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Females and males typically play different roles in survival of the species and would be expected to respond differently to food scarcity or excess. To elucidate the physiological basis of sex differences in responses to energy intake, we maintained groups of male and female rats for 6 months on diets with usual, reduced [20% and 40% caloric restriction (CR), and intermittent fasting (IF)], or elevated (high-fat/high-glucose) energy levels and measured multiple physiological variables related to reproduction, energy metabolism, and behavior. In response to 40% CR, females became emaciated, ceased cycling, underwent endocrine masculinization, exhibited a heightened stress response, increased their spontaneous activity, improved their learning and memory, and maintained elevated levels of circulating brain-derived neurotrophic factor. In contrast, males on 40% CR maintained a higher body weight than the 40% CR females and did not change their activity levels as significantly as the 40% CR females. Additionally, there was no significant change in the cognitive ability of the males on the 40% CR diet. Males and females exhibited similar responses of circulating lipids (cholesterols/triglycerides) and energy-regulating hormones (insulin, leptin, adiponectin, ghrelin) to energy restriction, with the changes being quantitatively greater in males. The high-fat/high-glucose diet had no significant effects on most variables measured but adversely affected the reproductive cycle in females. Heightened cognition and motor activity, combined with reproductive shutdown, in females may maximize the probability of their survival during periods of energy scarcity and may be an evolutionary basis for the vulnerability of women to anorexia nervosa.

Chronic manganese (Mn) exposure produces a neurological syndrome with psychiatric, cognitive, and parkinsonian features. Gene expression profiling in the frontal cortex of Cynomologous macaques receiving 3.3-5.0 mg Mn/kg weekly for 10 months showed that 61 genes were increased and four genes were decreased relative to controls from a total of 6766 genes. Gene changes were associated with cell cycle regulation, DNA repair, apoptosis, ubiquitin-proteasome system, protein folding, cholesterol homeostasis, axonal/vesicular transport, and inflammation. Amyloid-b (Ab) precursor-like protein 1, a member of the amyloid precursor protein family, was the most highly up-regulated gene. Immunohistochemistry confirmed increased amyloid precursor-like protein 1 protein expression and revealed the presence of diffuse Ab plaques in Mn-exposed frontal cortex. Cortical neurons and white matter fibers from Mn-exposed animals accumulated silver grains indicative of on-going degeneration. Cortical neurons also exhibited nuclear hypertrophy, intracytoplasmic vacuoles, and apoptosis stigmata. p53 immunolabeling was increased in the cytoplasm of neurons and in the nucleus and processes of glial cells in Mn-exposed tissue. In summary, chronic Mn exposure produces a cellular stress response leading to neurodegenerative changes and diffuse Ab plaques in the frontal cortex. These changes may explain the subtle cognitive deficits previously demonstrated in these same animals. Keywords: Alzheimer's disease, amyloid-b, amyloid-b precursor-like protein 1, manganese, neurodegeneration, nonhuman primates, p53. J. Neurochem. (2008) 105, 1948-1959. JOURNAL OF NEUROCHEMISTRY | 2008 | 105 | 1948-1959 doi: 10.1111/j.1471-4159.2008 Klos et al. 2006b) that may persist long after cessation of exposure (Bouchard et al. 2007). An association between environmental exposure to Mn and deficits in measures of intellectual functioning has also been described in children (Takser et al. 2003;Wasserman et al. 2006). It has been suggested that chronic exposure to elevated levels of Mn may alter cognitive domains mediated by the frontal cortex and subcortical structures (Josephs et al. 2005). However, there is relatively little or no information on Mn-induced effects on brain structures outside of the basal ganglia. The present study is part of an on-going multidisciplinary effort to characterize the neurological consequences of chronic exposure to Mn in non-human primates. The monkeys described in this communication have been previously shown to have subtle deficits in cognitive function and fine motor control (Schneider et al. 2006). They exhibit decreased levels of amphetamine-induced dopamine release in the striatum measured by positron emission tomography (Guilarte et al. 2006a) and decreased cerebral cortex N-acetylaspartate/creatine ratio measured by magnetic resonance spectroscopy indicative of neuronal loss or dysfunction (Guilarte et al. 2006b). We now present new evidence that in the frontal cortex of these same animals, Mn exposure produces ...

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