Dietary Cocoa Flavanols Do Not Alter Brain Excitability in Young Healthy Adults.

The ingestion of dietary cocoa flavanols acutely alters functions of the cerebral endothelium, but whether the effects of flavanols permeate beyond this to alter other brain functions remains unclear. Based on converging evidence, this work tested the hypothesis that cocoa flavanols would alter brain excitability in young healthy adults. In a randomised, cross-over, double-blinded, placebo-controlled design, transcranial magnetic stimulation was used to assess corticospinal and intracortical excitability before as well as 1 and 2 h post-ingestion of a beverage containing either high (695 mg flavanols, 150 mg (-)-epicatechin) or low levels (5 mg flavanols, 0 mg (-)-epicatechin) of cocoa flavanols. In addition to this acute intervention, the effects of a short-term chronic intervention where the same cocoa flavanol doses were ingested once a day for 5 consecutive days were also investigated. For both the acute and chronic interventions, the results revealed no robust alteration in corticospinal or intracortical excitability. One possibility is that cocoa flavanols yield no net effect on brain excitability, but predominantly alter functions of the cerebral endothelium in young healthy adults. Future studies should increase intervention durations to maximize the acute and chronic accumulation of flavanols in the brain, and further investigate if cocoa flavanols would be more effective at altering brain excitability in older adults and clinical populations than in younger adults.

Fat intake impairs the recovery of endothelial function following mental stress in young healthy adults.

Introduction: Mental stress has been identified as a trigger of cardiovascular events. A single episode of stress can induce acute impairments in endothelial function in healthy adults. Importantly, during stressful periods, individuals often resort to unhealthy behaviors, such as increased consumption of high-fat foods, which is also known to negatively impact endothelial function. Therefore, this study examined whether consumption of a high-fat meal would further exacerbate the negative effect of mental stress on vascular function. Methods: In a randomized, counterbalanced, cross- over, postprandial intervention study, 21 healthy males and females ingested a high-fat (56.5 g fat) or a low-fat (11.4 g fat) meal 1.5 h before an 8-min mental stress task (Paced-Auditory-Serial-Addition-Task, PASAT). Plasma triglyceride (TAG) concentration was assessed pre-and post-meal. Forearm blood flow (FBF), blood pressure (BP), and cardiovascular activity were assessed pre-meal at rest and post-meal at rest and during stress. Endothelial function, measured by brachial flow-mediated dilatation (FMD) was assessed pre-meal and 30 and 90 min following mental stress. Results: Plasma TAG concentration was significantly increased following the high-fat meal compared to the low-fat condition. Mental stress induced similar increases in peripheral vasodilation, BP, and cardiovascular activity, and impaired FMD 30 min post-stress, in both conditions. FMD remained significantly impaired 90 min following stress in the high-fat condition only, suggesting that consumption of fat attenuates the recovery of endothelial function following mental stress. Discussion: Given the prevalence of fat consumption during stressful periods among young adults, these findings have important implications for dietary choices to protect the vasculature during periods of stress.

Fat Consumption Attenuates Cortical Oxygenation during Mental Stress in Young Healthy Adults.

Mental stress has been associated with cardiovascular events and stroke, and has also been linked with poorer brain function, likely due to its impact on cerebral vasculature. During periods of stress, individuals often increase their consumption of unhealthy foods, especially high-fat foods. Both high-fat intake and mental stress are known to impair endothelial function, yet few studies have investigated the effects of fat consumption on cerebrovascular outcomes during periods of mental stress. Therefore, this study examined whether a high-fat breakfast prior to a mental stress task would alter cortical oxygenation and carotid blood flow in young healthy adults. In a randomised, counterbalanced, cross-over, postprandial intervention study, 21 healthy males and females ingested a high-fat (56.5 g fat) or a low-fat (11.4 g fat) breakfast 1.5 h before an 8-min mental stress task. Common carotid artery (CCA) diameter and blood flow were assessed at pre-meal baseline, 1 h 15 min post-meal at rest, and 10, 30, and 90 min following stress. Pre-frontal cortex (PFC) tissue oxygenation (near-infrared spectroscopy, NIRS) and cardiovascular activity were assessed post-meal at rest and during stress. Mental stress increased heart rate, systolic and diastolic blood pressure, and PFC tissue oxygenation. Importantly, the high-fat breakfast reduced the stress-induced increase in PFC tissue oxygenation, despite no differences in cardiovascular responses between high- and low-fat meals. Fat and stress had no effect on resting CCA blood flow, whilst CCA diameter increased following consumption of both meals. This is the first study to show that fat consumption may impair PFC perfusion during episodes of stress in young healthy adults. Given the prevalence of consuming high-fat foods during stressful periods, these findings have important implications for future research to explore the relationship between food choices and cerebral haemodynamics during mental stress.

Detrimental effects of physical inactivity on peripheral and brain vasculature in humans: Insights into mechanisms, long-term health consequences and protective strategies.

The growing prevalence of physical inactivity in the population highlights the urgent need for a more comprehensive understanding of how sedentary behaviour affects health, the mechanisms involved and what strategies are effective in counteracting its negative effects. Physical inactivity is an independent risk factor for different pathologies including atherosclerosis, hypertension and cardiovascular disease. It is known to progressively lead to reduced life expectancy and quality of life, and it is the fourth leading risk factor for mortality worldwide. Recent evidence indicates that uninterrupted prolonged sitting and short-term inactivity periods impair endothelial function (measured by flow-mediated dilation) and induce arterial structural alterations, predominantly in the lower body vasculature. Similar effects may occur in the cerebral vasculature, with recent evidence showing impairments in cerebral blood flow following prolonged sitting. The precise molecular and physiological mechanisms underlying inactivity-induced vascular dysfunction in humans are yet to be fully established, although evidence to date indicates that it may involve modulation of shear stress, inflammatory and vascular biomarkers. Despite the steady increase in sedentarism in our societies, only a few intervention strategies have been investigated for their efficacy in counteracting the associated vascular impairments. The current review provides a comprehensive overview of the evidence linking acute and short-term physical inactivity to detrimental effects on peripheral, central and cerebral vascular health in humans. We further examine the underlying molecular and physiological mechanisms and attempt to link these to long-term consequences for cardiovascular health. Finally, we summarize and discuss the efficacy of lifestyle interventions in offsetting the negative consequences of physical inactivity.

Non-pharmacological interventions for vascular health and the role of the endothelium.

The most common non-pharmacological intervention for both peripheral and cerebral vascular health is regular physical activity (e.g., exercise training), which improves function across a range of exercise intensities and modalities. Numerous non-exercising approaches have also been suggested to improved vascular function, including repeated ischemic preconditioning (IPC); heat therapy such as hot water bathing and sauna; and pneumatic compression. Chronic adaptive responses have been observed across a number of these approaches, yet the precise mechanisms that underlie these effects in humans are not fully understood. Acute increases in blood flow and circulating signalling factors that induce responses in endothelial function are likely to be key moderators driving these adaptations. While the impact on circulating factors and environmental mechanisms for adaptation may vary between approaches, in essence, they all centre around acutely elevating blood flow throughout the circulation and stimulating improved endothelium-dependent vascular function and ultimately vascular health. Here, we review our current understanding of the mechanisms driving endothelial adaptation to repeated exposure to elevated blood flow, and the interplay between this response and changes in circulating factors. In addition, we will consider the limitations in our current knowledge base and how these may be best addressed through the selection of more physiologically relevant experimental models and research. Ultimately, improving our understanding of the unique impact that non-pharmacological interventions have on the vasculature will allow us to develop superior strategies to tackle declining vascular function across the lifespan, prevent avoidable vascular-related disease, and alleviate dependency on drug-based interventions.

(-)-Epicatechin and its colonic metabolite hippuric acid protect against dexamethasone-induced atrophy in skeletal muscle cells.

Cocoa flavanols have been shown to improve muscle function and may offer a novel approach to protect against muscle atrophy. Hippuric acid (HA) is a colonic metabolite of (-)-epicatechin (EPI), the primary bioactive compound of cocoa, and may be responsible for the associations between cocoa supplementation and muscle metabolic alterations. Accordingly, we investigated the effects of EPI and HA upon skeletal muscle morphology and metabolism within an in vitro model of muscle atrophy. Under atrophy-like conditions (24h 100µM dexamethasone (DEX)), C2C12 myotube diameter was significantly greater following co-incubation with either 25µM HA (11.19±0.39µm) or 25µM EPI (11.01±0.21µm) compared to the vehicle control (VC; 7.61±0.16µm, both P < .001). In basal and leucine-stimulated states, there was a significant reduction in myotube protein synthesis (MPS) rates following DEX treatment in VC (P = .024). Interestingly, co-incubation with EPI or HA abrogated the DEX-induced reductions in MPS rates, whereas no significant differences versus control treated myotubes (CTL) were noted. Furthermore, co-incubation with EPI or HA partially attenuated the increase in proteolysis seen in DEX-treated cells, preserving LC3 α/ß II:I and caspase-3 protein expression in atrophy-like conditions. The protein content of PGC1α, ACC, and TFAM (regulators of mitochondrial function) were significantly lower in DEX-treated versus. CTL cells (all P < .050). However, co-incubation with EPI or HA was unable to prevent these DEX-induced alterations. For the first time we demonstrate that EPI and HA exert anti-atrophic effects on C2C12 myotubes, providing novel insight into the association between flavanol supplementation and favourable effects on muscle health.

Anthocyanins Promote Learning through Modulation of Synaptic Plasticity Related Proteins in an Animal Model of Ageing.

Anthocyanin-rich foods, such as berries, reportedly ameliorate age-related cognitive deficits in both animals and humans. Despite this, investigation into the mechanisms which underpin anthocyanin-mediated learning and memory benefits remains relatively limited. The present study investigates the effects of anthocyanin intake on a spatial working memory paradigm, assessed via the cross-maze apparatus, and relates behavioural test performance to underlying molecular mechanisms. Six-week supplementation with pure anthocyanins (2% w/w), administered throughout the learning phase of the task, improved both spatial and psychomotor performances in aged rats. Behavioural outputs were accompanied by changes in the expression profile of key proteins integral to synaptic function/maintenance, with upregulation of dystrophin, protein kinase B (PKB/Akt) and tyrosine hydroxylase, and downregulation of apoptotic proteins B-cell lymphoma-extra-large (Bcl-xL) and the phosphorylated rapidly accelerated fibrosarcoma (p-Raf). Separate immunoblot analysis supported these observations, indicating increased activation of extracellular signal-related kinase (ERK1), Akt Ser473, mammalian target of rapamycin (mTOR) Ser2448, activity-regulated cytoskeleton-associated protein (Arc/Arg 3.1) and brain-derived neurotrophic factor (BDNF) in response to anthocyanin treatment, whilst α-E-catenin, c-Jun N-terminal kinase (JNK1) and p38 protein levels decreased. Together, these findings suggest that purified anthocyanin consumption enhances spatial learning and motor coordination in aged animals and can be attributed to the modulation of key synaptic proteins, which support integrity and maintenance of synaptic function.

Cocoa Flavanols Improve Vascular Responses to Acute Mental Stress in Young Healthy Adults.

Mental stress has been shown to induce cardiovascular events, likely due to its negative impact on vascular function. Flavanols, plant-derived polyphenolic compounds, improve endothelial function and blood pressure (BP) in humans, however their effects during stress are not known. This study examined the effects of acute intake of cocoa flavanols on stress-induced changes on vascular function. In a randomised, controlled, double-blind, cross-over intervention study, 30 healthy men ingested a cocoa flavanol beverage (high-flavanol: 150 mg vs. low-flavanol < 4 mg (-)-epicatechin) 1.5 h before an 8-min mental stress task). Forearm blood flow (FBF), BP, and cardiovascular activity were assessed pre- and post-intervention, both at rest and during stress. Endothelial function (brachial flow-mediated dilatation, FMD) and brachial BP were measured before the intervention and 30 and 90 min post-stress. FMD was impaired 30 min post-stress, yet high-flavanol cocoa attenuated this decline and remained significantly higher compared to low-flavanol cocoa at 90 min post-stress. High-flavanol cocoa increased FBF at rest and during stress. Stress-induced cardiovascular and BP responses were similar in both conditions. Flavanols are effective at counteracting mental stress-induced endothelial dysfunction and improving peripheral blood flow during stress. These findings suggest the use of flavanol-rich dietary strategies to protect vascular health during stress.

Corrigendum: Cerebral Hemodynamic and Neurotrophic Factor Responses Are Dependent on the Type of Exercise.

[This corrects the article DOI: 10.3389/fphys.2020.609935.].

Fine wine or sour grapes? A systematic review and meta-analysis of the impact of red wine polyphenols on vascular health.

PURPOSE: Red wine polyphenols (RWP) are plant-based molecules that have been extensively studied in relation to their protective effects on vascular health in both animals and humans. The aim of this review was to quantify and compare the efficacy of RWP and pure resveratrol on outcomes measures of vascular health and function in both animals and humans. METHODS: Comprehensive database searches were carried out through PubMed, Web of Science and OVID for randomised, placebo-controlled studies in both animals and humans. Meta-analyses were carried out on acute and chronic studies of RWP in humans, alongside sub-group analysis where possible. Risk-of-bias assessment was carried out for all included studies based on randomisation, allocation, blinding, outcome data reporting, and other biases. RESULTS: 48 animal and 37 human studies were included in data extraction following screening. Significant improvements in measures of blood pressure and vascular function following RWP were seen in 84% and 100% of animal studies, respectively. Human studies indicated significant improvements in systolic blood pressure overall (- 2.6 mmHg, 95% CI: [- 4.8, - 0.4]), with a greater improvement in pure-resveratrol studies alone (- 3.7 mmHg, 95% CI: [- 7.3, - 0.0]). No significant effects of RWP were seen in diastolic blood pressure or flow-mediated dilation (FMD) of the brachial artery. CONCLUSION: RWP have the potential to improve vascular health in at risk human populations, particularly in regard to lowering systolic blood pressure; however, such benefits are not as prevalent as those observed in animal models.

Electrically stimulated hind limb muscle contractions increase adult hippocampal astrogliogenesis but not neurogenesis or behavioral performance in male C57BL/6J mice.

Regular exercise is crucial for maintaining cognitive health throughout life. Recent evidence suggests muscle contractions during exercise release factors into the blood which cross into the brain and stimulate adult hippocampal neurogenesis. However, no study has tested whether muscle contractions alone are sufficient to increase adult hippocampal neurogenesis and improve behavioral performance. Adult male, C57BL/6J mice were anesthetized and exposed to bilateral hind limb muscle contractions (both concentric and eccentric) via electrical stimulation (e-stim) of the sciatic nerve twice a week for 8 weeks. Each session lasted approximately 20 min and consisted of a total of 40 muscle contractions. The control group was treated similarly except without e-stim (sham). Acute neuronal activation of the dentate gyrus (DG) using cFos immunohistochemistry was measured as a negative control to confirm that the muscle contractions did not activate the hippocampus, and in agreement, no DG activation was observed. Relative to sham, e-stim training increased DG volume by approximately 10% and astrogliogenesis by 75%, but no difference in neurogenesis was detected and no improvement in behavioral performance was observed. E-stim also increased astrogliogenesis in CA1/CA2 hippocampal subfields but not in the cortex. Results demonstrate that muscle contractions alone, in absence of DG activation, are sufficient to increase adult hippocampal astrogliogenesis, but not neurogenesis or behavioral performance in mice.

Dietary flavanols improve cerebral cortical oxygenation and cognition in healthy adults.

Cocoa flavanols protect humans against vascular disease, as evidenced by improvements in peripheral endothelial function, likely through nitric oxide signalling. Emerging evidence also suggests that flavanol-rich diets protect against cognitive aging, but mechanisms remain elusive. In a randomized double-blind within-subject acute study in healthy young adults, we link these two lines of research by showing, for the first time, that flavanol intake leads to faster and greater brain oxygenation responses to hypercapnia, as well as higher performance only when cognitive demand is high. Individual difference analyses further show that participants who benefit from flavanols intake during hypercapnia are also those who do so in the cognitive challenge. These data support the hypothesis that similar vascular mechanisms underlie both the peripheral and cerebral effects of flavanols. They further show the importance of studies combining physiological and graded cognitive challenges in young adults to investigate the actions of dietary flavanols on brain function.

Brain α-Tocopherol Concentration and Stereoisomer Profile Alter Hippocampal Gene Expression in Weanling Mice.

BACKGROUND: Alpha-tocopherol (αT), the bioactive constituent of vitamin E, is essential for fertility and neurological development. Synthetic αT (8 stereoisomers; all rac-αT) is added to infant formula at higher concentrations than natural αT (RRR-αT only) to adjust for bio-potency differences, but its effects on brain development are poorly understood. OBJECTIVES: The objective was to determine the impact of bio-potency-adjusted dietary all rac-αT versus RRR-αT, fed to dams, on the hippocampal gene expression in weanling mice. METHODS: Male/female pairs of C57BL/6J mice were fed AIN 93-G containing RRR-αT (NAT) or all rac-αT (SYN) at 37.5 or 75 IU/kg (n = 10/group) throughout gestation and lactation. Male pups were euthanized at 21 days. Half the brain was evaluated for the αT concentration and stereoisomer distribution. The hippocampus was dissected from the other half, and RNA was extracted and sequenced. Milk αT was analyzed in separate dams. RESULTS: A total of 797 differentially expressed genes (DEGs) were identified in the hippocampi across the 4 dietary groups, at a false discovery rate of 10%. Comparing the NAT-37.5 group to the NAT-75 group or the SYN-37.5 group to the SYN-75 group, small differences in brain αT concentrations (10%; P < 0.05) led to subtle changes (<10%) in gene expression of 600 (NAT) or 487 genes (SYN), which were statistically significant. Marked differences in brain αT stereoisomer profiles (P < 0.0001) had a small effect on fewer genes (NAT-37.5 vs. SYN-37.5, 179; NAT-75 vs. SYN-75, 182). Most of the DEGs were involved in transcription regulation and synapse formation. A network analysis constructed around known vitamin E interacting proteins (VIPs) revealed a group of 32 DEGs between NAT-37.5 vs. SYN-37.5, explained by expression of the gene for the VIP, protein kinase C zeta (Pkcz). CONCLUSIONS: In weanling mouse hippocampi, a network of genes involved in transcription regulation and synapse formation was differentially affected by dam diet αT concentration and source: all rac-αT or RRR-αT.

Cerebral Hemodynamic and Neurotrophic Factor Responses Are Dependent on the Type of Exercise.

This study examined acute cerebral hemodynamic and circulating neurotrophic factor responses to moderate intensity continuous exercise (MICT), guideline-based high intensity interval exercise (HIIT), and sprint interval exercise (SIT). We hypothesized that the pattern of middle cerebral artery velocity (MCAv) response would differ between interval and continuous exercise, with SIT inducing the smallest increase from rest, while increases in neurotrophic factors would be intensity-dependent. In a randomized crossover design, 24 healthy adults (nine females) performed three exercise protocols: (i) MICT (30 min), (ii) HIIT (4 × 4 min at 85% HRmax), and (iii) SIT (4 × 30 s supramaximal). MCAv significantly increased from rest across MICT (Δ13.1 ± 8.5 cm⋅s-1, p < 0.001) and all bouts of HIIT (Δ15.2 ± 9.8 cm⋅s-1, p < 0.001), but only for the initial bout of SIT (Δ17.3 ± 11.6 cm⋅s-1, p < 0.001). Immediately following each interval bout, MCAv increased (i.e., rebounded) for the SIT (9-14% above rest, p ≤ 0.04), but not HIIT protocol. SIT alone induced significant elevations from rest to end-exercise in vascular endothelial growth factor (VEGF; Δ28 ± 36%, p = 0.017) and brain-derived neurotrophic factor (BDNF, Δ149% ± 162%, p < 0.001) and there were greater increases in lactate than in either other protocol (>5-fold greater in SIT, p < 0.001), alongside a small significant reduction at the end of active recovery in insulin-like growth factor 1 (IGF-1, Δ22 ± 21%, p = 0.002). In conclusion, while the nature of the response may differ, both guideline-based and sprint-based interval exercise have the potential to induce significant changes in factors linked to improved cerebrovascular and brain health.

A new perspective of the hippocampus in the origin of exercise-brain interactions.

Exercising regularly is a highly effective strategy for maintaining cognitive health throughout the lifespan. Over the last 20 years, many molecular, physiological and structural changes have been documented in response to aerobic exercise training in humans and animals, particularly in the hippocampus. However, how exercise produces such neurological changes remains elusive. A recent line of investigation has suggested that muscle-derived circulating factors cross into the brain and may be the key agents driving enhancement in synaptic plasticity and hippocampal neurogenesis from aerobic exercise. Alternatively, or concurrently, the signals might originate from within the brain itself. Physical activity also produces instantaneous and robust neuronal activation of the hippocampal formation and the generation of theta oscillations which are closely correlated with the force of movements. The repeated acute activation of the hippocampus during physical movement is likely critical for inducing the long-term neuroadaptations from exercise. Here we review the evidence which establishes the association between physical movement and hippocampal neuronal activation and discuss implications for long-term benefits of physical activity on brain function.

The impact of mechanically stimulated muscle-derived stromal cells on aged skeletal muscle.

Perivascular stromal cells, including mesenchymal stem/stromal cells (MSCs), secrete paracrine factor in response to exercise training that can facilitate improvements in muscle remodeling. This study was designed to test the capacity for muscle-resident MSCs (mMSCs) isolated from young mice to release regenerative proteins in response to mechanical strain in vitro, and subsequently determine the extent to which strain-stimulated mMSCs can enhance skeletal muscle and cognitive performance in a mouse model of uncomplicated aging. Protein arrays confirmed a robust increase in protein release at 24h following an acute bout of mechanical strain in vitro (10%, 1Hz, 5h) compared to non-strain controls. Aged (24month old), C57BL/6 mice were provided bilateral intramuscular injection of saline, non-strain control mMSCs, or mMSCs subjected to a single bout of mechanical strain in vitro (4×104). No significant changes were observed in muscle weight, myofiber size, maximal force, or satellite cell quantity at 1 or 4wks between groups. Peripheral perfusion was significantly increased in muscle at 4wks post-mMSC injection (p<0.05), yet no difference was noted between control and preconditioned mMSCs. Intramuscular injection of preconditioned mMSCs increased the number of new neurons and astrocytes in the dentate gyrus of the hippocampus compared to both control groups (p<0.05), with a trend toward an increase in water maze performance noted (p=0.07). Results from this study demonstrate that acute injection of exogenously stimulated muscle-resident stromal cells do not robustly impact aged muscle structure and function, yet increase the survival of new neurons in the hippocampus.

A unique combination of micronutrients rejuvenates cognitive performance in aged mice.

It is widely believed that diet can influence the onset and severity of cognitive aging, but the optimal combination of micronutrients and molecular and cellular mechanisms remain elusive. The purpose of this study was to compare the effects of eight distinct diets, consisting of various concentrations of selected micronutrients, on learning and memory as well as markers of neuronal plasticity, and metabolic and neuro-immune status of the aged hippocampus. Eighteen-month-old male and female C57BL/6J mice were fed the diets for 16 weeks, followed by learning and memory trials on the active avoidance task. Number of immature neurons were measured by immunohistochemical detection of doublecortin (DCX+) in the granule layer of the dentate gyrus. Amount of mitochondrial DNA (mtDNA) and gene expression of molecular markers of mitochondrial biogenesis (Ppargc1α, Sirt1, Tfam), and neuroinflammation (IL-10, Alox15, Ptgs2, IL-1ß, IL-6 and Tnf) were assessed by quantitative real time polymerase chain reaction (qRT-PCR) of hippocampal samples. Tissue levels of selected micronutrients and a number of metabolites were measured by liquid chromatography-mass spectrometry. The diet supplemented with RRR d-alpha tocopheryl acetate, citicholine, 5-methyltetrahydrofolic acid, quercetin and the n-3 fatty acid phosphatidylserine-docosahexaenoic acid, improved performance on the active avoidance learning and memory task compared to all the other less-complex diets. This diet also increased IL-10 expression and attenuated the age-related change in mtDNA content in the hippocampus without affecting metabolite levels. Results suggest cognitive benefits of wholesome diets are partially mediated through combined antioxidant and anti-inflammatory activities of optimized mixtures of micronutrients.

Long-lasting impairments in adult neurogenesis, spatial learning and memory from a standard chemotherapy regimen used to treat breast cancer.

The negative impact of chemotherapy on cognitive function in cancer patients has gained increasing attention in the last decade. Whilst the short-term acute effects on cognition are expected following chemotherapy, the persistence of such impairments in the long-term is still in question. This is despite clinical evidence indicating cognitive difficulties may persist well beyond treatment and affect quality of life. In the present study, we assessed the long-term (3 months) cognitive impact of chemotherapy in a mouse model intended to mimic the human female post-menopausal population receiving chemotherapy for breast cancer. Ovariectomized, female, C57BL/6J mice received two doses of Doxorubicin, Cyclophosphamide, and 5-Fluorouracil or saline vehicle (control), separated by one week. During this interval, mice received BrdU injections to label dividing cells. Results indicate a persistent impairment in learning and recall (1h, 24h and 48h) on the Morris water maze, reduced survival and differentiation of new neurons (BrdU+/NeuN+), and a persistent decline in proliferation of new cells (Ki67(+)) in the dentate gyrus. Locomotor activity, motor performance, and anxiety-like behavior were unaffected. We further evaluated the efficacy of a diet enriched in omega-3-fatty acids (DHA+EPA+DPA), in reversing long-term chemotherapy deficits but no rescue was observed. The model described produces long-term cognitive and cellular impairments from chemotherapy that mimic those observed in humans. It could be useful for identifying mechanisms of action and to test further the ability of lifestyle interventions (e.g., diet) for ameliorating chemotherapy-induced cognitive impairments.