Stress is linked to a wide variety of psychological and somatic ailments, including affective diseases (such as depression) and post-traumatic stress disorder. In recent years it has become increasingly clear that the impact of stress on pathology varies substantially from individual to individual (McEwen & Stellar, 1993; Radley et al., 2011). Defining mechanisms underlying individual differences is crucial to understanding the biological basis of stress control and using this knowledge to develop treatment strategies for stress-related diseases. This issue of European Journal of Neuroscience, Knapman et al. (2012) use state-of-the-art imaging methods and proteomics to explore neural events associated with differential stress reactivity in strains of mice selected for low, intermediate and high stress reactivity, as defined by the magnitude of corticosteroid responses to acute stressors. The strain with the greatest corticosterone reactivity to stress has memory deficits that are accompanied by lateralized reductions in hippocampal N-acetyl aspartate (NAA), reduced basal activity in the hippocampus and alterations in expression of hippocampal proteins regulating cellular energy metabolism. The data indicate a novel connection between susceptibility to stress and hippocampal (and perhaps cortical) metabolic function, suggesting mitochondrial dysfunction as a possible mechanism for stress vulnerability and, by extension, stress-related disease processes.
It is generally recognized that animal models of psychiatric disorders are problematic. The (always limited) validity of a model will depend on how well it matches the human disorder. For psychiatric disorders, features related to brain structure, metabolism and function will obviously be of primary relevance and interest. Beyond the implications for individual differences, this work demonstrates the power of advanced magnetic resonance techniques to probe in vivo metabolism and neuronal activity. NAA is now generally accepted as a relatively non-specific marker of neuronal integrity and mitochondrial metabolism (de Graaf, 2007). The value of magnetic resonance spectroscopy (MRS) lies in its ability to measure NAA (and several other major metabolites not probed in the present work) non-invasively and longitudinally in brain in both humans and animal models under a variety of parallel diagnostic criteria and treatment conditions. Longitudinal measures are of particular relevance for mechanistic approaches in animals, where one can achieve ‘before and after’ measurements associated with experimental interventions or genetic manipulations. Moreover, metabolic and functional measures may become clinically relevant at the early stages of a neurochemical disorder, before volume changes in the brain are apparent. Beyond MRS, manganese-enhanced magnetic resonance imaging, although not likely to be applicable to human studies, is becoming a useful adjunct to anatomical magnetic resonance imaging (Inoue et al., 2011) that can provide a crude but unique measure of the functional status of neuronal pathways. Studies like that of Knapman et al. (2012) can bridge the gap between detailed biochemical/proteomic analysis in animal models and dynamic functional/metabolic measures in the human brain.