Linking cerebral metabolic function to stress vulnerability (Commentary on Knapman et al.).
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ABSTRACT: Patients suffering from major depression have repeatedly been reported to have dysregulations in hypothalamus-pituitary-adrenal (HPA) axis activity along with deficits in cognitive processes related to hippocampal and prefrontal cortex (PFC) malfunction. Here, we utilized three mouse lines selectively bred for high (HR), intermediate, or low (LR) stress reactivity, determined by the corticosterone response to a psychological stressor, probing the behavioral and functional consequences of increased vs. decreased HPA axis reactivity on the hippocampus and PFC. We assessed performance in hippocampus- and PFC-dependent tasks and determined the volume, basal activity, and neuronal integrity of the hippocampus and PFC using in vivo manganese-enhanced magnetic resonance imaging and proton magnetic resonance spectroscopy. The hippocampal proteomes of HR and LR mice were also compared using two-dimensional gel electrophoresis and mass spectrometry. HR mice were found to have deficits in the performance of hippocampus- and PFC-dependent tests and showed decreased N-acetylaspartate levels in the right dorsal hippocampus and PFC. In addition, the basal activity of the hippocampus, as assessed by manganese-enhanced magnetic resonance imaging, was reduced in HR mice. The three mouse lines, however, did not differ in hippocampal volume. Proteomic analysis identified several proteins that were differentially expressed in HR and LR mice. In accordance with the notion that N-acetylaspartate levels, in part, reflect dysfunctional mitochondrial metabolism, these proteins were found to be involved in energy metabolism pathways. Thus, our results provide further support for the involvement of a dysregulated HPA axis and mitochondrial dysfunction in the etiology and pathophysiology of affective disorders.European Journal of Neuroscience 02/2012; 35(3):412-22. · 3.67 Impact Factor
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ABSTRACT: Manganese ion (Mn(2+)) is a calcium (Ca(2+)) analog that can enter neurons and other excitable cells through voltage gated Ca(2+) channels. Mn(2+) is also a paramagnetic that shortens the spin-lattice relaxation time constant (T(1)) of tissues where it has accumulated, resulting in positive contrast enhancement. Mn(2+) was first investigated as a magnetic resonance imaging (MRI) contrast agent approximately 20 years ago to assess the toxicity of the metal in rats. In the late 1990s, Alan Koretsky and colleagues pioneered the use of manganese enhanced MRI (MEMRI) towards studying brain activity, tract tracing and enhancing anatomical detail. This review will describe the methodologies and applications of MEMRI in the following areas: monitoring brain activity in animal models, in vivo neuronal tract tracing and using MEMRI to assess in vivo axonal transport rates.Reviews in the neurosciences 11/2011; 22(6):675-94. · 3.31 Impact Factor
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ABSTRACT: This article presents a new formulation of the relationship between stress and the processes leading to disease. It emphasizes the hidden cost of chronic stress to the body over long time periods, which act as a predisposing factor for the effects of acute, stressful life events. It also presents a model showing how individual differences in the susceptibility to stress are tied to individual behavioral responses to environmental challenges that are coupled to physiologic and pathophysiologic responses. Published original articles from human and animal studies and selected reviews. Literature was surveyed using MEDLINE. Independent extraction and cross-referencing by us. Stress is frequently seen as a significant contributor to disease, and clinical evidence is mounting for specific effects of stress on immune and cardiovascular systems. Yet, until recently, aspects of stress that precipitate disease have been obscure. The concept of homeostasis has failed to help us understand the hidden toll of chronic stress on the body. Rather than maintaining constancy, the physiologic systems within the body fluctuate to meet demands from external forces, a state termed allostasis. In this article, we extend the concept of allostasis over the dimension of time and we define allostatic load as the cost of chronic exposure to fluctuating or heightened neural or neuroendocrine response resulting from repeated or chronic environmental challenge that an individual reacts to as being particularly stressful. This new formulation emphasizes the cascading relationships, beginning early in life, between environmental factors and genetic predispositions that lead to large individual differences in susceptibility to stress and, in some cases, to disease. There are now empirical studies based on this formulation, as well as new insights into mechanisms involving specific changes in neural, neuroendocrine, and immune systems. The practical implications of this formulation for clinical practice and further research are discussed.Archives of Internal Medicine 10/1993; 153(18):2093-101. · 13.25 Impact Factor
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