Caloric restriction and neuropsychiatric phenotypes: A critical review of preclinical data

Caloric restriction (CR) is a dietary intervention with established benefits for physical health and lifespan. However, the effects of CR on behavior and neuropsychiatric phenotypes at a preclinical level remain understudied. Here, we critically reviewed existing literature assessing the impact of CR on neuropsychiatric phenotypes in rodents and identified 41 studies which fulfilled the inclusion criteria. We first establish the multifaceted interplay of diet, brain function and behavior and outline different variations of CR protocols as well as behavioral test batteries to assess diet effects on rodent emotionality. We then discuss findings from the included studies in mice and rats, also considering data from knockout mice and parental CR approaches. To synthesize an integrated hypothesis on how CR affects emotionality, we furthermore evaluate how distinct CR parameters, including protocol duration, severity, age of onset, initiation and parental origin shape CR effects on distinct neuropsychiatric phenotypes, such as anxiety-like and stress-coping behaviors. We report that despite increased CR-induced corticosterone levels, mild CR protocols (<40%) are overall beneficial, while detrimental effects are observed only in severe CR protocols (≥40%), indicating that severe CR is necessary but not sufficient for anxiogenesis. Αt the molecular level, involvement of orexigenic hormone and astrocytic ATP signaling pathways in modulating CR behavioral effects has been suggested, although existing data are limited, while maternal CR is predominantly anxiogenic for the offspring. Finally, we underline the need for targeted investigations in models of psychopathologies and inclusion of both sexes in preclinical rodent CR research to allow optimal translational implementation.