2025/12/1

Where Do Neurons Come From? What Are They? And Where Are They Going?

Our nervous system begins as only a few layers of cells immediately after fertilization. Long before anything resembling a “brain” exists, a portion of the ectoderm receives signals, commits to a new fate, and transforms into the neuroectoderm. This marks the starting point of the nervous system. The neural plate bends to form the neural tube, which becomes the axis of the brain and spinal cord and generates both neurons and glia. In contrast, neural crest cells undergo epithelial-to-mesenchymal transition, migrate away, and—ever versatile travelers—differentiate into sensory ganglia, autonomic neurons, and even melanocytes.

How do these emerging cells acquire their “neuronal identity”? Distinct signals and gene expression patterns along the dorsal–ventral and anterior–posterior axes of the neural tube provide positional cues that guide each cell’s fate. The blueprints for motor neurons, interneurons, sensory neurons, and many more are already being drawn at this stage. Once generated, neurons extend remarkably long axons, navigating toward their targets by attractive and repulsive cues such as netrin and semaphorin. Even after synapses form, the story is far from over—the brain boldly prunes its wiring and reshapes circuits according to neural activity. The nervous system is always in motion, always changing.

So, where are neuronal cells “going”? Before acquiring their full neuronal identity, many neurons migrate long distances from their birthplace to their final positions, using region-specific strategies—think of the classic “inside-out” pattern mentioned in lecture. Experiences and neural activity during development further sculpt the mature brain. Conversely, even subtle disruptions early in development can contribute to congenital anomalies, neurodevelopmental disorders, and epilepsy (see the previous column, “Form Follows Function”). Glioma cells, for their part, exploit these very developmental migration programs to infiltrate the brain (Masui et al. Brain Tumor Pathol 2008). Understanding the paths that neurons travel—illuminated today by organoid and stem-cell research—holds the key to unraveling disease mechanisms and building the foundations of future therapies.

2025/10/15

Form Follows Function

The principle “form ever follows function” is stated by the American architect Louis Sullivan. This idea provides an excellent guiding concept for understanding human physiology, including the nervous system. When considering the morphological features of neurons, one often highlights the prominent nucleolus and the Nissl bodies (free ribosomes and rough endoplasmic reticulum). These features clearly reflect the high level of protein synthesis in neurons. Among glial cells, oligodendrocytes can be recognized by their characteristic “fried-egg” perinuclear haloes. Although this artifactually results from lipid dissolution during tissue preparation, it makes sense when one recalls that oligodendrocytes are the cells responsible for myelin formation. This principle applies naturally to the brain’s macrostructure as well. The folia of the cerebellum enable dense packing of neural circuits that support precise motor control. The six-layered structure of the cerebral cortex reflects the division of labor among input, output, and integrative functions (see the previous column “Brain and Integration”).

From this, we derive a pathomechanism of disease development: 1) abnormal morphology → 2) abnormal function → 3) clinical disorder. For example, in cortical dysplasia, developmental abnormalities disrupt the layered structure of the cerebral cortex. As a result, neuronal integration fails and neurons become excessively excited, producing epileptic seizures. Morphology can also provide diagnostic clues. In conditions such as cortical dysplasia or brain tumors, one may encounter atypical cells whose lineage (neuronal or glial) is ambiguous. The presence of Nissl bodies indicates them as neuronal origin. Even more interesting is the case of oligodendroglioma, in which oligodendrocyte-like cells (OLCs) proliferate. When artificial intelligence (AI) is tasked with diagnosing these tumors, it appears to focus on the same perinuclear clearing—the “fried-egg” feature—that human pathologists do. It may not be an exaggeration to say that pathologists are a group of people captivated by “form,” but perhaps we may find ourselves working surprisingly well with machines. Has this timeless yet ever-renewing concept of “form” begun to draw your attention?

2025/09/08

Brain and Integration

Our lab is the Department of Integrative Neuroscience, and the word integrative carries a special significance. But what exactly does ‘integration’ mean in the context of neuroscience? From a microscopic perspective, integration refers to the process by which a neuron combines signals from multiple sources to determine its output. In other words, excitatory and inhibitory inputs are integrated spatially and temporally at the dendrites and soma. When the combined input exceeds a threshold, the neuron generates an action potential. Beneath the “all-or-none” law lies this process of collective decision-making. From a macroscopic perspective, integration describes how the nervous system processes diverse streams of information in response to environmental and internal cues, ultimately enabling appropriate behavior and cognition. Integration is therefore indispensable for the functioning of the brain—and the mind.

The concept of integration also arises frequently in neurological disorders. In the diagnosis of brain tumors, classical morphology (phenotype) is combined with molecular genetic abnormalities (genotype/epigenotype) to reach what is called an integrated diagnosis. A more direct example can be found in schizophrenia, a psychiatric disorder in which the ability to integrate thought, behavior, and emotion is impaired. At the microscopic level, this reflects dysfunction in the neuronal process of integrating synaptic inputs—with certain neuronal signals disproportionately dominant. In this sense, our department is uniquely positioned as an integration of anatomy, physiology, and pathology, making it ideally suited to confront these neurological disorders. Whether in normal brain function or in disease, approaching neuroscience through the lens of integration offers a deeper and more comprehensive understanding.