Article Figures & Data
Figures
- Figure 1.
The brain is a primary organ that perceives and responds to what is stressful to an individual. The major function of cortisol and other mediators of allostasis is to promote adaptation. However, overuse and/or dysregulation among the mediators of allostasis lead to allostatic load (or overload) and accelerate disease processes such as cardiovascular disease, diabetes, and affective disorders. Three limbic brain regions are noted.
- Figure 2.
Key elements of the limbic HPA. Glucocorticoids feed back to the brain to restrain the stress response. They produce their actions via GRs and MRs, which are generally classified as ligand-dependent transcription factors that are expressed in multiple brain regions, especially the hippocampus. Glucocorticoid effects in the brain involve not only direct and indirect genomic actions, but also direct stimulation of glutamate release and stimulation of endocannabinoid production, which then feed back on glutamate and GABA release and actions in mitochondria to affect Ca2+ buffering and free radical formation. BDNF, in the presence of glucocorticoids, phosphorylates the GR at sites that facilitate its translocation to the cell nucleus for transcriptional actions; this effect is synergistic with the ability of glucocorticoids to promote the phosphorylation of the TrkB receptor independently of BDNF. Table 1 refers to mechanistic studies of mediators and cellular processes that are involved in the remodeling of neurons in hippocampus, amygdala, and prefrontal cortex.
- Figure 3.
Glucocorticoids, excitatory amino acids and other mediators and processes noted in Table 1 operate in a nonlinear, biphasic manner to promote adaptive plasticity, on the one hand, and to impair resilience and promote damage, on the other hand. Lack of resilience in the aftermath of stressful experiences needs external intervention, as is the case for affective disorders.
Tables
- Table 1.
Some molecules implicated in stress-related remodeling in hippocampus, amygdala, and prefrontal cortex
General class Molecule Function References Secreted signaling molecules BDNF Facilitates plasticity or growth
Floor and ceiling effectsChen et al., 2006; Govindarajan et al., 2006; Bath et al., 2013 FGF2 Facilitates neuroplasticity and neurogenesis in development and adulthood Perez et al., 2009 ; Turner et al, 2012 t-PA Mediates stress-induced spine loss in CA1 hippocampus and medial amygdala
t-PA release regulated by CRFPawlak et al., 2003, 2005; Matys et al., 2004; Bennur et al., 2007 Lipocalin-2 secreted protein Induced by acute stress
Lipocalin-2 knockout increases neuronal excitability and anxiety.Mucha et al., 2011; Skrzypiec et al., 2013 Endocannabinoids Induced via glucocorticoids
Regulate emotionality, HPA habituation and turn off
Buffer against stress induced remodelingHill and McEwen, 2010; Hill et al., 2010, 2013; Gunduz-Cinar et al., 2013 CRF after t-PA Stimulates rPA release; mediates plasticity of spine synapses Matys et al., 2004; Regev and Baram, 2014 Cell surface and nucleo–cytoplasmic interactions PSA-NCAM Cell surface “anti-stickiness”
Endonuclease N removes PSA from NCAM; dendrite expansion
Facilitate plasticity but also limits itSandi, 2004; Rutishauser, 2008; McCall et al., 2013; Nacher et al., 2013 Cell adhesion molecules Chronic stress disrupts neuroligin–neurexin interaction
Chronic stress reduces nectin-3 via MMP9 proteasevan der Kooij et al., 2014a,b NUP62 Reduction leads to dendrite shrinkage
Possibly due to nuclear-cytoplasmic communicationKinoshita et al., 2014 t-PA, Tissue plasminogen activator; PSA-NCAM, polysialic acid linked to neural cell adhesion molecule; rPA, raphe pallidus.
Cause References Hippocampal shrinkage Chronic stress Gianaros et al., 2007a,b, 2008, 2014 Major depression Sheline et al., 2019 PTSD Vythilingam et al., 2002; Pitman et al., 2006 Borderline personality disorder Driessen et al., 2000 Cushing's disease Starkman et al., 1992, 1999 Dementia de Leon et al., 1988 Type 2 diabetes Gold et al., 2007; Yau et al., 2012 Chronic inflammation Marsland et al., 2008 Chronic jet lag Cho, 2001 Hippocampal enlargement Exercise Erickson et al., 2011 Intense learning Draganski et al., 2006 The most extensive information about structural plasticity and damage in the human brain exists for hippocampus, but there is also increasing information about such changes in structure, activity and connectivity in human amygdala and prefrontal cortex. For example, the amygdala becomes more active and undergoes structural changes in mood disorders (Price and Drevets, 2010) and to threat in people of low socioeconomic (SES) standing (Gianaros et al., 2008), while low SES was associated with smaller gray matter volume in the dorsal anterior cingulate cortex, reduced myelin content and greater systemic preclinical atherosclerosis and IL-6 (Gianaros et al., 2007a,b, 2014). All of these conditions include increased frequency of mood disorders.
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- Article
- Abstract
- Introduction
- The major neural and molecular elements of the stress system
- How brain and body systems continually interact for brain health and disease
- Experience and the epigenetic life course
- The central role of glucocorticoids and their receptors
- Stress and affective disorders: reverse translation to animal models
- Brain health and the broader social context
- Future directions: the neurobiology of stress as the basic science of affective disorders
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