The Root of Thought

1. Glia, Not Neurons, Dominate Brain Volume and Influence

Back in the 1960s, it was discovered that glial cells are 90 percent of the brain.

Glia's numerical superiority. For decades, neuroscience has focused on neurons, yet glial cells constitute the vast majority of brain cells. This numerical dominance suggests a far more significant role for glia than previously acknowledged. The ratio of glia to neurons increases with the perceived intelligence of a species, from leeches to humans.

Challenging the neuron doctrine. The traditional view, known as the Neuron Doctrine, posits that neurons are the primary functional units of the brain. However, emerging research suggests that glia play a crucial role in information processing, brain injury recovery, and the development of neurological disorders. This challenges the long-held belief in neuronal supremacy.

Rethinking brain function. The sheer abundance of glia, coupled with their diverse functions, necessitates a re-evaluation of how we understand the brain. Glia are not merely support cells but active participants in neural communication and cognitive processes. This paradigm shift has the potential to revolutionize our understanding of the brain and its disorders.

2. Historical Bias Favored Neurons, Obscuring Glial Importance

But the Neuron Doctrine has become more religion than scientific truth, explaining away even the most blatant facts with assertions such as, “We use only 10 percent of our brain.”

Early misconceptions. The Neuron Doctrine, championed by figures like Ramón y Cajal, solidified the neuron's central role in brain function. Glia were relegated to a supporting role, viewed as mere "nerve putty" or insulators. This historical bias hindered glial research for decades.

The rise of the neuron. The advent of the microscope and the discovery of electrical signaling in neurons further cemented the neuron's dominance. Glia, lacking such clear-cut electrical activity, were largely ignored. This focus on neurons led to a neglect of glial research, despite their abundance in the brain.

Challenging the status quo. The historical emphasis on neurons has created a skewed understanding of brain function. By recognizing the limitations of the Neuron Doctrine and embracing the complexity of glial cells, we can unlock new insights into the brain's inner workings. This requires a shift in perspective and a willingness to challenge long-held assumptions.

3. Electricity in the Body: A Misleading Clue

In the eighteenth century, electricity was the rage in science.

Galvani's frog legs. Luigi Galvani's experiments with frog legs demonstrated the existence of "animal electricity," further fueling the focus on electrical signaling in neurons. This discovery, while groundbreaking, inadvertently overshadowed other potential forms of cellular communication.

The allure of electrical impulses. The rapid and easily measurable nature of electrical impulses made them an attractive candidate for the primary mode of brain communication. This led to the development of sophisticated techniques for studying neuronal activity, while glial signaling remained largely unexplored.

Beyond electrical signaling. While neurons communicate through electrical impulses, glia utilize a more complex system involving calcium waves and chemical signaling. This alternative mode of communication may be better suited for certain types of information processing, such as long-term memory and complex cognitive functions.

4. Astrocytes: The Brain's Versatile Master Cells

If you look at a tulip, you wouldn’t think it was an armadillo.

Diverse glial cell types. Glia encompass a variety of cell types, each with specialized functions. These include:

• Schwann cells: Myelinate axons in the peripheral nervous system
• Oligodendrocytes: Myelinate axons in the central nervous system
• Microglia: Immune cells of the brain
• Astrocytes: Regulate the brain's environment and communicate with neurons

Astrocytes' multifaceted roles. Astrocytes, the most abundant glial cells in the cortex, perform a wide range of functions, including:

• Regulating blood flow to neurons
• Maintaining the chemical balance of the extracellular space
• Releasing transmitters to control neuronal firing
• Forming the blood-brain barrier

The astrocyte's unique position. Astrocytes' close proximity to both blood vessels and neurons positions them as key regulators of brain function. Their ability to control blood flow, maintain chemical balance, and communicate with neurons makes them essential for neural health and cognitive processes.

5. Calcium Waves: Glia's Unique Communication System

Since the 1980s, scientists discovered the smooth flow of calcium oscillations or waves.

Beyond electrical spikes. Unlike neurons, which communicate through rapid electrical impulses, glia signal through slower, wavelike fluctuations in calcium ion concentration. These calcium waves can spread across networks of interconnected glial cells.

Gap junctions: Glial connections. Astrocytes connect to each other through gap junctions, specialized channels that allow for the passage of ions and small molecules. These gap junctions facilitate the propagation of calcium waves across glial networks.

Information processing potential. The slower, more fluid nature of calcium wave communication may be conducive to complex information processing. Calcium waves can integrate signals from multiple sources and modulate neuronal activity over extended periods. This suggests that glia play a crucial role in higher-level cognitive functions.

6. Glia-Neuron Interaction: A Two-Way Street, Glia in Control

Haydon described the neuron-astrocyte-neuron action as the “tripartite synapse.”

Transmitter receptors on glia. Glia express receptors for virtually every neurotransmitter used by neurons. This allows them to sense neuronal activity and respond accordingly.

Glia release transmitters. Glia can also release neurotransmitters, influencing neuronal firing. This bidirectional communication challenges the traditional view of neurons as the sole drivers of brain activity.

The tripartite synapse revisited. The concept of the tripartite synapse, involving a neuron, a presynaptic neuron, and an astrocyte, highlights the complex interplay between these cells. However, it doesn't fully capture the astrocyte's ability to initiate signaling independently of neuronal input. The astrocyte is not just a support cell but an active participant in synaptic transmission.

7. Glia Shape Brain Development and Learning

After the neuronal framework is established, avenues and highways traversing the bulb behind our eyes, mouth, nose, and between our ears, extending to our limbs through our tail-like spine, are ready to be populated with our mind.

Radial glia as neural progenitors. During brain development, radial glia serve as scaffolding for migrating neurons. They also act as neural progenitors, giving rise to both neurons and glia.

Glia influence synaptogenesis. Astrocytes play a crucial role in synaptogenesis, the formation of new synapses. They release factors that promote synapse formation and maturation.

Glia and synaptic pruning. Glia are also involved in synaptic pruning, the elimination of unnecessary synapses. This process is essential for refining neural circuits and optimizing brain function.

8. Memory is Tied to Glial Activity

In calcium wave firing, as each wave rises, a shot of glutamate is released from the astrocyte.

Glia in long-term potentiation. Long-term potentiation (LTP), a cellular mechanism underlying learning and memory, is influenced by glial activity. Astrocytes can modulate synaptic transmission and contribute to the strengthening of neural connections.

Glia and memory consolidation. Glia may also play a role in memory consolidation, the process by which short-term memories are transformed into long-term memories. Calcium waves in astrocytes can spread to all adjacent astrocytes. Formation of memories is in the hippocampus, but information resides throughout the cortex. This is the domain of the astrocyte.

Glia as information storage units. The ability of glia to communicate through calcium waves and influence neuronal activity suggests that they may serve as information storage units in the brain. This challenges the traditional view of neurons as the sole repositories of memory.

9. Glia Regeneration: The Key to Brain Health

Astrocytes are the basis for life in the brain.

Adult neurogenesis and gliogenesis. For years, it was believed that the adult brain was incapable of generating new neurons. However, recent research has shown that neurogenesis, the birth of new neurons, does occur in certain brain regions. More importantly, astrocytes are constantly dividing and regenerating in the adult brain.

Glia as stem cells. Astrocytes act as stem cells, capable of self-renewal and differentiation into other cell types. This regenerative capacity is essential for maintaining brain health and repairing damage.

Glia and brain plasticity. The ability of glia to regenerate and remodel neural circuits contributes to brain plasticity, the brain's ability to adapt and change throughout life. This plasticity is crucial for learning, memory, and recovery from injury.

10. Glial Abnormalities Underlie Brain Disorders

The electrical stimulation can mimic the substantia nigra firing and restore movement.

Glia in neurodegenerative diseases. Abnormalities in glial function have been implicated in a variety of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS).

Glia in psychiatric disorders. Glial dysfunction has also been linked to psychiatric disorders, such as depression and schizophrenia. This suggests that glia play a crucial role in mood regulation and cognitive stability.

Glia as therapeutic targets. The growing recognition of glia's importance in brain disorders has opened up new avenues for therapeutic intervention. Targeting glial function may offer novel strategies for treating a wide range of neurological and psychiatric conditions.

Last updated: April 7, 2025