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Review
, 14 (5), 481-97

Stress Risk Factors and Stress-Related Pathology: Neuroplasticity, Epigenetics and Endophenotypes

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Review

Stress Risk Factors and Stress-Related Pathology: Neuroplasticity, Epigenetics and Endophenotypes

Jason J Radley et al. Stress.

Abstract

This paper highlights a symposium on stress risk factors and stress susceptibility, presented at the Neurobiology of Stress workshop in Boulder, CO, in June 2010. This symposium addressed factors linking stress plasticity and reactivity to stress pathology in animal models and in humans. Dr. J. Radley discussed studies demonstrating prefrontal cortical neuroplasticity and prefrontal control of hypothalamo-pituitary-adrenocortical axis function in rats, highlighting the emerging evidence of the critical role that this region plays in normal and pathological stress integration. Dr. M. Kabbaj summarized his studies of possible epigenetic mechanisms underlying behavioral differences in rat populations bred for differential stress reactivity. Dr. L. Jacobson described studies using a mouse model to explore the diverse actions of antidepressants in brain, suggesting mechanisms whereby antidepressants may be differentially effective in treating specific depression endophenotypes. Dr. R. Yehuda discussed the role of glucocorticoids in post-traumatic stress disorder (PTSD), indicating that low cortisol level may be a trait that predisposes the individual to development of the disorder. Furthermore, she presented evidence indicating that traumatic events can have transgenerational impact on cortisol reactivity and development of PTSD symptoms. Together, the symposium highlighted emerging themes regarding the role of brain reorganization, individual differences, and epigenetics in determining stress plasticity and pathology.

Conflict of interest statement

DECLARATION OF INTEREST

The authors have no conflict of interest.

Figures

Figure 1
Figure 1
Diagram illustrating the effects of chronic stress (3 weeks of restraint) on structural plasticity in mPFC pyramidal neurons. Fluorescent dye-injections of pyramidal neurons were made in the dorsal anterior cingulate (ACd) and prelimbic (PL) areas of the rat. An atlas plate (lower left) depicts the approximate region within mPFC that neurons were filled for morphologic analyses. Distance in millimeters relative to bregma is indicated; adapted from Swanson (1992). Schematic neurons are shown for control (left) and chronic restraint stress (right), with arrows highlighting the fact that dendritic atrophy and spine/excitatory synapse loss is most prominent on distal apical dendrites (right). Also shown in each panel are examples of confocal laser-scanning microscopy images of dendritic segments. fa, forceps anterior, corpus callosum.
Figure 2
Figure 2
Schematic drawing of a sagittal section through the rat basal forebrain highlighting possible circuitry by which the medial prefrontal cortex (mPFC) may influence stress-related hypothalamic paraventricular nucleus (PVH) effector mechanisms. These studies have also established a contingent of GABAergic neurons in anterior bed nucleus of the stria terminalis (aBST) as the likely source of relays for prelimbic cortex (PL) inhibitory influences over acute stress-induced hypothalamo-pituitary-adrenocortical (HPA) axis output. The dashed line from the infralimbic cortex (IL) indicates that the projection has not been formally established. ac, anterior commissure; Ant. Pit., anterior pituitary; ACd, anterior cingulate cortex, dorsal subdivision; aBST, bed nucleus of the stria terminalis, anterior subdivision; cc, corpus callosum; CRH, corticotropin-releasing hormone; mPFC, medial prefrontal cortex; IL, infralimbic area; ot, optic tract; Pre-Auto, preautonomic subdivisions; PVH, paraventricular nucleus of the hypothalamus; PL, prelimbic area.
Figure 3
Figure 3
Proposed role of the anterior bed nucleus of the stria terminalis (aBST) as an integrator of limbic cortical influences during emotional stress-induced hypothalmo-pituitary-adrenocortical (HPA) axis output in the rat. Anatomical and lesion data support the pathways highlighted in red with aBST providing an important source of GABAergic innervation of PVH, and relaying limbic cortical influences from the hippocampal formation (HF) and medial prefrontal cortex (mPFC) (i.e., prelimbic cortex (PL)). The paraventricular thalamic nucleus (PVT) is shown (highlighted in black), as it is known to influence HPA output, notably via glucocorrticoid receptor-mediated negative feedback (Jaferi and Bhatnagar, 2006). Like the ventral subliculum (vSUB) and PL, PVT does not provide any direct innervation of the hypothalamic paraventricular nucleus (PVH), but does issue projections to the aBST. Chronic stress may compromise these inhibitory influences over PVH/HPA output via aBST, manifesting in corticosterone hypersecretion, as evident in depression.
Figure 4
Figure 4
Proposed model for glucocorticoid receptor (GR) -related effects of antidepressant effects on hypothalamo-pituitary-adrenocortical (HPA) axis activity and mood. Representative tricyclic (TCA) (imipramine) and monamine oxidase inhibitor (MAOI)(phenylzine) antidepressants have opposing effects on HPA activity, potentially via opposing effects on GR in feedback sites within the forebrain. The ability of TCA to facilitate and MAOI to impair glucocorticoid feedback could contribute to normalizing HPA activity in melancholic or atypical depression, respectively. The selective serotonin reuptake inhibitor (SSRI) fluoxetine did not exhibit marked effects on HPA activity and is not included in this part of the model. Antidepressants could also regulate mood through direct and indirect effects on GR. TCA, MAOI, and SSRI antidepressants had similar effects to inhibit GR expression and relieve GR-mediated inhibition of monoamine-synthesizing enzymes in the locus coeruleus and dorsal raphé nucleus, which could contribute to the increases in norepinephrine and serotonin thought to be important to antidepressant response. Alternatively or in addition, changes in GR in HPA feedback-related regions (observed primarily for TCA and MAOI) could indirectly affect glucocorticoid-sensitive mood centers by raising or lowering glucocorticoid levels.

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