Parkinson's disease (PD) patients often exhibit impaired regulation of heart rate by the autonomic nervous system (ANS) that may precede motor symptoms in many cases. Results of autopsy studies suggest that brainstem pathology, including the accumulation of -synuclein, precedes damage to dopaminergic neurons in the substantia nigra in PD. However, the molecular and cellular mechanisms responsible for the early dysfunction of brainstem autonomic neurons are unknown. Here we report that mice expressing a mutant form of synuclein that causes familial PD exhibit aberrant autonomic control of the heart characterized by elevated resting heart rate and an impaired cardiovascular stress response, associated with reduced parasympathetic activity and accumulation of synuclein in the brainstem. These ANS abnormalities occur early in the disease process. Adverse effects of synuclein on the control of heart rate are exacerbated by a high energy diet and ameliorated by intermittent energy restriction. Our findings establish a mouse model of early dysregulation of brainstem control of the cardiovascular system in PD, and further suggest the potential for energy restriction to attenuate ANS dysfunction, particularly in overweight individuals. In another study we found that mortality from focal ischemic stroke was increased with advancing age and reduced by an intermittent fasting (IF) diet. Brain damage and functional impairment were reduced by IF in young and middle-aged mice, but not in old mice. The basal and poststroke levels of neurotrophic factors (brain-derived neurotrophic factor and basic fibroblast growth factor), protein chaperones (heat shock protein 70 and glucose regulated protein 78), and the antioxidant enzyme heme oxygenase-1 were decreased, whereas levels of inflammatory cytokines were increased in the cerebral cortex and striatum of old mice compared with younger mice. IF coordinately increased levels of protective proteins and decreased inflammatory cytokines in young, but not in old mice. We further found that intermittent fasting suppresses activation of the so-called 'inflammasome' in brain cells, which was associated with improved functional outcome in the mouse stroke model. We conclude that dietary energy intake differentially modulates neurotrophic and inflammatory pathways to protect neurons against ischemic injury, and these beneficial effects of IF are compromised during aging, resulting in increased brain damage and poorer functional outcome. The 3xTgAD mouse model was used to test the hypothesis that a ketone ester-based diet can ameliorate AD pathogenesis. Beginning at a presymptomatic age, 2 groups of male 3xTgAD mice were fed a diet containing a physiological enantiomeric precursor of ketone bodies (KET) or an isocaloric carbohydrate diet. The results of behavioral tests performed at 4 and 7 months after diet initiation revealed that KET-fed mice exhibited significantly less anxiety in 2 different tests. 3xTgAD mice on the KET diet also exhibited significant, albeit relatively subtle, improvements in performance on learning and memory tests. Immunohistochemical analyses revealed that KET-fed mice exhibited decreased Abeta; deposition in the subiculum, CA1 and CA3 regions of the hippocampus, and the amygdala. KET-fed mice exhibited reduced levels of hyperphosphorylated tau deposition in the hippocampus and amygdala. These findings demonstrate a therapeutic benefit of a diet containing a ketone ester in a mouse model of Alzheimer's disease. The impact of dietary factors on brain health and vulnerability to disease is increasingly appreciated. The results of epidemiological studies, and intervention trials in animal models suggest that diets rich in phytochemicals can enhance neuroplasticity and resistance to neurodegeneration. Here we describe how interactions of plants and animals during their co-evolution, and resulting reciprocal adaptations, have shaped the remarkable characteristics of phytochemicals and their effects on the physiology of animal cells in general, and neurons in particular. Based on our own research and evolutionary considerations, we developed a novel hypothesis to explain the beneficial effects of diets rich in fruits and vegetables on health, including brain health. Plants do not have the option of fleeing predators. As a consequence, they have developed an elaborate set of chemical defenses to ward off insects and other creatures that want to make them into a meal. Toxins that plants use against predators are consumed by us at low levels in fruits and vegetables. Exposure to these chemicals causes a mild stress reaction that lends resilience to cells in our bodies. Adaptation to these stresses, a process called hormesis, accounts for a number of health benefits, including protection against brain disorders, that we receive from eating vegetables and fruits. Survival advantages were conferred upon plants capable of producing noxious bitter-tasting chemicals, and on animals able to tolerate the phytochemicals and consume the plants as an energy source. The remarkably diverse array of phytochemicals present in modern fruits, vegetables spices, tea and coffee may have arisen, in part, from the acquisition of adaptive cellular stress responses and detoxification enzymes in animals that enabled them to consume plants containing potentially toxic chemicals. Interestingly, some of the same adaptive stress response mechanisms that protect neurons against noxious phytochemicals are also activated by dietary energy restriction and vigorous physical exertion, two environmental challenges that shaped brain evolution. We have elucidated some of the signaling pathways relevant to cellular energy metabolism that are modulated by 'neurohormetic phytochemicals' (potentially toxic chemicals produced by plants that have beneficial effects on animals when consumed in moderate amounts). We highlight the cellular bioenergetics-related sirtuin, adenosine monophosphate activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and insulin-like growth factor 1 (IGF-1) pathways. The inclusion of dietary neurohormetic phytochemicals in an overall program for brain health that also includes exercise and energy restriction may find applications in the prevention and treatment of a range of neurological disorders.

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Mattson, Mark P; Moehl, Keelin; Ghena, Nathaniel et al. (2018) Intermittent metabolic switching, neuroplasticity and brain health. Nat Rev Neurosci 19:63-80
Raefsky, Sophia M; Furman, Ran; Milne, Ginger et al. (2018) Deuterated polyunsaturated fatty acids reduce brain lipid peroxidation and hippocampal amyloid ?-peptide levels, without discernable behavioral effects in an APP/PS1 mutant transgenic mouse model of Alzheimer's disease. Neurobiol Aging 66:165-176
Hou, Yujun; Lautrup, Sofie; Cordonnier, Stephanie et al. (2018) NAD+ supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci U S A 115:E1876-E1885
Mattson, Mark P; Arumugam, Thiruma V (2018) Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States. Cell Metab 27:1176-1199
Nigam, Saket M; Xu, Shaohua; Kritikou, Joanna S et al. (2017) Exercise and BDNF reduce A? production by enhancing ?-secretase processing of APP. J Neurochem 142:286-296
Raefsky, Sophia M; Mattson, Mark P (2017) Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance. Free Radic Biol Med 102:203-216
McGee-Lawrence, Meghan E; Wenger, Karl H; Misra, Sudipta et al. (2017) Whole-Body Vibration Mimics the Metabolic Effects of Exercise in Male Leptin Receptor-Deficient Mice. Endocrinology 158:1160-1171
Liu, Yong; Zhou, Li-Jun; Wang, Jun et al. (2017) TNF-? Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury. J Neurosci 37:871-881
Yao, Pamela J; Manor, Uri; Petralia, Ronald S et al. (2017) Sonic hedgehog pathway activation increases mitochondrial abundance and activity in hippocampal neurons. Mol Biol Cell 28:387-395
Mattson, Mark P; Longo, Valter D; Harvie, Michelle (2017) Impact of intermittent fasting on health and disease processes. Ageing Res Rev 39:46-58

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