PURPOSE:The relationship between exercise and brain function has been studied extensively; however, whether different exercise modalities promote hippocampal neurogenesis and cognitive function through shared or distinct biological pathways remains unclear. This study examined the effects of endurance training (ET), resistance training (RT), and high-intensity interval training (HIIT) on hippocampal neurogenesis, spatial memory, and neurotrophic factors. METHODS:Forty 3-month-old male C57BL/6J mice were randomized to control (SED), ET, RT, or HIIT groups. Following the training intervention, adult hippocampal neurogenesis was assessed in the dentate gyrus using BrdU⁺/NeuN⁺ immunolabeling. Hippocampal measures of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), and fibronectin type III domain-containing protein (FNDC5), were quantified. Spatial memory was evaluated using the Barnes maze. RESULTS:All exercise modalities increased the number of BrdU⁺/NeuN⁺ cells compared with sedentary controls (RT, p<0.001; ET, p=0.001; HIIT, p=0.016). Each modality produced a distinct molecular profile. RT elicited the greatest increases in hippocampal BDNF compared to all groups (RT vs. ET, p=0.007; RT vs. HIIT, p<0.001; RT vs. SED, p<0.001) and increased IGF-1 levels (RT vs. SED, p=0.014). ET increased hippocampal FDNC5 (ET vs. SED, p=0.033), whereas HIIT did not alter measured neurotrophic or myokine levels. Only RT and ET improved spatial learning. CONCLUSIONS:Although all exercise modalities increased hippocampal neurogenesis, only those associated with elevations in neurotrophic factors demonstrated improvements in spatial learning. These findings suggest that different exercise modalities may promote hippocampal plasticity through distinct biological profiles and that increases in neurogenesis alone may not be sufficient to enhance cognitive function.

This study examined the effects of resistance training (RT) and supraphysiological nandrolone decanoate (ND) administration on hippocampal neurogenesis, neurotrophic signaling, and behavior. Forty 3-month-old male C57BL/6 J mice were randomized to RT or sedentary (SED) conditions. Each group was further divided into sham (S) or ND (38 mg·kg-1·wk.-1) treatment groups. All interventions lasted 7 wk. Adult hippocampal neurogenesis was quantified in the dentate gyrus using BrdU+/NeuN+ immunolabeling. Hippocampal expression of brain-derived neurotrophic factor (BDNF), androgen receptor (AR), estrogen receptor-β (ER-β), insulin-like growth factor-1 (IGF-1), and irisin was assessed by western blot analyses. No significant exercise × treatment interactions were observed for any of the behavior measures. When collapsed across treatments, RT exhibited a greater number of open-arm entries (p = 0.006) and reduced average latency times (p = 0.002) than SED. ND administration did not alter behavioral outcomes. RT (p = 0.001) and ND (p = 0.032) each independently increased hippocampal BrdU+/NeuN+ cell numbers, with no additive effects. AR expression for SED-S was significantly lower (p's < 0.05) than all other groups and IGF-1 expression for RT-S was significantly greater (p's < 0.05) than all other groups. Main effects revealed that RT and ND resulted in significant elevations in AR, ER-β and BDNF expressions. In conclusion, RT enhanced hippocampal plasticity and behavioral performance, whereas supraphysiological ND administration produced distinct molecular changes without conferring additive behavioral or neuroplastic benefit.

Increasing evidence indicates skeletal muscle function is associated with cognition. Muscle-secreted protease Cathepsin B (Ctsb) is linked to memory in animals and humans, but has an unclear role in neurodegenerative diseases. To address this question, we utilized an AAV-vector-mediated approach to express Ctsb in skeletal muscle of APP/PS1 Alzheimer's disease (AD) model mice. Mice were treated with Ctsb at 4 months of age, followed by behavioral analyses 6 months thereafter. Here we show that muscle-targeted Ctsb treatment results in long-term improvements in motor coordination, memory function, and adult hippocampal neurogenesis, while plaque pathology and neuroinflammation remain unchanged. Additionally, in AD mice, Ctsb treatment normalizes hippocampal, muscle, and plasma proteomic profiles to resemble that of wildtype (WT) controls. In AD mice, Ctsb increases the abundance of hippocampal proteins involved in mRNA metabolism and protein synthesis, including those relevant to adult neurogenesis and memory function. Furthermore, Ctsb treatment enhances plasma metabolic and mitochondrial processes. In muscle, Ctsb treatment elevates protein translation in AD mice, whereas in WT mice mitochondrial proteins decrease. In WT mice, Ctsb treatment causes memory deficits and results in protein profiles across tissues that are comparable to AD control mice. Overall, the biological changes in the treatment groups are consistent with effects on memory function. Thus, skeletal muscle Ctsb application has potential as an AD therapeutic intervention.

Alzheimer's disease (AD) is the leading cause of morbidity and mortality worldwide, as a result of cognitive decline and neurological dysfunction. In AD, reduced cerebral blood flow and impaired vascularization result from capillary bed degeneration and decreased angiogenesis, as observed in both patients and animal models. Physical exercise is recognized as a potential intervention to delay AD progression and reduce disease risk. While most studies have focused on the benefits of aerobic exercise (AE), emerging evidence suggests that resistance exercise (RE) also exerts positive effects on overall health and cognitive function in aging and AD. However, a notable gap in knowledge remains regarding the effects of RE on cerebral blood flow and vascular structure. This review explores the processes by which AE and RE influence brain vascularization in aging and AD, including blood flow, endothelial function, angiogenesis and neurotrophic factor levels. Based on pre-clinical and clinical studies, we conclude that both AE and RE contribute to improved cerebral blood flow and vascular function, promoting vascular repair in the aging and AD-affected brain. By examining the relationship between exercise modalities and brain vascularization, this review expands knowledge regarding the processes underlying the neuroprotective effects of exercise in neurodegenerative and aging conditions.

Exercise has a remarkable capacity to improve brain function by fostering neuronal plasticity, which enables us to better cope with various psychological and cognitive challenges. Numerous studies have demonstrated the neuroprotective effects of exercise. However, the underlying molecular mechanisms of the neuroprotective effects of exercise are not yet fully understood. In particular, the role of exercise-induced secretion of peripheral factors into circulation that influence the brain is understudied. Recent research has shown that extracellular vesicles (EVs), including microvesicles (MVs) and exosomes, are secreted during exercise. The discovery that EVs can mediate intracellular communication by delivering cargo signifies a promising area of research to understand the impact of exercise on the brain. In the present review, we provide an overview of recent advancements in understanding the regulatory mechanisms of EV biogenesis and discuss how EV molecular composition is influenced by exercise. Additionally, we highlight the potential role of EVs as exercise-specific mediators and as a promising therapeutic tool for neurodegenerative diseases, such as Alzheimer's disease.

Brain-derived neurotrophic factor (BDNF)—a key neurotrophin involved in synaptic plasticity, neurogenesis, and neuroprotection—has been shown to mediate sex differences in verbal learning and memory (VLM) ability, but it remains unclear whether this relationship is conditionally dependent upon carriage of the Val66Met polymorphism in the BDNF gene. This study investigates how BDNF Val66Met carriage influences the mediation of sex differences in VLM scores by plasma BDNF levels in a cohort enriched for AD risk. Cognitively unimpaired participants in the Wisconsin Registry for Alzheimer’s Prevention (WRAP; n=198, age 63.8±6y, 66% women, 66% family history of AD, 38% apolipoprotein E4 (APOE-ε4) carriers, 31% BDNF Val66Met carriers) underwent the Rey Auditory Verbal Learning Test (RAVLT). Scores from learning trials 3-5 and the delayed recall test were aggregated as a VLM performance index. Plasma BDNF levels were measured using a Human BDNF Quantikine Immunoassay (R&D Systems). Striatified mediation analysis and bootstrapping were performed to test the conditional dependence of BDNF mediation on BDNF Val66Met carriage, and model covariates included age, APOE-ε4 carriage, parental history of AD, education, hippocampal volume, and date difference between VLM and plasma data acquisition. Stratified mediation models showed a significant association between sex and VLM scores in BDNF Val66Met carriers [β=-0.61; p=0.04], but no significant association between sex and BDNF levels [β=0.06; p=0.85]. By comparison, in BDNF Val66Val homozygotes, women had significantly higher BDNF levels [β=-0.62; p<0.01] and VLM scores [β=-0.77; p<0.01], and bootstrapping showed BDNF to be a significant partial mediator of the effect of sex on VLM [β=-0.14; 95% CI: -.292, -.021]. This study indicates that BDNF Val66Met carriage may attenuate the mediating role of plasma BDNF expression on the relationship between sex and VLM scores.

Muscle secretes factors during exercise that enhance cognition. Myokine Cathepsin B (Ctsb) is linked to memory function, but its role in neurodegenerative disease is unclear. Here we show that AAV-vector-mediated Ctsb overexpression in skeletal muscle in an Alzheimer's Disease (AD) mouse model (APP/PS1), improves motor coordination, memory function and adult hippocampal neurogenesis, while plaque pathology and neuroinflammation remain unchanged. Additionally, in AD mice, Ctsb treatment modifies hippocampal, muscle and plasma proteomic profiles to resemble that of wildtype controls. Conversely, in wildtype mice, Ctsb expression causes memory deficits and results in protein profiles across tissues that are comparable to AD control mice. In AD mice, Ctsb treatment increases the abundance of hippocampal proteins involved in mRNA metabolism and protein synthesis, including those relevant to adult hippocampal neurogenesis and memory function. Furthermore, Ctsb treatment enhances plasma metabolic and mitochondrial processes, and reduces inflammatory responses. In muscle, Ctsb expression elevates protein translation in AD mice, whereas in wildtype mice mitochondrial proteins decrease. Overall, the biological changes in the treatment groups are consistent with effects on memory function. Thus, skeletal muscle Ctsb application has potential as an AD therapeutic intervention.

AbstractINTRODUCTIONThis study examined whether sex differences in verbal learning and memory (VLM) are mediated by plasma brain‐derived neurotrophic factor (BDNF) expression.METHODSIn a sample of n = 201 participants (63.81 ± 6.04 years, 66.2% female, 65.7% family history of Alzheimer's disease [AD], 38% apolipoprotein E [APOE] ε4+) from the Wisconsin Registry for Alzheimer's Prevention, VLM was measured using trials 3 through 5 and delayed recall from the Rey Auditory Verbal Learning Test. Plasma BDNF was measured using a Human BDNF Quantikine Immunoassay. Mediation analysis used bootstrapping, and stratified mediation models tested the conditional dependence of APOE ε4 carriage.RESULTSBDNF partially mediated the sex–VLM relationship (β = −0.07; 95% confidence interval [CI]: −0.18, −0.01). Female APOE ε4 carriers had higher VLM scores (β = −0.53; p = 0.03), while female non‐carriers had both higher BDNF levels (β = −0.68; p < 0.01) and VLM scores (β = −1.06; p < 0.01); BDNF was again a significant mediator (β = −0.18; 95% CI: −0.37, −0.05).DISCUSSIONThis study found that circulating BDNF mediates higher verbal memory scores in females—particularly in APOE ε4 non‐carriers.Highlights Sex differences in verbal learning and memory (VLM) were mediated by plasma brain‐derived neurotrophic factor (BDNF) levels. Women exhibited higher VLM scores and plasma BDNF levels compared to men. The protective effect of BDNF in women was attenuated by apolipoprotein E ε4 carriage. Findings suggest sex‐specific mechanisms against verbal memory decline in aging.

The Topoisomerase 3B (Top3b) - Tudor domain containing 3 (Tdrd3) protein complex is the only dual-activity topoisomerase complex that can alter both DNA and RNA topology in animals. TOP3B mutations in humans are associated with schizophrenia, autism and cognitive disorders; and Top3b-null mice exhibit several phenotypes observed in animal models of psychiatric and cognitive disorders, including impaired cognitive and emotional behaviors, aberrant neurogenesis and synaptic plasticity, and transcriptional defects. Similarly, human TDRD3 genomic variants have been associated with schizophrenia, verbal short-term memory and educational attainment. However, the importance of Tdrd3 in normal brain function has not been examined in animal models. Here we generated a Tdrd3-null mouse strain and demonstrate that these mice display both shared and unique defects when compared to Top3b-null mice. Shared defects were observed in cognitive behaviors, synaptic plasticity, adult neurogenesis, newborn neuron morphology, and neuronal activity-dependent transcription; whereas defects unique to Tdrd3-deficient mice include hyperactivity, changes in anxiety-like behaviors, olfaction, increased new neuron complexity, and reduced myelination. Interestingly, multiple genes critical for neurodevelopment and cognitive function exhibit reduced levels in mature but not nascent transcripts. We infer that the entire Top3b-Tdrd3 complex is essential for normal brain function, and that defective post-transcriptional regulation could contribute to cognitive and psychiatric disorders.

Obesity has been linked to a range of pathologies, including dementia. In contrast, regular physical activity is associated with the prevention or reduced progression of neurodegeneration. Specifically, physical activity can improve memory and spatial cognition, reduce age-related cognitive decline, and preserve brain volume, but the mechanisms are not fully understood. Accordingly, we investigated whether any detrimental effects of high-fat diet (HFD)-induced obesity on cognition, motor behavior, adult hippocampal neurogenesis, and brain-derived neurotrophic factor (BDNF) could be mitigated by voluntary exercise training in male C57Bl/6 mice. HFD-induced impairment of motor function was not reversed by exercise. Importantly, voluntary wheel running improved long-term memory and increased hippocampal neurogenesis, suggesting that regular physical activity may prevent cognitive decline in obesity.

Exercise may prevent or delay aging-related memory loss and neurodegeneration. In rodents, running increases the number of adult-born neurons in the dentate gyrus (DG) of the hippocampus, in association with improved synaptic plasticity and memory function. However, it is unclear whether adult-born neurons remain fully integrated into the hippocampal network during aging and whether long-term running affects their connectivity. To address this issue, we labeled proliferating DG neural progenitor cells with retrovirus expressing the avian TVA receptor in two-month-old sedentary and running male C57Bl/6 mice. More than six months later, we injected EnvA-pseudotyped rabies virus into the DG as a monosynaptic retrograde tracer, to selectively infect TVA expressing "old" new neurons. We identified and quantified the direct afferent inputs to these adult-born neurons within the hippocampus and (sub)cortical areas. Here, we show that long-term running substantially modifies the network of the neurons generated in young adult mice, upon middle-age. Exercise increases input from hippocampal interneurons onto "old" adult-born neurons, which may play a role in reducing aging-related hippocampal hyperexcitability. In addition, running prevents the loss of adult-born neuron innervation from perirhinal cortex, and increases input from subiculum and entorhinal cortex, brain areas that are essential for contextual and spatial memory. Thus, long-term running maintains the wiring of "old" new neurons, born during early adulthood, within a network that is important for memory function during aging.

Adult neurogenesis occurs in the dentate gyrus (DG) of the rodent hippocampus throughout life, producing new granule cells (GCs) that migrate from a stem cell niche called the subgranular zone (SGZ) into the adjacent granule cell layer (GCL). Seizures associated with temporal lobe epilepsy alter adult neurogenesis and promote the formation of hyperexcitable circuits. Stem cell therapies for treating intractable seizure disorders are based on the premise that transplantation of GABAergic interneurons will strengthen inhibitory connections within the hippocampus and reduce hyperexcitability. Grafts of medial ganglionic eminence (MGE)-derived fetal GABAergic progenitors into the DG of adult mice with pilocarpine-induced TLE have been shown to suppress spontaneous recurrent seizures. In addition, the transplanted cells formed functional inhibitory synaptic connections with hippocampal neurons, including adult-born GCs. However, it is unknown whether MGE grafts change adult-born GC connectivity. To address this question, we compared the first-order monosynaptic inputs to adult-born GCs in TLE mice with or without MGE-derived interneuron grafts. Here we show that TLE increased excitatory inputs from endogenous hippocampal, entorhinal cortex, and medial septum/diagonal band neurons onto adult-born GCs. In contrast, in TLE mice with grafts, these excitatory inputs were reduced, coinciding with transplanted GABAergic interneuron innervation of adult-born GCs. These findings indicate that GABAergic interneuron transplantation into the dentate gyrus may prevent epilepsy-associated alterations in the connectivity of adult-born GCs.

Over the past two decades, adult hippocampal neurogenesis has become a well-established phenomenon. However, our understanding of how adult-born hippocampal neurons process information and contribute to memory formation has been limited by a strong focus on new neuron number, rather than on the structure and function of the underlying circuitry. With the advent of new viral neuroanatomical tracers, we are now able to expand our knowledge to the analysis of the physiological role of new neurons in the adult brain network. In particular, combining the use of retrovirus to label dividing dentate gyrus progenitor cells with recombinant rabies virus has enabled the investigation of specific monosynaptic connections between new neurons and select brain areas and cell types. This technology, in combination with electrophysiological approaches, has now allowed us to visualize and analyze the network of new neurons in the adult brain. Moreover, changes in new neuron circuitry as a result of behavioral changes, genetic modification, or pathological conditions can be reliably monitored and characterized. Altogether, we provide the background and guidelines for the optimal use and application of this novel methodology.

The health benefits of exercise are well-recognized and are observed across multiple organ systems. These beneficial effects enhance overall resilience, healthspan and longevity. The molecular mechanisms that underlie the beneficial effects of exercise, however, remain poorly understood. Since the discovery in 2000 that muscle contraction releases IL-6, the number of exercise-associated signalling molecules that have been identified has multiplied. Exerkines are defined as signalling moieties released in response to acute and/or chronic exercise, which exert their effects through endocrine, paracrine and/or autocrine pathways. A multitude of organs, cells and tissues release these factors, including skeletal muscle (myokines), the heart (cardiokines), liver (hepatokines), white adipose tissue (adipokines), brown adipose tissue (baptokines) and neurons (neurokines). Exerkines have potential roles in improving cardiovascular, metabolic, immune and neurological health. As such, exerkines have potential for the treatment of cardiovascular disease, type 2 diabetes mellitus and obesity, and possibly in the facilitation of healthy ageing. This Review summarizes the importance and current state of exerkine research, prevailing challenges and future directions.

There is accumulating evidence that exercise improves brain function and may delay or prevent the onset neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Studies in humans show that physical activity can enhance or maintain gray and white matter volume, improve cerebral blood flow, cognition and mood. In rodent models, voluntary wheel running as well as forced treadmill training result in upregulation of adult neurogenesis, neurotransmitters, neurotrophins, angiogenesis, mitochondrial biogenesis, especially in the hippocampus a brain area important for learning and memory. In addition, exercise reduces neural oxidative stress and neuroinflammation. Moreover, multiple aspects of memory function in rodents such as spatial navigation, object recognition and pattern separation are enhanced by running [1]. However, the underlying mechanisms remain elusive. In particular, the role of peripheral factors in brain function have only recently begun to be addressed and are the topic of this Special Issue. Linking the circulation of an aged mouse to that of a young mouse, results in reduced adult neurogenesis, whereas an infusion of plasma derived from exercising young or aged mice into their sedentary counterparts improves adult neurogenesis and memory function [2, 3]. Multiple peripheral organs,

Alzheimer’s disease (AD) is the most common cause of dementia and there is currently no cure. Novel approaches to treat AD and curb the rapidly increasing worldwide prevalence and costs of dementia are needed. Physical inactivity is a significant modifiable risk factor for AD, estimated to contribute to 12.7% of AD cases worldwide. Exercise interventions in humans and animals have shown beneficial effects of exercise on brain plasticity and cognitive functions. In animal studies, exercise also improved AD pathology. The mechanisms underlying these effects of exercise seem to be associated mainly with exercise performance or cardiorespiratory fitness. In addition, exercise-induced molecules of peripheral origin seem to play an important role. Since exercise affects the whole body, there likely is no single therapeutic target that could mimic all the benefits of exercise. However, systemic strategies may be a viable means to convey broad therapeutic effects in AD patients. Here, we review the potential of physical activity and exercise training in AD prevention and treatment, shining light on recently discovered underlying mechanisms and concluding with a view on future development of exercise-free treatment strategies for AD.

AdipoRon, an adiponectin receptor agonist, elicits similar antidiabetic, anti-atherogenic, and anti-inflammatory effects on mouse models as adiponectin does. Since AdipoRon can cross the blood-brain barrier, its chronic effects on regulating hippocampal function are yet to be examined. This study investigated whether AdipoRon treatment promotes hippocampal neurogenesis and spatial recognition memory in a dose-dependent manner. Adolescent male C57BL/6J mice received continuous treatment of either 20 mg/kg (low dose) or 50 mg/kg (high dose) AdipoRon or vehicle intraperitoneally for 14 days, followed by the open field test to examine anxiety and locomotor activity, and the Y maze test to examine hippocampal-dependent spatial recognition memory. Immunopositive cell markers of neural progenitor cells, immature neurons, and newborn cells in the hippocampal dentate gyrus were quantified. Immunosorbent assays were used to measure the serum levels of factors that can regulate hippocampal neurogenesis, including adiponectin, brain-derived neurotrophic factor (BDNF), and corticosterone. Our results showed that 20 mg/kg AdipoRon treatment significantly promoted hippocampal cell proliferation and increased serum levels of adiponectin and BDNF, though there were no effects on spatial recognition memory and locomotor activity. On the contrary, 50 mg/kg AdipoRon treatment impaired spatial recognition memory, suppressed cell proliferation, neuronal differentiation, and cell survival associated with reduced serum levels of BDNF and adiponectin. The results suggest that a low-dose AdipoRon treatment promotes hippocampal cell proliferation, while a high-dose AdipoRon treatment is detrimental to the hippocampus function.