Linking cerebral metabolic function to stress
vulnerability (Commentary on Knapman et al.)
James P. Herman,1Diana Lindquist2and Richard A. Komoroski1,3
1Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH 45237, USA
2Department of Radiology, Imaging Research Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
3Center for Imaging Research, University of Cincinnati, Cincinnati, OH, USA
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.
de Graaf, R.A. (2007) In vivo NMR Spectroscopy. Principles and Techniques. Wiley, Chichester.
Inoue, T., Majid, T. & Pautler, R.G. (2011) Manganese enhanced MRI (MEMRI): neurophysiological applications. Rev. Neurosci., 22, 675–694.
Knapman, A., Kaltwasser, S., Martins-de-Souza, D., Holsboer, F., Landgraf, R., Turck, C., Czisch, M. & Touma, C. (2012) Increased stress reactivity is associated
with reduced hippocampal activity and neuronal integrity along with changes in energy metabolism. Eur. J. Neurosci., 35, 412–422.
McEwen, B.S. & Stellar, E. (1993) Stress and the individual. Mechanisms leading to disease. Arch. Intern. Med., 153, 2093–2101.
Radley, J.J., Kabbaj, M., Jacobson, L., Heydendael, W., Yehuda, R. & Herman, J.P. (2011) Stress risk factors and stress-related pathology: neuroplasticity,
epigenetics and endophenotypes. Stress, 14, 481–497.
European Journal of Neuroscience, Vol. 35, pp. 411, 2012
ª 2012 The Authors. European Journal of Neuroscience ª 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd
European Journal of Neuroscience