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and exhibit complex cortical folding. Notably, human cultures. Advances in genetic engineering, particularly
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3
brains possess unique structures such as the inner fiber CRISPR-Cas9 technology, have enabled the generation of
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layer and the outer subventricular zone (oSVZ), which organoid models with specific mutations linked to NDDs.
harbor intermediate progenitor cells and outer radial These models have provided crucial insights into how
glial cells (oRGCs). These structures, absent from genetic alterations disrupt brain development and function.
4,5
rodents, play a crucial role in cortical expansion and The integration of high-resolution imaging, single-cell
neurogenesis. Given these distinctions, the development of RNA sequencing (scRNA-seq), and electrophysiological
humanized model systems that accurately replicate human approaches has further expanded the potential of brain
neurodevelopmental processes remains a critical area of organoids in studying disease mechanisms. Techniques
research. such as calcium imaging, patch-clamp recordings, and
Primary human brain tissue, typically obtained from multi-electrode arrays allow for the investigation of
surgical procedures or electively terminated fetuses, serves synaptic activity and network connectivity, shedding light
as a valuable model for studying human neurodevelopment on neuronal dysfunction in NDDs. 7,17,18 Furthermore, these
and its associated disorders. This tissue retains the full organoid-based models serve as platforms for identifying
6
spectrum of essential cell types, thereby enabling the potential therapeutic strategies, including gene therapies,
investigation of human-specific mechanisms. However, pharmacological interventions, and targeted modulation of
its utility is constrained by several challenges, including signaling pathways. 19
limited availability, difficulties in maintaining long-term By offering a physiologically relevant and scalable system
cultures, and variability in genetic background, which can for studying human brain development and disease, brain
affect experimental reproducibility. 7 organoids have transformed neurodevelopmental research.
In recent years, human brain organoids have emerged Their continued refinement will undoubtedly contribute to
as indispensable models for studying neurodevelopmental a deeper understanding of neurological disorders and the
disorders (NDDs). These self-assembling, three- development of novel therapeutic strategies.
dimensional (3D) cultures recapitulate key functional and This article highlights the significance of brain organoids
structural features of the fetal human brain. Generated derived from hPSCs as advanced models that accurately
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from human pluripotent stem cells (hPSCs) under specific replicate human brain architecture and facilitate the
3D culture conditions, brain organoids develop organized investigation of NDDs, effectively addressing the limitations
structures comprising neuronal progenitors, neurons, of traditional animal models. By integrating high-resolution
and glial cells, mimicking the cellular diversity and analyses and innovative culture techniques, this research
9,10
cytoarchitecture of the developing brain. They also retain enhances the physiological relevance of these organoids,
hallmark features of human neurodevelopment, including yielding valuable insights into the cellular and molecular
extended neuroepithelial expansion, enriched populations mechanisms underlying NDDs. Ultimately, this article
of oRGCs, and characteristic gene expression patterns. As highlights the transformative potential of brain organoids
such, brain organoids provide an advanced model system in unraveling the impact of genetic and environmental
for investigating neurodevelopmental processes and factors on neurodevelopment, offering deeper insights into
disorders. 11,12 brain development and related disorders while paving the

The advent of brain organoid technology has significantly way for innovative therapeutic strategies.
enhanced our ability to study neurodevelopmental diseases,
bridging the gap between genetic and molecular mechanisms 2. Orchestrating brain development:
and clinical phenotypes. Traditional animal models, while From neural tube formation to NDDs and
instrumental in neuroscience research, often fail to capture organoid modeling
the full spectrum of human brain development, particularly Brain development is a precisely orchestrated process
in disorders influenced by both genetic and environmental involving a series of tightly regulated events that commence
factors, such as autism, schizophrenia, and epilepsy. Brain with neurulation. During this stage, the neural plate of the
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organoids offer a physiologically relevant platform for embryonic ectoderm folds and fuses to form the neural
modeling these diseases, enabling researchers to examine tube, which undergoes segmentation and patterning to
cellular diversity, tissue architecture, and functional activity generate all regions of the central nervous system (CNS).
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in a human-specific context. 14
The ventricular zone (VZ), located at the apical surface of
In addition, organoid models facilitate the study of key the neural tube, harbors neuroepithelial cells (NECs), the
developmental processes such as neurogenesis, progenitor multipotent stem cells of the nervous system. Initially,
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differentiation, and synaptogenesis, which are not easily NECs undergo extensive proliferation to expand the stem
assessed using conventional two-dimensional (2D) cell pool before differentiating into radial glial cells (RGCs),

Volume 1 Issue 3 (2025) 2 doi: 10.36922/OR025100010