On Biology and Cellular Neuroscience

Life on Earth has existed for over three billion years. It has evolved through mutations and natural selection as described in the 19th century by Charles Darwin and Alfred Russell Wallace. It is diverse with beneficial mutations accumulating over these years. Diversity is essential and remains in the DNA of all living things.

Due to its complexity and diversity, biology can be challenging for the student to master. It may be divided into various fields and subfields. Botany and zoology are two primary divisions. Animal physiology is a branch of zoology. Neuroscience is a subfield of animal physiology, and cellular neuroscience is a further subset of neuroscience. This essay discusses topics related to cellular neuroscience.

To begin though, it may be useful to consider the brain’s role in the central nervous system. The brain is composed of neurons and glia, which total hundreds of billions of cells. Cellular neuroscience primarily focuses on the structures and functions of neurons, glia, and their connections.

As a rough overview, the nervous system consists of the brain (cerebrum, cerebellum, midbrain, brainstem), the spinal cord, and the peripheral nervous system. The spinal cord exits the skull through the foramen magnum and is divided into cervical, thoracic, lumbar, sacrum, and coccyx regions. The peripheral nervous system includes sensory, motor, and autonomic neurons which reside outside the skull and spinal column. The autonomic nervous system, which is partly within the peripheral portion, automatically maintains the body’s physiological stability through a process termed homeostasis. 

Understanding the many regions and functions of the human brain and spinal cord is challenging. This understanding began with ancient physicians. Notable among them, the Greek physician Galen (129-216 AD), treated the Roman gladiators among his duties, noting the result of brain damage in different regions to the loss of body function. Today, some brain regions and body functions are determined during routine surgery. Electrically stimulating brain or spinal regions of conscious patients helps the surgeon to identify their functions. Neurons, synapses, and supportive glia form the cellular basis for brain and spinal cord function.

This essay aims to describe neurons, glia, and their connections. For in-depth information, refer to Principles of Neural Science by Kandell, Schwartz, and Jessell, or Neuroscience by Purves et al. Here, I’ll summarize some facts for high school or college science students.

Neurons and Glia

As mentioned previously, neurons and glia form the nervous system. Each cell type has a membrane that encloses and protects its internal components from the external environment (see https://ronaldabercrombie.blog/2024/05/14/where-physics-and-biology-intersect/). The cell membrane is a complex structure but is made primarily of phospholipids. A thin enclosing sheet of phospholipids forms a barrier between the inside and outside of the cell. Cell membranes are less than 100 Angstroms across and are formed with two phospholipid molecules forming a symmetrical pair spanning from one side to the other. The hydrophilic portions of the phospholipids in this barrier are adjacent to the water, and the hydrophobic portions form the cell membrane interior portion.

All life exists in an aqueous environment protected by a cell membrane. Special pathways called transporters or channels allow hydrophilic solutes to pass through. Some transporters can even move substances against their natural tendency to disperse. The process of natural dispersion across this membrane is determined by the temperature and by forces related to voltage and concentration differences. To counter the process of natural dispersion, the input of external energy is required.

Much of the energy within neurons is stored in the electrochemical gradient of the cell membrane. Sodium ions dominate outside the cell, while potassium ions dominate inside. This difference is maintained by transporters like the sodium/potassium ATPase, which uses ATP as the energy source to exchange three sodium for two potassium ions, establishing the ionic difference between the inside and outside of neurons and other cell types. There is also a voltage difference across this membrane, which is negative on the inside.

There are other ion pumps that utilize ATP for transport, such as those for calcium and hydrogen ions. Subsets of these pumps have evolved over a very long time of evolution. The calcium pump of the sarcoplasmic reticulum in muscles is currently well-studied. Its three-dimensional crystal structure has been published by Toyoshima, Nakasako, Nomura, and Ogawa (Nature, 2000).

Those transporters that move substances against their electrochemical energy gradient require energy as previously stated. The first law of thermodynamics requires this. This energy must come from an external source. In plants, the energy for active transport may come from sunlight, while in both plants and animals, it may come from the chemical energy within ATP molecular bonds generated within mitochondria from nutrients that are transported into the cell.

Alternatively, a helper molecule may be co-transported or counter-transported during the process. In this case, the energy may be derived from the helper molecule’s electrochemical gradient.

Transporters that use sunlight are involved in photosynthesis; transporters that pump sodium, potassium, calcium, hydrogen, or other ions may use chemical energy from ATP; co-transporters may move hydrogen, sodium, potassium, magnesium, calcium, or chloride, extracting the needed energy from the helper’s electrochemical energy gradient. There are many examples of these processes.

An example of using the electrochemical gradient generated by transporters is found in the nervous system’s rapid electrical signaling over long distances. This is accomplished through traveling waves of electrical disturbance termed action potentials. British scientists Allen Hodgkin and Andrew Huxley described this in a series of papers that won them the Nobel Prize in 1963. When the electrical potential across a neuronal membrane drops below threshold, then gateways, pathways, or channels quickly open allowing sodium ions to enter the cell; this movement of electrically positive sodium ions causes the membrane potential to become electrically positive on the inside. Nearly as quickly as this permeability increase occurs, it spontaneously stops, and further sodium ion movement is briefly blocked. As the influx of sodium into the cell decreases, potassium ions, which have a high concentration within the cell, begin to flow out. In flowing out of the cell, the exiting positively charged potassium ions restore the membrane potential to its original state.

The sodium/potassium pump restores ionic balance of the neuron by removing excess sodium and replenishing potassium lost during action potentials.

The action potential propagates swiftly along the neuron’s axon as an electrical signaling wave. Initially, this is a passive process, but the passive depolarization triggers action potentials at a leading edge. The action potential only moves forward because trailing regions enter a brief inactive state, preventing backward propagation. The, so called, refractory period, the inactive period, also limits the frequency of action potentials.

Advances in World War II electronics enabled Alan Hodgkin and Andrew Huxley to study neuron electrical behavior. Hodgkin gained this knowledge during his military service in Wales. Post-war, they realized that holding membrane voltage constant while measuring currents would help clarify the ionic processes of action potentials. Using the squid’s giant axon for its large size, they detailed how neurons signal rapidly over long distances, providing animals a quick-response evolutionary advantage.

Glia, derived from the Greek word for glue, were initially thought to hold neurons together. They don’t signal directly but they do more than stick things together. They support neuronal signaling by 1) wrapping and insulating some axons to speed action potential propagation, 2) distributing ions and nutrients among neurons, 3) repairing small central nervous system injuries, 4) guiding neurons during embryological development, and 5) maintaining a “blood-brain barrier” by supporting endothelial cells that line brain capillaries.

The brain’s complex neuronal and synaptic connections make it challenging to restore lost functions after injury. In contrast, the peripheral nervous system has glial cells (Schwann cells) that may help direct axon regrowth, making recovery more likely there. Central nervous system injuries are harder to heal due to the complexity of cellular connections and the formation of scar tissue, which blocks reconnections. Therefore, protecting the central nervous system is crucial; the hard skull helps provide this.

Synapses.

The connections (synapses) between neurons were initially studied by scientists using light microscopy. Notable among these early researchers was the Spanish neuroanatomist Santiago Ramón y Cajal (1852-1936). The term “synapses” was coined by Charles Scott Sherrington (1857-1952), a British neuroscientist in the late 19th and early 20th centuries. During Cajal’s and Sherrington’s era, it was crucial to determine whether neurons, observed through microscopes with closely opposed or “touching” regions, were individually self-sufficient, or if these touching surfaces indicated a continuous neuronal entity. Specifically, whether the cytoplasmic and electrical connectivity between neurons was continuous or if neurons were electrically isolated from one another. Cajal and others supported the idea that synaptic connections occur between separate and independent neuronal cells. It was later discovered that some neurons do form cytoplasmic electrical connections, although this is less common in mammals where complex connectivity is necessary to support complex behavior. These less common types of connections are known as electrical synapses and are another example of biological diversity.

Information transfer between neurons

The brain and nervous system’s complexity allows quick environmental responses, learning, and memory. This relies on the synapses between neurons. Synapses provide what has become known as neuronal “plasticity” or neuronal changeability. Bernard Katz’s book, Nerve, Muscle, and Synapse is a good reference for understanding nerve-muscle synapses, a key area of neuroscience. As it happens and for good functional reasons, the nerve-muscle synapse is not very changeable. For detailed studies, consult other advanced textbooks such as Principles of Neural Science by Kandell et al., Neuroscience by Purves et al., and Ionic Channels of Excitable Membranes by Hille.

Intracellular parts of neurons and glia

At various stages of evolutionary development, living cells gained functional enhancements: a nucleus; intracellular membrane structures including rough and smooth endoplasmic reticulum; a Golgi apparatus; a nuclear envelope; and mitochondria. Internal structures may assist with the shape and the movement of some cells. These structures are known as the cytoskeleton, which play significant roles in neurons and glia as well as other cell types.

It’s important to name, identify, and understand the functions of cellular elements. Some are listed below with brief descriptions:

a. Nucleus — contains genetic material (DNA) enabling cell reproduction.

b. Rough endoplasmic reticulum — an intracellular membrane vesicle containing ribosomes that translate genetic information from the nucleus (via mRNA) into protein.

c. Smooth endoplasmic reticulum — serves multiple functions, including storage and release of calcium ions (Ca⁺⁺) during cell signaling, metabolism of carbohydrates, and phospholipid synthesis.

d. Sarcoplasmic reticulum — stores intracellular calcium in muscle cells.

e. Golgi apparatus — processes, stores, and transports lipids and proteins synthesized in the smooth and rough endoplasmic reticulum.

f. Nuclear envelope — a double-layered membrane protecting the nucleus.

g. Mitochondria — generates energy in the form of ATP using atmospheric oxygen.

h. Cytoskeleton — examples include microtubules and microfilaments that support neuronal cell structure.

Intracellular signaling requires diffusible molecules.

How does one part of a cell’s interior receive information from another? This usually involves signaling molecules that diffuse across intracellular regions. An example of a signaling molecule is calcium, which can be free (Ca⁺⁺) or bound to another molecule (Ca⁺⁺-R). Ca⁺⁺-R can be either anchored or mobile, but Ca⁺⁺-R is less mobile than free (Ca⁺⁺).

Only a small portion of the total calcium in the cell exists as the free ion. The low concentration of Ca⁺⁺ makes it suitable as a signaling agent as even a small amount entering from outside or released from intracellular storage cause a significant and detectable change in its intracellular concentration, making the intracellular calcium signal clear and unmistakable.

An increase in free calcium signals biological processes such as the release of synaptic transmitters, the release of hormones, and muscle contraction. The nerve-muscle synapse serves as an example; skeletal muscle contraction demonstrates the final stage of movement. The next section discusses a hormone.

Extracellular signaling can be intimate or diffuse.

A neurotransmitter is a chemical that influences nearby neurons or muscle cells. If released into the bloodstream to impact distant targets, it is known as a hormone. Billions of years of evolution on Earth have led to a vast diversity and complexity of neurotransmitters and hormones.

Examples of hormonal release occur in the pituitary gland, a pea-sized protrusion located at the brain’s base, beneath the hypothalamus. The hypothalamus is located below the thalamus, a fist-sized structure that acts as an information transfer hub near the brain’s center.

The pituitary is crucial for many physiological functions including reproduction in mammals. In fish, amphibians, birds, and insects, the production of gametes—sperm in males and eggs in females are required for reproduction.

In humans, a monthly release of hormones from the hypothalamus triggers egg release from follicles. How does this occur? Hypothalamic neurons release luteinizing hormone-releasing hormone (LHRH), which travels to the pituitary. There, LHRH prompts gonadotrophs to release luteinizing hormone (LH) into the bloodstream. LH eventually reaches the ovaries, leading to the release of an ovum into the fallopian tube.

The processes just described are only a small part of ovulation in mammals, but it illustrates the complexity of this process. Complexity of all the biological activities that have evolved over time cannot be fully described here, obviously, but these examples of biology’s complexity and scale are amazing to consider.