Cholinergic fibers are nerve cells that use the neurotransmitter acetylcholine to communicate information throughout the nervous system. Tissues that use or respond to this chemical messenger are described as cholinergic. This system of nerve fibers is integral to a vast array of bodily functions, from conscious muscle movements to the automatic regulation of internal organs. Acetylcholine’s name describes its chemical makeup as an ester of acetic acid and choline.
Location and Types of Cholinergic Fibers
Cholinergic fibers are extensively distributed throughout the central and peripheral nervous systems. In the central nervous system (CNS), which includes the brain and spinal cord, cholinergic neurons originate in areas like the basal forebrain and brainstem, projecting widely to regions such as the cerebral cortex and hippocampus.
In the peripheral nervous system (PNS), these fibers are categorized by their roles in the somatic and autonomic systems. Within the somatic system, cholinergic fibers are responsible for activating skeletal muscles at the neuromuscular junction, enabling voluntary movement. The autonomic nervous system (ANS), which controls involuntary bodily processes, relies heavily on cholinergic signaling.
All preganglionic neurons for both the sympathetic and parasympathetic divisions of the ANS are cholinergic. Furthermore, all postganglionic parasympathetic fibers release acetylcholine to carry out “rest and digest” functions. Some postganglionic sympathetic neurons are also cholinergic, such as those that stimulate sweat glands and certain blood vessels.
Acetylcholine Synthesis, Release, and Inactivation
The function of a cholinergic fiber depends on the precise management of its neurotransmitter, acetylcholine (ACh). This cycle begins inside the nerve terminal, where ACh is synthesized from choline and acetyl-CoA by the enzyme choline acetyltransferase (ChAT). Once produced, ACh is packaged into small sacs called synaptic vesicles for storage, which protects it from degradation within the neuron.
When a nerve impulse travels down the fiber and reaches the terminal, it causes channels in the cell membrane to open, allowing calcium ions to enter. This influx of calcium is the direct cue for the synaptic vesicles to fuse with the neuron’s outer membrane. This fusion releases ACh into the synaptic cleft, the small gap between the neuron and its target cell.
After its release, ACh’s action is intentionally brief. The enzyme acetylcholinesterase (AChE) is present in the synapse and rapidly breaks down ACh into choline and acetate, terminating the signal. This rapid inactivation prevents continuous, unwanted stimulation of the target cell. Much of the choline is then transported back into the nerve terminal to be recycled for new acetylcholine synthesis.
Cholinergic Receptors and Cellular Responses
The effects of acetylcholine on a target cell are determined by the type of receptor it binds to. These receptors are proteins on the surface of the post-synaptic cell that fall into two main categories: nicotinic and muscarinic. The names are derived from other substances—nicotine and muscarine—that can also activate these specific receptors.
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels. When acetylcholine binds to these receptors, the channel opens, allowing ions like sodium and potassium to pass through the cell membrane. This ion flow causes rapid depolarization of the cell, leading to an excitatory response. Nicotinic receptors are found at the neuromuscular junction, in autonomic ganglia, and throughout the central nervous system.
Muscarinic acetylcholine receptors (mAChRs) are G-protein coupled receptors, which initiate a more complex and slower cascade of events inside the cell. There are five main subtypes (M1-M5), which can be either excitatory or inhibitory depending on the signaling pathways they trigger. These receptors are predominantly found on the target organs of the parasympathetic nervous system, such as the heart, smooth muscle, and glands, as well as in the brain.
Key Roles of Cholinergic Signaling in the Body
One of the primary roles of cholinergic signaling is in somatic motor control. Acetylcholine released at the neuromuscular junction is the chemical signal that triggers the contraction of all voluntary skeletal muscles.
Within the autonomic nervous system, cholinergic signaling is the primary driver of the parasympathetic division’s “rest and digest” functions. For instance, it slows the heart rate, decreases blood pressure, and stimulates the digestive tract to process food and eliminate waste. It also promotes processes like salivation and constricts the pupils. Cholinergic fibers also contribute to specific sympathetic responses, such as activating sweat glands to regulate body temperature.
In the central nervous system, cholinergic neurons projecting to the cortex and hippocampus are involved in higher-order cognitive functions, including learning, the formation of memories, and sustaining attention. These fibers also play a part in regulating arousal, wakefulness, and the transitions between sleep cycles, particularly REM sleep.
Cholinergic System in Health and Disease
The functioning of the cholinergic system is necessary for health, and its disruption is linked to several diseases. In Alzheimer’s disease, for example, there is a marked degeneration of cholinergic neurons in the brain, leading to the characteristic cognitive decline. Myasthenia gravis is an autoimmune disorder where the body produces antibodies that attack nicotinic acetylcholine receptors at the neuromuscular junction, causing muscle weakness and fatigue. An imbalance in cholinergic activity can also contribute to the symptoms of Parkinson’s disease.
The system’s accessibility also makes it a target for various toxins and pharmacological agents. Nerve gases and certain pesticides, for instance, act by inhibiting acetylcholinesterase, leading to a toxic overstimulation of cholinergic receptors. Conversely, botulinum toxin causes paralysis by blocking the release of acetylcholine from nerve terminals.
The clinical relevance of this system has led to the development of numerous drugs that target it. Acetylcholinesterase inhibitors are used to boost cholinergic signaling in patients with myasthenia gravis and to improve cognitive symptoms in Alzheimer’s disease. Other drugs, known as muscarinic antagonists like atropine, are used to block parasympathetic effects, for instance, to increase a dangerously slow heart rate.