.377, P < 0.0001) and Bdnf IV (Group (F(5,53) = 13.90,P < 0.0001) promoters during consolidation in a persistent manner, providing initial insight for maintenance of exercise benefits on long term memory.Disrupted ACVR1C function under adequate learning conditions in adults impairs memory (t(17) = 4.65, P = 0.0002) and synaptic plasticity (t(18) = 3.512, P = 0.0025).Conversely, overexpression of ACVR1C enables learning under inadequate training conditions in adults (t(18) = 3.303, P = 0.004) and enhances LTP (t(14) = 3.953, P = 0.0014).Furthermore, Acvr1c expression is impaired in the aging human (t(91) = 6.64,P = 0.0001), mouse (t(26) = 2.72, P = 0.01) and AD mouse brain (5xFAD) (Age: (F(2,48) = 54.95,P < 0.0001), and over-expression of Acvr1c ameliorates plasticity www.nature.com/npp1234567890();,:and cognitive impairment in aging (18 mo.C57: Behavior: (t(12) = 2.350, P = 0.036), LTP: (t(14) = 3.953, P = 0.001), 12 mo.5xFAD: Behavior: (t(21) = 2.287, P = 0.032), LTP: (t(16) = 5.617, P < 0.0001), 18 mo.5xFAD: LTP: (t(10) = 9.653, P = 0.001)).Conclusions: Together, these findings provide a new paradigm for uncovering mechanistic drivers of exercise-facilitated learning and provide opportunity to explore how specific exercise parameters allow for periods of maintained epigenetic and molecular changes through sedentary periods that facilitate cognitive function.As we have demonstrated here, identification of such mechanisms may extend beyond the context of exercise and aid in ameliorating age and AD-associated cognitive impairment.