ABSTRACT
Dogs develop cognitive decline and a progressive accumulation of oxidative damage. In a previous longitudinal study, we demonstrated that aged dogs treated with either an antioxidant diet or with behavioral enrichment show cognitive improvement. The antioxidant diet included cellular antioxidants (vitamins E and C, fruits and vegetables) and mitochondrial cofactors (lipoic acid and carnitine). Behavioral enrichment consisted of physical exercise, social enrichment, and cognitive training. We hypothesized that the antioxidant treatment improved neuronal function through increased mitochondrial function. Thus, we measured reactive oxygen species (ROS) production and bioenergetics in mitochondria isolated from young, aged, and treated aged animals. Aged canine brain mitochondria show significant increases in ROS production and a reduction in NADH-linked respiration. Mitochondrial function (ROS and NADH-linked respiration) was improved selectively in aged dogs treated with an antioxidant diet. In contrast, behavioral enrichment had no effect on any mitochondrial parameters. These results suggest that an antioxidant diet improves cognition by maintaining mitochondrial homeostasis, which may be an independent molecular pathway not engaged by behavioral enrichment.
Subject(s)
Aging/metabolism , Brain/metabolism , Food, Formulated , Memory Disorders/diet therapy , Memory Disorders/metabolism , Mitochondria/metabolism , Aging/drug effects , Aging/pathology , Animals , Antioxidants/pharmacology , Antioxidants/therapeutic use , Behavior, Animal/drug effects , Behavior, Animal/physiology , Brain/drug effects , Brain/physiopathology , Coenzymes/pharmacology , Coenzymes/therapeutic use , Cognitive Behavioral Therapy/methods , Disease Models, Animal , Dogs , Environment, Controlled , Exercise Therapy/methods , Female , Humans , Male , Memory Disorders/physiopathology , Mitochondria/drug effects , Oxidative Stress/drug effects , Oxidative Stress/physiology , Physical Conditioning, Animal/methods , Treatment OutcomeABSTRACT
The effects of stress, including their putative contribution to pathological psychiatric conditions, are crucially governed by the age at which the stress takes place. However, the cellular and molecular foundations for the impact of stress on neuronal function, and their change with age, are unknown. For example, it is not known whether 'psychological' stress signals are perceived by similar neuronal populations at different ages, and whether they activate similar or age-specific signaling pathways that might then mediate the spectrum of stress-evoked neuronal changes. We employed restraint and restraint/noise stress to address these issues in juvenile (postnatal day 18, [P18]) and adult rats, and used phosphorylation of the transcription factor CREB (pCREB) and induction of c-fos as markers of hippocampal neuronal responses. Stress-activated neuronal populations were identified both anatomically and biochemically, and selective blockers of the stress-activated hippocampal peptide, corticotropin-releasing hormone (CRH) were used to probe the role of this molecule in stress-induced hippocampal cell activation. Stress evoked strikingly different neuronal response patterns in immature vs adult hippocampus. Expression of pCREB appeared within minutes in hippocampal CA3 pyramidal cells of P18 rats, followed by delayed induction of Fos protein in the same cell population. In contrast, basal pCREB levels were high in adult hippocampus and were not altered at 10-120 min by stress. Whereas Fos induction was elicited by stress in the adult, it was essentially confined to area CA1, with little induction in CA3. At both age groups, central pretreatment with either a nonselective blocker of CRH receptors (alpha-helical CRH [9-41]) or the CRF1-selective antagonist, NBI 30775, abolished stress-evoked neuronal activation. In conclusion, hippocampal neuronal responses to psychological stress are generally more rapid and robust in juvenile rats, compared to fully mature adults, and at both ages, CRH plays a key role in this process. Enhanced hippocampal response to stress during development, and particularly the activation of the transcription factor CREB, may contribute to the enduring effects of stress during this period on hippocampal function.
