Brain cell

A brain cell, also referred to as a neural cell, is a specialized cell within the brain and central nervous system that forms the structural and functional basis of neural tissue, primarily comprising neurons and glial cells.^[1] Neurons are electrically excitable cells responsible for transmitting information through electrical and chemical signals, enabling processes such as sensory perception, motor control, cognition, and behavior.^[1] Each neuron typically features a cell body (soma), dendrites that receive signals, and an axon that conducts signals away to other cells.^[2] In the human brain, there are approximately 86 billion neurons, which interact via synapses to form complex networks underlying thought and action.^[3] Glial cells, often called neuroglia, outnumber neurons in certain brain regions but total around 85 billion in the human brain, providing essential support without directly transmitting signals.^[3] Major types include astrocytes, which regulate the blood-brain barrier, maintain nutrient supply, and modulate synaptic activity; oligodendrocytes, which produce myelin sheaths to insulate axons and speed signal conduction; and microglia, which act as immune defenders by clearing debris and responding to injury or infection.^[4] Together, these cell types ensure the brain's structural integrity, metabolic homeostasis, and plasticity, with disruptions linked to neurological disorders such as Alzheimer's disease and multiple sclerosis.^[5]

Overview

Definition and Classification

Brain cells, also known as neural cells, constitute the fundamental units of the central nervous system (CNS), which encompasses the brain and spinal cord, enabling the processing, integration, and transmission of information essential for nervous system function.^[6] These cells are broadly categorized into two primary types: neurons, which are excitable cells specialized for generating and propagating electrical and chemical signals, and glial cells (or neuroglia), which are non-excitable cells that provide structural, metabolic, and protective support to neurons without directly participating in signal transmission.^[7] In the adult human brain, isotropic fractionation studies have estimated approximately 86 billion neurons and a comparable number of glial cells, totaling around 170 billion cells, challenging earlier misconceptions of vastly higher glial counts.^[8] The classification of brain cells begins with the primary dichotomy between neurons and glia, reflecting their distinct roles in CNS architecture. Neurons are further subdivided into sensory neurons, which transmit signals from sensory receptors to the CNS; motor neurons, which carry signals from the CNS to effectors like muscles; and interneurons, which facilitate communication between other neurons within the CNS.^[9] Glial cells, comprising the majority of CNS cells by volume, include subtypes such as astrocytes, which maintain the blood-brain barrier and regulate the extracellular environment; oligodendrocytes, which produce myelin sheaths for neuronal axons in the brain; and microglia, which act as resident immune cells monitoring for pathogens and injury.^[6] A key distinction of brain cells from those in the peripheral nervous system (PNS) lies in their limited regenerative capacity; while PNS neurons can often regrow axons after injury due to a supportive environment, CNS neurons generally fail to regenerate effectively, leading to persistent deficits following damage.^[10] This foundational cellular composition underpins the brain's capacity for cognition and behavior, as explored in subsequent sections on structure and function.^[8]

Evolutionary and Historical Context

The evolutionary origins of brain cells trace back to the emergence of simple nervous systems in early metazoans, with cnidarians such as jellyfish and sea anemones representing one of the earliest groups to possess a diffuse nerve net around 600 million years ago during the Ediacaran period.^[11] These primitive neural elements, consisting of interconnected neurons without centralized structures, facilitated basic sensory-motor coordination and marked the initial divergence of neuronal lineages from secretory cells in animal evolution.^[12] Over subsequent evolutionary epochs, particularly with the Cambrian explosion, these systems complexified in bilaterians and vertebrates, evolving into organized central nervous systems with layered cellular architectures that supported advanced cognition and behavior.^[13] Glial cells, often viewed as supportive counterparts to neurons, likely co-evolved alongside neuronal complexity, sharing a common ancestral origin from neuroglandular progenitors in early animals.^[14] In non-bilaterian invertebrates like cnidarians, rudimentary glial-like cells provided structural support, but their diversification accelerated in vertebrates, particularly mammals, where glia assumed specialized roles such as myelination and metabolic regulation, paralleling the increased neuronal density and brain size seen in mammalian lineages.^[15] This glial expansion contributed to the enhanced efficiency of neural signaling in complex brains, with mammalian glia exhibiting greater transcriptional diversity than in simpler organisms.^[16] Historically, the study of brain cells began in the mid-19th century when Rudolf Virchow coined the term "neuroglia" in 1858 to describe the connective tissue matrix enveloping neurons, initially perceiving it as a passive scaffold akin to glue.^[17] A pivotal paradigm shift occurred in the 1890s through Santiago Ramón y Cajal's application of Camillo Golgi's silver staining technique, which allowed visualization of individual neurons as discrete, contiguous units rather than a fused reticulum as proposed by the reticular theory.^[18] Cajal's observations, detailed in works like La Texture du Système Nerveux (1894–1904), established the neuron doctrine, affirming neurons as independent cells communicating via junctions, a view that overturned Golgi's reticular model despite their shared 1906 Nobel Prize.^[19] The 20th century brought further revelations through technological advances, with electron microscopy in the 1950s unveiling the ultrastructure of synapses as specialized intercellular contacts, as demonstrated by studies from George Palay and Eduardo De Robertis showing vesicle-laden presynaptic terminals.^[20] This confirmed Cajal's predictions of contact-based communication, shifting focus from gross anatomy to molecular interfaces. In the 2020s, single-cell RNA sequencing has identified novel glial subtypes, such as regionally distinct astrocyte populations and microglia variants, revealing previously unrecognized heterogeneity that refines our understanding of glial contributions to brain function and disease.^[21] These milestones underscore ongoing evolutionary and historical insights into brain cells as dynamic, interdependent networks.

Neuronal Cells

Structure of Neurons

Neurons exhibit a highly specialized morphology designed for efficient information processing and transmission in the nervous system. The fundamental components of a neuron include the soma (cell body), dendrites, axon, and axon terminals, each contributing to the cell's overall architecture. This structure allows neurons to integrate inputs and distribute outputs over distances, with variations in size and shape depending on their location and type.^[22][23] The soma forms the neuron's metabolic center, containing the nucleus, endoplasmic reticulum, Golgi apparatus, mitochondria, and other organelles necessary for protein synthesis and energy production. Its diameter typically ranges from 4 to 100 micrometers, with smaller examples like cerebellar granule cells measuring 6–8 μm and larger ones, such as Purkinje cells or motor neurons, reaching 60–80 μm. The soma often appears polygonal or spherical and connects directly to dendrites and the axon at specialized regions like the axon hillock.^[23][22] Dendrites extend from the soma as branched, tree-like processes that maximize surface area for potential connections. They emerge in a stellate arrangement, tapering as they branch outward, and frequently bear dendritic spines—actin-rich protrusions that serve as primary sites for synaptic contacts, with individual cortical neurons accommodating up to approximately 10,000 spines across their dendritic arbor. In pyramidal neurons, which dominate the cerebral cortex, the dendritic tree features a prominent apical dendrite arising from the soma and extending toward the pial surface, often bifurcating into oblique branches and a distal tuft for expanded coverage.^[22][24][25] The axon originates from the soma via the axon hillock and extends as a single, elongated fiber, sometimes reaching lengths of up to 1 meter in human motor neurons to span from the spinal cord to extremities. Composed of axoplasm surrounded by the axolemma, the axon maintains a uniform diameter and culminates in axon terminals, or synaptic boutons, which branch into fine arborizations containing vesicles for target interactions.^[23][22] Axonal specializations include the myelin sheath, a multilayered lipid membrane that insulates segments of the axon to enhance signaling efficiency; in the central nervous system, this sheath is formed by oligodendrocytes wrapping multiple axonal internodes. Gaps between these wrappings, known as nodes of Ranvier, expose short stretches of the axon (typically 1–2 μm long) and feature high concentrations of ion channels. These structural adaptations, particularly evident in myelinated fibers, allow neurons to vary dramatically in overall size and complexity across brain regions.^[22]

Function of Neurons

Neurons maintain a resting membrane potential of approximately -70 mV, primarily through the action of the Na⁺/K⁺-ATPase pump, which actively transports three sodium ions out of the cell and two potassium ions in, using ATP to counterbalance passive ion diffusion across the membrane.^[26][27] This electrochemical gradient sets the stage for signal generation, where depolarizing stimuli from synaptic inputs reduce the membrane potential. If depolarization reaches a threshold of about -55 mV at the axon hillock, voltage-gated sodium channels open rapidly, initiating an action potential—a brief reversal of the membrane potential to around +30 mV followed by repolarization via potassium efflux.^[28][29] The dynamics of action potential generation are quantitatively described by the Hodgkin-Huxley model, developed from voltage-clamp experiments on squid axons, which mathematically captures the contributions of sodium, potassium, and leak currents to membrane excitability.^[30] The core equation governing changes in membrane potential $V$V over time is: $$\frac{dV}{dt} = \frac{1}{C_m} \left( I - g_{Na} m^3 h (V - E_{Na}) - g_K n^4 (V - E_K) - g_L (V - E_L) \right)$$dtdV​=Cm​1​(I−gNa​m3h(V−ENa​)−gK​n4(V−EK​)−gL​(V−EL​)) where $C_m$Cm​ is membrane capacitance, $I$I is applied current, $g_{Na}$gNa​, $g_K$gK​, and $g_L$gL​ are maximum conductances for sodium, potassium, and leak channels, $E_{Na}$ENa​, $E_K$EK​, and $E_L$EL​ are reversal potentials, and $m$m, $h$h, and $n$n are activation/inactivation gating variables that evolve based on voltage-dependent rate constants.^[30] This model explains how regenerative sodium influx triggers the rapid upstroke of the action potential, while delayed potassium activation ensures repolarization and a refractory period. Once initiated, action potentials propagate along the axon without decrement, enabling reliable signal transmission over long distances. In myelinated axons, saltatory conduction—where the action potential "jumps" between nodes of Ranvier—accelerates this process to speeds up to 120 m/s, far exceeding the 1 m/s in unmyelinated fibers, due to the insulating myelin sheath briefly referenced from neuronal structure.^[31] At the axon terminal, the action potential triggers calcium influx, leading to synaptic transmission via neurotransmitter release into the synaptic cleft; glutamate serves as the primary excitatory neurotransmitter, binding to ionotropic receptors like AMPA and NMDA to depolarize the postsynaptic neuron, while GABA acts as the main inhibitory neurotransmitter, hyperpolarizing the membrane through chloride influx via GABA_A receptors.^[32][33] Neurons integrate thousands of synaptic inputs primarily at the soma and axon initial segment, summing excitatory and inhibitory postsynaptic potentials to determine whether the threshold for firing is reached, thus encoding complex information in firing patterns. Synaptic plasticity, such as long-term potentiation (LTP), strengthens these connections following coincident pre- and postsynaptic activity, as first demonstrated in hippocampal slices where high-frequency stimulation induced persistent synaptic enhancement lasting hours.^[34] This process aligns with the Hebbian rule, positing that "cells that fire together wire together," where repeated correlated firing leads to synaptic strengthening, a foundational principle for learning and memory.^[35] Despite comprising only 2% of body mass, the brain's neurons demand 20% of the body's ATP, underscoring their high energy cost for maintaining potentials, signaling, and plasticity.^[36]

Glial Cells

Types and Structure of Glia

Glial cells, collectively known as neuroglia, encompass a diverse group of non-neuronal cells in the central nervous system (CNS) that provide structural and supportive roles, differing from neurons in their lack of excitability and action potential generation. The major types include astrocytes, oligodendrocytes, microglia, and ependymal cells, each exhibiting distinct morphologies adapted to their locations within the brain and spinal cord. These cells have regional glia-to-neuron ratios varying from approximately 0.2:1 in the cerebellum to about 4:1 in the cerebrum, tied to neuronal density across brain structures.^[37][38] Astrocytes are the most abundant glial cells, characterized by their star-shaped morphology with a central cell body and numerous radiating processes that extend throughout the gray and white matter. These processes often contact synapses, blood vessels, and other neural elements, forming a network that interlaces with neuronal structures. Protoplasmic astrocytes predominate in gray matter, featuring bushy, highly branched processes rich in intermediate filaments like glial fibrillary acidic protein (GFAP), while fibrous astrocytes in white matter have longer, less branched processes with more prominent GFAP bundles. A key structural feature is the formation of endfeet, specialized expansions at the process tips that ensheath blood vessels and contribute to the architecture of the blood-brain barrier.^[38][39] In the cerebellum, specialized astrocytes known as Bergmann glia exhibit a unipolar morphology, with somata located in the Purkinje cell layer and elongated radial processes extending toward the pial surface, providing a scaffold-like arrangement.^[40][38] Oligodendrocytes, primarily found in the CNS, possess a rounded cell body with a small nucleus and extend multiple long, thin cytoplasmic processes that wrap around axons to form myelin sheaths. Unlike Schwann cells in the peripheral nervous system, a single oligodendrocyte can myelinate up to 50 axons, with each process forming a segmented myelin layer around portions of multiple nearby axons, creating compact, multilayered insulating structures. These cells appear in two main forms: interfascicular oligodendrocytes, located between bundles of myelinated axons in white matter, and satellite oligodendrocytes, which cluster around neuronal cell bodies in gray matter. Their cytoplasm contains abundant rough endoplasmic reticulum and polyribosomes, supporting the synthesis of myelin components.^[41][38] Microglia, the resident immune cells of the CNS, derive from yolk sac hematopoietic progenitors and display a highly ramified morphology with an elongated nucleus and minimal cytoplasm surrounding short, branched processes that extend from the cell body. In their resting state, these processes are dynamic and finely branched, forming an extensive arborization that tiles the brain parenchyma without significant overlap. This ramified structure allows microglia to occupy distinct territories, with process lengths varying by brain region but typically spanning tens of micrometers.^[42][43] Ependymal cells form a simple cuboidal to columnar epithelial lining along the ventricles of the brain and the central canal of the spinal cord, creating a barrier between the cerebrospinal fluid and neural tissue. These cells feature apical surfaces adorned with multiple motile cilia and microvilli, while their basal surfaces connect to underlying astrocytes via gap junctions. Tanycytes, a subtype prevalent in the floor of the third ventricle, exhibit elongated processes that extend deeper into the parenchyma, blending epithelial and glial characteristics.^[44][38]

Roles of Glial Cells

Glial cells fulfill essential supportive and modulatory roles in the brain, maintaining homeostasis, facilitating neuronal signaling, and responding to physiological demands. Astrocytes, the most abundant glial type, play a central role in regulating the extracellular ionic environment by buffering potassium ions (K⁺) released during neuronal activity, thereby preventing hyperexcitability and supporting efficient synaptic transmission.^[45] They also contribute to nutrient supply by transporting glucose across the blood-brain barrier and metabolically coupling with neurons through the astrocyte-neuron lactate shuttle, where astrocytes convert glucose to lactate via glycolysis and provide it to neurons for oxidative metabolism during high-energy demands.^[46] Furthermore, astrocytes maintain the integrity of the blood-brain barrier by inducing endothelial tight junctions and modulating vascular permeability, ensuring selective nutrient and waste exchange.^[47] Oligodendrocytes enhance neuronal conduction velocity by forming myelin sheaths around axons, which act as electrical insulators that reduce membrane capacitance and enable saltatory conduction, allowing action potentials to propagate rapidly over long distances.^[48] This myelination is crucial for the efficient timing of neural circuits, particularly in white matter tracts. Microglia, as the brain's resident immune cells, actively prune excess synapses during early development to refine neural connectivity, using complement-dependent phagocytosis to eliminate weak or inactive connections and promote circuit maturation.^[49] In response to injury or pathology, microglia rapidly phagocytose cellular debris, pathogens, and apoptotic neurons, mitigating inflammation and facilitating tissue repair.^[50] Ependymal cells line the brain's ventricular system and contribute to cerebrospinal fluid (CSF) production by secreting ions and water, which helps maintain intracranial pressure and provides a buoyant environment for the brain.^[51] They also support neurogenesis in the adult brain by facilitating the directed flow of CSF, which carries signaling molecules to neural stem cells in neurogenic niches like the subventricular zone.^[52] Beyond these functions, glial cells actively participate in synaptic signaling through the tripartite synapse model, where astrocytes act as a third partner alongside pre- and postsynaptic neurons, sensing synaptic activity via receptors and modulating transmission.^[53] This involvement includes gliotransmission, a process in which astrocytes release glutamate in a calcium (Ca²⁺)-dependent manner from intracellular stores, influencing neuronal excitability and synaptic plasticity.^[54] Additionally, astrocytes contribute to the glymphatic system, a brain-wide waste clearance pathway that is markedly enhanced during slow-wave sleep, promoting the removal of proteins like amyloid-β through perivascular CSF-ISF exchange.^[55]

Interactions and Brain Organization

Neuron-Glia Interactions

Neuron-glia interactions encompass a range of communication modes that enable bidirectional signaling and functional cooperation between neurons and glial cells, particularly astrocytes and oligodendrocytes, at the cellular level. These interactions are essential for modulating neuronal excitability, synaptic transmission, and myelin dynamics, ensuring efficient neural processing. Astrocytes, in particular, form intimate associations with neuronal synapses, contacting up to ~140,000 synapses per cell in rodents and up to 2 million in humans, which facilitates precise regulation of local neural activity.^[56][57] Chemical signaling represents a primary mode of neuron-glia communication, where astrocytes release gliotransmitters such as glutamate and ATP in response to neuronal activity-induced calcium elevations. These gliotransmitters act on neuronal receptors to alter excitability; for instance, astrocytic glutamate can enhance synaptic strength by activating presynaptic metabotropic glutamate receptors, thereby influencing information processing in neural circuits over timescales from milliseconds to seconds.^[56][58] This release is calcium-dependent and can propagate effects across nearby neurons, as demonstrated in studies of the visual cortex where astrocyte-derived signals modulate visually evoked responses.^[59] Mechanical coupling occurs through gap junctions formed by connexin proteins, such as connexin 43 in astrocytes, which directly link neuronal and glial cytoplasms for the exchange of ions, metabolites, and second messengers. These junctions enable bidirectional electrical and chemical communication; for example, in hippocampal cultures, gap junctions allow astrocytes to transmit hyperpolarizing currents to neurons, reducing excitability, while neuronal signals can propagate into astrocytic networks.^[60] This coupling supports synchronized activity, with connexin expression defining distinct pathways for neuron-glia versus glia-glia interactions. Contact-mediated interactions involve adhesion molecules like integrins, which mediate physical attachments between neuronal axons and glial processes. β1-integrins on oligodendrocytes sense axonal diameter and initiate myelination by promoting axoglial adhesion and signaling, ensuring myelin formation matches neuronal caliber for optimal conduction velocity. Similarly, neuronal integrins interact with astrocytic surfaces to stabilize synaptic contacts, influencing neurite outgrowth and synaptogenesis. In cooperative processes, astrocytes contribute to synaptic modulation by rapidly uptaking excess neurotransmitters, such as glutamate via excitatory amino acid transporters (EAATs), to prevent excitotoxicity and fine-tune synaptic strength. This uptake not only maintains extracellular homeostasis but also generates astrocytic sodium signals that can trigger gliotransmitter release, thereby closing feedback loops that regulate long-term potentiation and memory formation. For myelination, neuronal activity provides feedback to oligodendrocytes; optogenetic stimulation of premotor cortical neurons increases oligodendrocyte precursor cell proliferation fourfold and enhances myelin thickness (reducing g-ratio from 0.756 to 0.701), promoting adaptive myelination that improves motor function.^[61] Key aspects of these interactions include calcium waves in astrocytic networks, which propagate signals up to 1 mm through gap junctions and extracellular ATP diffusion, coordinating glial responses to neuronal inputs across local domains. Neuromodulation further integrates these dynamics, as noradrenaline activates astrocytic α1-adrenoreceptors, triggering calcium elevations that release gliotransmitters and modulate neuronal circuits in arousal and attention states. Discoveries in the 2010s using optogenetics illuminated bidirectional signaling; for example, light-activated channelrhodopsin in astrocytes evoked neuronal calcium responses via gliotransmitter release, while neuronal optostimulation induced astrocytic waves, confirming reciprocal control in hippocampal and cortical networks. Recent studies (as of 2025) have shown neuron-to-glia signaling, such as via phosphatidylserine, drives experience-dependent synaptic pruning during critical periods.^[62]

Brain-Wide Cellular Networks

The mammalian cerebral cortex is structured into six distinct layers, with pyramidal neurons forming the predominant cell type in layers 2 through 6, accounting for 70–80% of neurons in these regions and serving as the primary projection neurons.^[63] These pyramidal neurons exhibit diverse morphologies and connectivity patterns that span cortical layers, facilitating integration across the brain's surface.^[64] Interneurons, comprising the remaining neuronal population, are distributed throughout these layers and play a key role in modulating pyramidal cell activity through targeted inhibition, thereby shaping local circuit dynamics.^[65] Beyond the cortex, white matter tracts consist of bundled myelinated axons that enable long-range communication between brain regions; the corpus callosum, the largest such tract, contains 200–250 million contralateral axonal projections wrapped in myelin sheaths produced by oligodendrocytes.^[66] Subcortical structures, such as the basal ganglia, feature mixed populations of neurons and glia organized into interconnected nuclei that support motor and cognitive functions.^[67] These regions include diverse neuronal types like medium spiny neurons alongside glial cells, with glia-to-neuron ratios varying regionally but contributing to structural support and metabolic regulation.^[68] Organizational principles extend to modular circuits, exemplified by the hippocampus, where mossy fiber pathways from dentate gyrus granule cells project to CA3 pyramidal neurons, forming specialized ensembles critical for memory encoding and pattern separation.^[69] Astrocytes, a major glial type, line perivascular spaces surrounding blood vessels, facilitating cerebrospinal fluid flow and waste clearance to maintain ionic and metabolic homeostasis, which in turn supports the stability of these extended networks.^[70] Glial cell densities exhibit regional variation, with higher concentrations in white matter (approximately 85,867 non-neuronal cells per milligram) compared to gray matter (53,398 cells per milligram), reflecting their enriched roles in myelination and axonal support.^[71] Microglia and astrocytes show elevated densities in white matter tracts, aiding in the maintenance of tract integrity.^[72] Advances in connectome mapping during the 2020s have revealed these brain-wide patterns through techniques like diffusion MRI, which reconstructs major fiber tracts non-invasively, as demonstrated by the Human Connectome Project's high-resolution datasets.^[73] Complementary electron microscopy efforts, such as those in the BRAIN Initiative, provide synaptic-level detail in mammalian models, while projects like FlyWire—mapping over 140,000 neurons in the fruit fly brain—offer scalable analogies for inferring human connectivity principles.^[74][75] In 2025, the MICrONS Project advanced this with unprecedented synaptic-level maps of complex brain regions.^[76] Functional networks, such as the default mode network (DMN), integrate these cellular ensembles across medial prefrontal, posterior cingulate, and lateral parietal cortices, encompassing billions of neurons and glia to underpin self-referential cognition during rest.^[77] The DMN's architecture, characterized by strong structural and functional connectivity overlap, highlights how cellular networks scale to support distributed processing.^[78]

Development and Maintenance

Embryonic Development of Brain Cells

The embryonic development of brain cells begins with the formation of the neural tube during the third week of gestation. At this stage, the notochord induces the overlying ectoderm to thicken into the neural plate, which subsequently folds to form neural grooves and elevations known as neural folds. By the end of the fourth week, these folds fuse in a zipper-like manner from the midline outward, creating a closed neural tube that will give rise to the central nervous system, including the brain and spinal cord.^[79] Following neural tube closure, neural progenitor cells proliferate extensively within the ventricular zone (VZ), a transient layer lining the neural tube's lumen. This zone serves as the primary site for generating the progenitor pool through initial symmetric divisions that expand cell numbers, transitioning later to asymmetric divisions that produce one progenitor and one differentiating cell. Proliferation in the VZ is crucial for establishing the foundational population of brain cells, with progenitors adopting radial glial morphologies that support both self-renewal and the onset of neurogenesis.^[80] Radial glia cells, emerging from VZ progenitors, act as scaffolds guiding the migration of newly generated neurons to their appropriate positions in the developing cortex. These elongated processes extend from the VZ to the pial surface, enabling neurons to ascend in a radial manner and settle into layer-specific arrangements, a process that continues until approximately week 20 of gestation when cortical layering is largely established. This glia-guided migration ensures the ontogeny of cortical columns and functional organization.^[81] Differentiation of brain cells from common neural progenitors occurs in a temporally regulated sequence, with neurons becoming post-mitotic early through asymmetric cell divisions. In these divisions, one daughter cell retains progenitor identity while the other exits the cell cycle to differentiate into a neuron, driven by the unequal segregation of fate determinants such as Numb protein. Glial cells, including oligodendrocytes, arise later from the same progenitor pool; for instance, OLIG2-positive cells in the ventral domains commit to the oligodendrocyte lineage after motor neuron production ceases, promoting myelination through transcriptional regulation in collaboration with factors like Nkx2.2.^[82][83] Key signaling pathways, such as Sonic hedgehog (Shh) and Wnt, orchestrate progenitor fate decisions during these stages. Shh, secreted from the notochord and floor plate, establishes ventral identities by activating Gli transcription factors, while Wnt signaling promotes dorsal fates through β-catenin stabilization; their coordinated action via Gli3 repressors and activators patterns the telencephalon into distinct neuronal subtypes. In humans, this proliferative phase peaks in mid-gestation, generating up to 250,000 neurons per minute to build the brain's cellular architecture.^[84][85] The subventricular zone (SVZ), adjacent to the VZ, emerges as a secondary proliferative niche during late embryogenesis and persists into adulthood as a site of ongoing neurogenesis. In the embryo, SVZ progenitors contribute to cortical interneurons and oligodendrocytes; in adult rodents, this region retains stem-like cells that generate neuroblasts migrating to the olfactory bulb, while in adult humans, such migration to the olfactory bulb is limited, with progenitors more commonly contributing to striatal interneurons or gliogenesis. Recent stem cell models from the 2020s, using human induced pluripotent stem cells to recapitulate cortical development, have confirmed the bipotent potential of these progenitors, revealing lineage switches between neuronal and glial fates influenced by temporal cues like EGFR expression surges around gestational week 20.^[86][87][88]

Cellular Repair and Aging

Brain cells employ several mechanisms to maintain integrity and respond to damage throughout life. Microglia, the resident immune cells of the brain, play a central role in repair by phagocytosing damaged or apoptotic cells and debris following injury, thereby preventing secondary damage and facilitating tissue remodeling.^[89] This process is essential for clearing toxic aggregates and reshaping the extracellular matrix to support functional recovery.^[90] Astrocytes contribute to repair through reactive astrogliosis, where they proliferate and form glial scars around injury sites, creating a barrier that isolates necrotic tissue and promotes wound healing, though this can sometimes impede axonal regrowth.^[91] Additionally, limited adult neurogenesis occurs in the hippocampus, where neural stem cells generate new neurons—estimates vary from approximately 700 per day based on 2013 studies to negligible levels in others—contributing to potential turnover of the dentate gyrus neuronal population and supporting learning and memory plasticity, though the extent in adult humans remains controversial.^[92][93] Aging introduces progressive changes that challenge these repair processes and lead to cellular decline. Neuronal loss is minimal, with studies showing preservation of neuron numbers in many brain regions despite an overall brain volume reduction of approximately 0.2% per year after age 35, accelerating to 0.5% annually by age 60.^[94] In contrast, glial cells exhibit senescence, particularly microglia, which become primed for activation, resulting in chronic low-grade neuroinflammation that exacerbates tissue damage and impairs cognitive function.^[95] Oligodendrocytes also undergo age-related alterations, including myelin sheath thinning, which reduces axonal conduction velocity by up to 70% in affected segments and diminishes the efficiency of neural signaling, particularly in high-frequency tasks.^[96] The glymphatic system, responsible for clearing metabolic waste through cerebrospinal and interstitial fluid exchange, declines with age, leading to impaired removal of proteins like amyloid-beta and contributing to accumulation of cellular debris that hinders repair.^[97] Recent research in the 2020s has explored senolytic drugs, such as dasatinib combined with quercetin, which selectively eliminate senescent glia, including microglia, thereby reducing neuroinflammation and improving brain function in aging models.^[98] These interventions highlight potential therapeutic strategies to enhance cellular maintenance and mitigate age-related decline.^[99]