Brain organoids are three-dimensional cultures that contain multiple
types of cells and cytoarchitectures, and resemble fetal human brain
structurally and functionally. These organoids are being used
increasingly to model brain development and disorders, however, they
only partially recapitulate such processes, because of several
limitations, including inability to mimic the distinct cortical layers,
lack of functional neuronal circuitry as well as non-neural cells and
gyrification, and increased cellular stress. Efforts to create improved
brain organoid culture systems have led to region-specific organoids,
vascularized organoids, glia-containing organoids, assembloids, sliced
organoids and polarized organoids. Assembloids are fused region-specific
organoids, which attempt to recapitulate inter-regional and
inter-cellular interactions as well as neural circuitry development by
combining multiple brain regions and/or cell lineages. As a result,
assembloids can be used to model subtle functional aberrations that
reflect complex neurodevelopmental, neuropsychiatric and
neurodegenerative disorders. Mammalian organisms possess a highly
complex neuroendocrine system, the stress system, whose main task is the
preservation of systemic homeostasis, when the latter is threatened by
adverse forces, the stressors. The main central parts of the stress
system are the paraventricular nucleus of the hypothalamus and the locus
caeruleus/norepinephrine-autonomic nervous system nuclei in the
brainstem; these centers innervate each other and interact reciprocally
as well as with various other CNS structures. Chronic dysregulation of
the stress system has been implicated in major pathologies, the
so-called chronic non-communicable diseases, including neuropsychiatric,
neurodegenerative, cardiometabolic and autoimmune disorders, which lead
to significant population morbidity and mortality. We speculate that
brain organoids and/or assembloids could be used to model the
development, regulation and dysregulation of the stress system and to
better understand stress-related disorders. Novel brain organoid
technologies, combined with high-throughput single-cell omics and gene
editing, could, thus, have major implications for precision medicine