RESUMEN
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.
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Disfunción Cognitiva , Regulación de la Expresión Génica , Animales , Humanos , Ratones , Secuencia de Aminoácidos , Neurogénesis/genética , Plasticidad Neuronal/genética , Proteínas/genética , Proteínas/metabolismoRESUMEN
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.
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Neurogénesis , Carrera , Ratones , Masculino , Animales , Neurogénesis/fisiología , Neuronas/fisiología , Hipocampo/fisiología , Memoria Espacial/fisiología , Carrera/fisiología , Giro Dentado/fisiologíaRESUMEN
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.
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Conectoma , Epilepsia del Lóbulo Temporal , Ratones , Animales , Neuronas/fisiología , Hipocampo , Encéfalo , Interneuronas/fisiologíaRESUMEN
The Topoisomerase 3B (Top3b) - Tudor domain containing 3 (Tdrd3) protein complex is the only dual-activity topoisomerase complex in animals that can alter the topology of both DNA and RNA. 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 impairments in cognitive and emotional behaviors, aberrant neurogenesis and synaptic plasticity, and transcriptional defects. Similarly, human TDRD3 genomic variants have been associated with schizophrenia, verbal shorten-memory and learning, and educational attainment. However, the importance of Tdrd3 in normal brain function has not been examined in animal models. Here we built 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, 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 impairment and psychiatric disorders.
RESUMEN
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.
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Diabetes Mellitus Tipo 2 , Adipoquinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Ejercicio Físico/fisiología , Humanos , Músculo Esquelético/metabolismo , Obesidad/metabolismoRESUMEN
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.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/prevención & control , Animales , Cognición , Ejercicio Físico/psicología , Humanos , Plasticidad Neuronal , Factores de RiesgoRESUMEN
An inaugural workshop supported by "The Leo and Anne Albert Charitable Trust," was held October 4-7, 2019 in Scottsdale, Arizona, to focus on the effects of exercise on the brain and to discuss how physical activity may prevent or delay the onset of aging-related neurodegenerative conditions. The Scientific Program Committee (led by Dr. Jeff Burns) assembled translational, clinical, and basic scientists who research various aspects of the effects of exercise on the body and brain, with the overall goal of gaining a better understanding as to how to delay or prevent neurodegenerative diseases. In particular, research topics included the links between cardiorespiratory fitness, the cerebrovasculature, energy metabolism, peripheral organs, and cognitive function, which are all highly relevant to understanding the effects of acute and chronic exercise on the brain. The Albert Trust workshop participants addressed these and related topics, as well as how other lifestyle interventions, such as diet, affect age-related cognitive decline associated with Alzheimer's and other neurodegenerative diseases. This report provides a synopsis of the presentations and discussions by the participants, and a delineation of the next steps towards advancing our understanding of the effects of exercise on the aging brain.
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Hyperlipidemia and hypertension are modifiable risk factors for cognitive decline. About 25% of adults over age 65 use both antihypertensives (AHTs) and statins to treat these conditions. Recent research in humans suggests that their combined use may delay or prevent dementia onset. However, it is not clear whether and how combination treatment may benefit brain function. To begin to address this question, we examined effects of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and Captopril, an angiotensin-converting enzyme inhibitor (ACEI), administration on memory function, anxiety-like behavior, adult hippocampal neurogenesis and angiogenesis in adult and middle-aged male C57Bl/6J mice. In adult mice (3-months-old) combination (combo) treatment, as well as administration of each compound individually, for six weeks, accelerated memory extinction in contextual fear conditioning. However, pattern separation in the touchscreen-based location discrimination test, a behavior linked to adult hippocampal neurogenesis, was unchanged. In addition, dentate gyrus (DG) neurogenesis and vascularization were unaffected. In middle-aged mice (10-months-old) combo treatment had no effect on spatial memory in the Morris water maze, but did reduce anxiety in the open field test. A potential underlying mechanism may be the modest increase in new hippocampal neurons (~20%) in the combo as compared to the control group. DG vascularization was not altered. Overall, our findings suggest that statin and anti-hypertensive treatment may serve as a potential pharmacotherapeutic approach for anxiety, in particular for post-traumatic stress disorder (PTSD) patients who have impairments in extinction of aversive memories.
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Factores de Edad , Antihipertensivos/farmacología , Miedo/efectos de los fármacos , Memoria/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Animales , Extinción Psicológica/efectos de los fármacos , Miedo/fisiología , Hipocampo/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Masculino , Ratones Endogámicos C57BL , Neurogénesis/fisiología , Neuronas/fisiologíaRESUMEN
Increasing evidence indicates that physical activity and exercise training may delay or prevent the onset of Alzheimer's disease (AD). However, systemic biomarkers that can measure exercise effects on brain function and that link to relevant metabolic responses are lacking. To begin to address this issue, we utilized blood samples of 23 asymptomatic late middle-aged adults, with familial and genetic risk for AD (mean age 65 years old, 50% female) who underwent 26 weeks of supervised treadmill training. Systemic biomarkers implicated in learning and memory, including the myokine Cathepsin B (CTSB), brain-derived neurotrophic factor (BDNF), and klotho, as well as metabolomics were evaluated. Here we show that aerobic exercise training increases plasma CTSB and that changes in CTSB, but not BDNF or klotho, correlate with cognitive performance. BDNF levels decreased with exercise training. Klotho levels were unchanged by training, but closely associated with change in VO2peak. Metabolomic analysis revealed increased levels of polyunsaturated free fatty acids (PUFAs), reductions in ceramides, sphingo- and phospholipids, as well as changes in gut microbiome metabolites and redox homeostasis, with exercise. Multiple metabolites (~30%) correlated with changes in BDNF, but not CSTB or klotho. The positive association between CTSB and cognition, and the modulation of lipid metabolites implicated in dementia, support the beneficial effects of exercise training on brain function. Overall, our analyses indicate metabolic regulation of exercise-induced plasma BDNF changes and provide evidence that CTSB is a marker of cognitive changes in late middle-aged adults at risk for dementia.
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Enfermedad de Alzheimer , Factor Neurotrófico Derivado del Encéfalo/sangre , Catepsina B/sangre , Cognición , Ejercicio Físico , Proteínas Klotho/sangre , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Ácidos Grasos Omega-3/sangre , Femenino , Microbioma Gastrointestinal , Humanos , Hidroxiprolina/sangre , Metabolismo de los Lípidos , Masculino , Metabolómica , Persona de Mediana Edad , Prolina/análogos & derivados , Prolina/sangre , Factores de RiesgoRESUMEN
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.
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Envejecimiento/fisiología , Hipocampo/fisiología , Neurogénesis/efectos de los fármacos , Piperidinas/farmacología , Adiponectina/sangre , Animales , Glucemia/metabolismo , Factor Neurotrófico Derivado del Encéfalo/sangre , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Corticosterona/sangre , Giro Dentado/efectos de los fármacos , Giro Dentado/fisiología , Hipocampo/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Modelos Biológicos , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , Memoria Espacial/efectos de los fármacosRESUMEN
New neurons are generated in adult mammals. Adult hippocampal neurogenesis is considered to play an important role in cognition and mental health. The number and properties of newly born neurons are regulatable by a broad range of physiological and pathological conditions. To begin to understand the underlying cellular mechanisms and functional relevance of adult neurogenesis, many studies rely on quantification of adult-born neurons. However, lack of standardized methods to quantify new neurons is impeding research reproducibility across laboratories. Here, we review the importance of stereology, and propose why and how it should be applied to the study of adult neurogenesis.
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Encéfalo/citología , Encéfalo/fisiología , Células-Madre Neurales/citología , Células-Madre Neurales/fisiología , Neurogénesis/fisiología , Adulto , Células Madre Adultas/citología , Células Madre Adultas/fisiología , Animales , Giro Dentado/citología , Giro Dentado/fisiología , Humanos , Modelos Neurológicos , Plasticidad NeuronalRESUMEN
Topoisomerase 3ß (Top3ß) is the only dual-activity topoisomerase in animals that can change topology for both DNA and RNA, and facilitate transcription on DNA and translation on mRNAs. Top3ß mutations have been linked to schizophrenia, autism, epilepsy, and cognitive impairment. Here we show that Top3ß knockout mice exhibit behavioural phenotypes related to psychiatric disorders and cognitive impairment. The mice also display impairments in hippocampal neurogenesis and synaptic plasticity. Notably, the brains of the mutant mice exhibit impaired global neuronal activity-dependent transcription in response to fear conditioning stress, and the affected genes include many with known neuronal functions. Our data suggest that Top3ß is essential for normal brain function, and that defective neuronal activity-dependent transcription may be a mechanism by which Top3ß deletion causes cognitive impairment and psychiatric disorders.
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Disfunción Cognitiva/genética , ADN-Topoisomerasas de Tipo I/genética , Trastornos Mentales/genética , Neurogénesis/genética , Plasticidad Neuronal/genética , Animales , Técnicas de Observación Conductual , Conducta Animal , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/patología , Modelos Animales de Enfermedad , Femenino , Hipocampo/citología , Hipocampo/diagnóstico por imagen , Hipocampo/crecimiento & desarrollo , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos Mentales/diagnóstico , Trastornos Mentales/patología , Ratones , Ratones Noqueados , Neuronas/patología , Técnicas Estereotáxicas , Potenciales Sinápticos/genética , Transcripción Genética/fisiologíaRESUMEN
RATIONALE: Abuse of the psychostimulant methamphetamine (METH) can cause long-lasting damage to brain monoaminergic systems and is associated with profound mental health problems for users, including lasting cognitive impairments. Animal models of METH exposure have been useful in dissecting the molecular effects of the drug on cognition, but many studies use acute, non-contingent "binge" administrations of METH which do not adequately approximate human METH use. Long-term METH exposure via long-access (LgA) self-administration paradigms has been proposed to more closely reflect human use and induce cognitive impairments. OBJECTIVE: To better understand the role of contingency and patterns of exposure in METH-induced cognitive impairments, we analyzed behavioral and neurochemical outcomes in adult male rats, comparing non-contingent "binge" METH administration with contingent (LgA) METH self-administration and non-contingent yoked partners. RESULTS: Binge METH (40 mg/kg, i.p., over 1 day) dramatically altered striatal and hippocampal dopamine, DOPAC, 5-HT, 5-HIAA, BDNF, and TrkB 75 days after drug exposure. In contrast, 6-h LgA METH self-administration (cumulative 24.8-48.9 mg METH, i.v., over 16 days) altered hippocampal BDNF in both contingent and yoked animals but reduced striatal 5-HIAA in only contingent animals. Neurochemical alterations following binge METH administration were not accompanied by cognitive deficits in Morris water maze, novel object recognition, or Y-maze tests. However, contingent LgA METH self-administration resulted in impaired spatial memory in the water maze. CONCLUSIONS: Overall, substantial differences in neurochemical markers between METH exposure and self-administration paradigms did not consistently translate to deficits in cognitive tasks, highlighting the complexity of correlating METH-induced neurochemical changes with cognitive outcomes.
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Estimulantes del Sistema Nervioso Central/administración & dosificación , Cognición/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Metanfetamina/administración & dosificación , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Cognición/fisiología , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Ácido Hidroxiindolacético/metabolismo , Masculino , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/metabolismo , Ratas , Ratas Wistar , Autoadministración/psicologíaRESUMEN
Frontotemporal dementia (FTD) is characterized by neuronal loss in the frontal and temporal lobes of the brain. Here, we provide the first evidence of striking morphological alterations in dentate granule cells (DGCs) of FTD patients and in a mouse model of the disease, TauVLW mice. Taking advantage of the fact that the hippocampal dentate gyrus (DG) gives rise to newborn DGCs throughout the lifetime in rodents, we used RGB retroviruses to study the temporary course of these alterations in newborn DGCs of female TauVLW mice. In addition, retroviruses that encode either PSD95:GFP or Syn:GFP revealed striking alterations in the afferent and efferent connectivity of newborn TauVLW DGCs, and monosynaptic retrograde rabies virus tracing showed that these cells are disconnected from distal brain regions and local sources of excitatory innervation. However, the same cells exhibited a predominance of local inhibitory innervation. Accordingly, the expression of presynaptic and postsynaptic markers of inhibitory synapses was markedly increased in the DG of TauVLW mice and FTD patients. Moreover, an increased number of neuropeptide Y-positive interneurons in the DG correlated with a reduced number of activated egr-1+ DGCs in TauVLW mice. Finally, we tested the therapeutic potential of environmental enrichment and chemoactivation to reverse these alterations in mice. Both strategies reversed the morphological alterations of newborn DGCs and partially restored their connectivity in a mouse model of the disease. Moreover, our data point to remarkable morphological similarities between the DGCs of TauVLW mice and FTD patients.SIGNIFICANCE STATEMENT We show, for the first time to our knowledge, that the population of dentate granule cells is disconnected from other regions of the brain in the neurodegenerative disease frontotemporal dementia (FTD). These alterations were observed in FTD patients and in a mouse model of this disease. Moreover, we tested the therapeutic potential of two strategies, environmental enrichment and chemoactivation, to stimulate the activity of these neurons in mice. We found that some of the alterations were reversed by these therapeutic interventions.
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Giro Dentado/metabolismo , Giro Dentado/patología , Modelos Animales de Enfermedad , Demencia Frontotemporal/metabolismo , Demencia Frontotemporal/patología , Neurogénesis/fisiología , Factores de Edad , Animales , Femenino , Demencia Frontotemporal/genética , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Fragile X syndrome results from a loss of the RNA-binding protein fragile X mental retardation protein (FMRP). How FMRP regulates neuronal development and function remains unclear. Here we show that FMRP-deficient immature neurons exhibit impaired dendritic maturation, altered expression of mitochondrial genes, fragmented mitochondria, impaired mitochondrial function, and increased oxidative stress. Enhancing mitochondrial fusion partially rescued dendritic abnormalities in FMRP-deficient immature neurons. We show that FMRP deficiency leads to reduced Htt mRNA and protein levels and that HTT mediates FMRP regulation of mitochondrial fusion and dendritic maturation. Mice with hippocampal Htt knockdown and Fmr1-knockout mice showed similar behavioral deficits that could be rescued by treatment with a mitochondrial fusion compound. Our data unveil mitochondrial dysfunction as a contributor to the impaired dendritic maturation of FMRP-deficient neurons and suggest a role for interactions between FMRP and HTT in the pathogenesis of fragile X syndrome.
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Dendritas/metabolismo , Giro Dentado/metabolismo , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Proteína Huntingtina/metabolismo , Dinámicas Mitocondriales , Animales , Giro Dentado/crecimiento & desarrollo , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Técnicas de Silenciamiento del Gen , Genes Mitocondriales , Proteína Huntingtina/genética , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Estrés OxidativoRESUMEN
No medications prevent or reverse age-related cognitive decline. Physical activity (PA) enhances memory in rodents, but findings are mixed in human studies. As a result, exercise guidelines specific for brain health are absent. Here, we re-examine results from human studies, and suggest the use of more sensitive tasks to evaluate PA effects on age-related changes in the hippocampus, such as relational memory and mnemonic discrimination. We discuss recent advances from rodent and human studies into the underlying mechanisms at both the central and peripheral levels, including neurotrophins and myokines that could contribute to improved memory. Finally, we suggest guidelines for future research to help expedite well-founded PA recommendations for the public.