Dysfunction in neural circuits involved in the pathophysiology of mood disordersPostmortem studies in mood disorders indicate altered numbers of neurons and glial cells
Section snippets
Stress and morphopathology of depression
Cortical regions such as the hippocampus (limbic archicortex) and prefrontal cortex (PFC; association neocortex) have been implicated in the neuropathology of depression and the response to stress. Reductions in the volume of the hippocampus are reported in subjects with a history of depression Bremner et al 2000, Krishnan et al 1991, Shah et al 1998, Sheline et al 1996, Shankaranarayana Rao et al 1999. Interestingly, the loss of hippocampal volume is correlated with the total lifetime duration
Evidence for involvement of the prefrontal cortex in the neuropathology of depression
Several lines of evidence suggest that the PFC is involved in the neuropathology of major depressive disorder (MDD) and bipolar disorder (BPD, manic–depressive). In both MDD and BPD abnormal symptoms such as disturbances of social behavior, depressed moods, and deficits in working memory suggest pathophysiologic involvement of the PFC. Direct evidence obtained from neuroimaging studies further suggests that the PFC may be a common site of neuropathology in mood disorders. In BPD and MDD the PFC
Cell pathology in depression
Recent postmortem studies demonstrate that mood disorders are characterized by specific histopathologic changes in both neurons and glial cells. These alterations at the microscopic level may give rise to the volume reductions and metabolic abnormalities reported in mood disorders in neuroimaging studies and contribute to identifying dysfunctional neuronal circuits and their cellular components in these disorders.
Two independent postmortem studies morphometrically estimated cell number and
Cell loss versus cell atrophy
Recent postmortem studies reveal several patterns of morphometric cellular changes in mood disorders: cell loss (subgenual prefrontal cortex), cell atrophy (and possibly cell loss, dlPFC and ORB), or increased numbers of cells (hypothalamus, dorsal raphe nucleus) are reported.
Loss of glial but not neuronal cells is observed in mood disorders in the subgenual prefrontal region, whereas lamina-specific reductions in the density of both neurons and glia are reported in the dlPFC and ORB regions in
Neuron–glia interactions
The cellular changes described here indicate that both types of brain cells, neurons and glia, are abnormal in mood disorders. The question remains whether depressed patients are genetically predisposed for the cellular changes detected postmortem and had smaller neurons and/or less glia from birth, or whether the cellular changes are a consequence of MDD. Alternatively, those genetically predisposed to the greatest histopathologic alterations may exhibit a greater vulnerability to depression.
Cellular changes and prolonged PFC development
The most pronounced reductions in neuronal density in MDD and BPD are observed in superficial prefrontal layers II and III in both mood disorders. Neurons of these layers show greater plasticity than neurons of deep layers V and VI due to their late neurogenesis and extremely prolonged postnatal development. The prolonged postnatal development may render these neurons more susceptible to environmental factors related to the appearance of depression. The maturation and stabilization of neural
Neurotrophic/neuroprotective factors and cell pathology
Experimental data with in situ hybridization histochemistry indicate that the development of cortical neuronal circuits may be related to the expression of specific target-derived neurotrophic factors such as brain-derived neurotrophic factor (BDNF; Huntley et al 1992). Expression of BDNF mRNA increases during later stages of prefrontal cortical development and continues into adulthood Friedman et al 1991, Maisonpierre et al 1990, and the deprivation of neurotrophic factors activates cell death
A link between cellular changes and the action of therapeutic drugs
The neurotrophins and monoamine neurotransmitters appear to play related roles in stress, depression, and therapies for treating depression. From animal studies reporting that stress and antidepressant treatments regulate specific neurotrophin-related target genes within the central nervous system, it has been proposed that, in individuals genetically predisposed to clinical depression, cellular changes may be related to stress-induced changes in neurotrophin-related intracellular mechanisms
Acknowledgements
The work reviewed here was supported by a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award and a NARSAD Independent Investigator Award, National Institute of Mental Health Grant No. 55872, and the American Foundation for Suicide Prevention.
The author thanks Craig Stockmeier, Ph.D., for helpful comments on the manuscript and editorial assistance.
Aspects of this work were presented at the conference “Depression in the Twenty-First Century: New
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