Prolonged stress can cause psychological disorders and brain dysfunction. However, it is controversial whether this also increases the risk of developing a neurodegenerative disease such as Alzheimer's or Parkinson's in old age.
A very early and particularly stressful situation occurs when a baby or toddler is separated from its mother, for example, during the transition to daycare. Depending on the age, this situation can lead to permanent damage, which is particularly visible in social behavior and memory functions. It is now considered certain that young children who are separated from their mother or central attachment figure too early and too suddenly and for too long carry an increased risk that their personality development will be damaged. Other causes would be recurrent experiences of violence or neglect.
Whether these children are more likely than others to develop dementia during their lifetime needs to be clarified in larger prospective studies in the future. The data available to date are based on retrospective cohort studies and are therefore subject to some uncertainty.
In today's blog, I would like to discuss stress-induced changes in the brain that have been collected in animal models of maternal separation and provide an indication that it is not primarily the neurons but the glial cells that are altered by high levels of stress hormones. As a consequence, neurons located in particular in the temporal or temporal lobe of our brain will be damaged. The inner (medial) parts of this brain area, which makes up a major part of the limbic system, react very sensitively to disturbances of various kinds. These are primarily the hippocampus and the entorhinal cortex close to it.
The temporal lobe contains developmentally old structures that are more easily damaged by stress hormones than other regions. This is mainly due to cortisol, which is released from the adrenal gland during severe psychological stress. Chronically elevated levels of this hormone lead to neuronal degeneration. After severe post-traumatic stress disorder, for example, the volume of the hippocampus and the cingulate gyrus is reduced. The latter is a large brain convolution located above the major commissural fiber tracts (see figure below). Interestingly, after 5-10 years, affected individuals have twice the risk of dementia compared to individuals who have not experienced severe psychological trauma.
In the depth of the brain lies the limbic system running in the form of an arc around the diencephalon (limbus is the edge, fornix the arc, MK = mamillary body). Above the fornix is the corpus callosum, the largest connection (commissure) of the two hemispheres. The neocortex is developmentally younger and, with 6 layers, more complex in construction than the three-layered hippocampus, the archicortex (Fig. 1.3 from Klimaschewski L.P. , Parkinson's and Alzheimer's diseases today. Springer, 2021).
In animal models of Alzheimer's disease, i.e., genetically modified mice with increased deposition of Aβ-amyloid, separation stress (removal from the dam for 3 hours daily for 2 weeks after birth) results in impaired spatial memory, increased microglial activation, and disruption of the blood-brain barrier. There is vasoconstriction and a reduced number of pericytes, which normally rest on the capillaries and regulate their width. The resulting decreased clearance of Aβ-peptides and other proteins leads to increased fibrin formation, causing microinfarcts and secondary inflammatory changes. These neuropathological changes observed in animal models can also be regularly observed in Alzheimer's patients. As Haruo Okado's research group found last year, separation from the dam alone leads to increased cortisol release and activation of microglial cells in the young without, however, causing vascular damage or Aβ deposition. Thus, the latter are observed only in those mice genetically predisposed to Alzheimer-like pathology.
In another research study, an interdisciplinary team of scientists at the Institute of Microscopic Anatomy and Neurobiology at Mainz University Hospital was able to show that early childhood stress experiences can also have a long-lasting effect on the so-called NG2 glial cells, precursors of oligodendrocytes that form myelin sheaths. Giulia Treccani's team found a link between stress-induced cortisol release in young animals and altered gene expression in NG2 glial cells in the hippocampus. They identified a gene encoding a subunit of an ion channel (Scn7a, sodium channel protein type 7 subunit alpha). In the stressed animals, this increased the current density of voltage-activated sodium channels. Since decreased cognitive abilities were later detectable in the adult animals, the authors of this work assume impaired communication between the NG2 glial cells and neurons leading to delayed brain maturation.
The described morphological and functional changes are not only detectable in the hippocampus of experimental animals, but also in the prefrontal cortex located behind the forehead. Here, reduced dendrite trees on neurons and a decrease in synaptic contacts were observed, which interfere with the formation of neuronal networks. In older age, these cortical areas are particularly sensitive to secondary damage, which occurs, for example, as a consequence of circulatory disturbances.
However, when transferring the results presented here from animals to humans, it must be taken into account that there is a large phylogenetic distance between mice and humans (the common ancestor lived about 70 million years ago). Furthermore, a variety of genetic and environmental variables exist that can cause neurodegeneration during human life or bring forward its onset. However, the effects of early childhood stress on brain development and on elevating the risk of developing personality and memory disorders at an early age have become increasingly clear in recent years.
References:
Short AK, Baram TZ. Early-life adversity and neurological disease: age-old questions and novel answers. Nature Reviews Neurology, 2019, 15:657
Treccani G, Yigit H, Lingner T, Schleuβner V, Mey F, van der Kooij MA, et al. Early life adversity targets the transcriptional signature of hippocampal NG2+ glia and affects voltage gated sodium (Nav) channels properties. Neurobiology of Stress, 2021, 15:100338.
Tanaka T, Hirai S, Hosokawa M, Saito T, Sakuma H, Saido T, et al. Early-life stress induces the development of Alzheimer's disease pathology via angiopathy. Experimental Neurology, 2021, 337:113552.
Catale C, Carola V, Viscomi M. Early life stress-induced neuroinflammation and neurological disorders: a novel perspective for research. Neural Regeneration Research, 2022, 17:1971
Image credit: iStock/Jatuporn Tansirimas
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