In neuroscience, Dale's principle (or Dale's law) is a rule attributed to the English neuroscientist Henry Hallett Dale. The principle basically states that a neuron performs the same chemical action at all of its synaptic connections to other cells, regardless of the identity of the target cell. However, there has been disagreement about the precise wording.
Because of an ambiguity in the original statement, there are actually two versions of the principle, one that has been shown definitively to be false, and another that remains a valuable rule of thumb. The term "Dale's principle" was first used by Sir John Eccles in 1954, in a passage reading, "In conformity with Dale's principle (1934, 1952) that the same chemical transmitter is released from all the synaptic terminals of a neurone…" [1] [2] Some modern writers have understood the principle to state that neurons release one and only one transmitter at all of their synapses, which is false. Others, including Eccles himself in later publications, have taken it to mean that neurons release the same set of transmitters at all of their synapses.
Dale himself never stated his "principle" in an explicit form. The source that Eccles referred to was a lecture published by Dale in 1934, called Pharmacology and nerve endings, describing some of the early research into the physiology of neurotransmission. [3] At that time, only two chemical transmitters were known, acetylcholine and noradrenaline (then thought to be adrenaline). [4] In the peripheral nervous system, cholinergic and adrenergic transmission were known to arise from different groups of nerve fibers. Dale was interested in the possibility that a neuron releasing one of these chemicals in the periphery might also release the same chemical at central synapses. He wrote:
It is to be noted, further, that in the cases for which direct evidence is already available, the phenomena of regeneration appear to indicate that the nature of the chemical function, whether cholinergic or adrenergic, is characteristic for each particular neurone, and unchangeable. [3]
And near the end of the paper:
When we are dealing with two different endings of the same sensory neurone, the one peripheral and concerned with vasodilatation and the other at a central synapse, can we suppose that the discovery and identification of a chemical transmitter of axon-reflex vasodilatation would furnish a hint as to the nature of the transmission process at a central synapse? The possibility has at least some value as a stimulus to further experiment. [3]
With only two transmitter chemicals known to exist at the time, the possibility of a neuron releasing more than one transmitter at a single synapse did not enter anybody's mind, and so no care was taken to frame hypotheses in a way that took this possibility into account. The resulting ambiguity in the initial statements led to some confusion in the literature about the precise meaning of the principle. [5] Nicoll and Malenka, for example, understood it to state that a neuron always releases one and only one neurotransmitter at all of its synapses. [6] In this form it is certainly false. Many neurons release more than one neurotransmitter, in what is called "cotransmission". Although there were earlier hints, the first formal proposal of this discovery did not come until 1976. [7] Most neurons release several different chemical messengers. [8] In modern neuroscience, neurons are often classified by their neurotransmitter and most important cotransmitter, for example striatal GABA neurons utilize either opioid peptides or substance P as the primary cotransmitter.
In a 1976 publication, however, Eccles interpreted the principle in a subtly different way:
"I proposed that Dale’s Principle be defined as stating that at all the axonal branches of a neurone, there was liberation of the same transmitter substance or substances." [9]
The addition of "or substances" is critical. With this change, the principle allows for the possibility of neurons releasing more than one transmitter, and only asserts that the same set are released at all synapses. In this form, it continues to be an important rule of thumb, with only a few known exceptions, [10] including David Sulzer and Stephen Rayport's finding that dopamine neurons also release glutamate as a neurotransmitter, but at separate release sites. [11]
Within a nervous system, a neuron, neurone, or nerve cell is an electrically excitable cell that fires electric signals called action potentials across a neural network. Neurons communicate with other cells via synapses, which are specialized connections that commonly use minute amounts of chemical neurotransmitters to pass the electric signal from the presynaptic neuron to the target cell through the synaptic gap.
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.
In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes that impact the body, then works in tandem with the endocrine system to respond to such events. Nervous tissue first arose in wormlike organisms about 550 to 600 million years ago. In vertebrates it consists of two main parts, the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the brain and spinal cord. The PNS consists mainly of nerves, which are enclosed bundles of the long fibers, or axons, that connect the CNS to every other part of the body. Nerves that transmit signals from the brain are called motor nerves or efferent nerves, while those nerves that transmit information from the body to the CNS are called sensory nerves or afferent. Spinal nerves are mixed nerves that serve both functions. The PNS is divided into three separate subsystems, the somatic, autonomic, and enteric nervous systems. Somatic nerves mediate voluntary movement. The autonomic nervous system is further subdivided into the sympathetic and the parasympathetic nervous systems. The sympathetic nervous system is activated in cases of emergencies to mobilize energy, while the parasympathetic nervous system is activated when organisms are in a relaxed state. The enteric nervous system functions to control the gastrointestinal system. Both autonomic and enteric nervous systems function involuntarily. Nerves that exit from the cranium are called cranial nerves while those exiting from the spinal cord are called spinal nerves.
Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie perception and thought. They allow the nervous system to connect to and control other systems of the body.
Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic.
The autonomic nervous system (ANS), formerly referred to as the vegetative nervous system, is a division of the nervous system that operates internal organs, smooth muscle and glands. The autonomic nervous system is a control system that acts largely unconsciously and regulates bodily functions, such as the heart rate, its force of contraction, digestion, respiratory rate, pupillary response, urination, and sexual arousal. This system is the primary mechanism in control of the fight-or-flight response.
Sir Bernard Katz, FRS was a German-born British physician and biophysicist, noted for his work on nerve physiology; specifically, for his work on synaptic transmission at the nerve-muscle junction. He shared the Nobel Prize in physiology or medicine in 1970 with Julius Axelrod and Ulf von Euler. He was made a Knight Bachelor in 1969.
Sir Henry Hallett Dale was an English pharmacologist and physiologist. For his study of acetylcholine as agent in the chemical transmission of nerve pulses (neurotransmission) he shared the 1936 Nobel Prize in Physiology or Medicine with Otto Loewi.
Otto Loewi was a German-born pharmacologist and psychobiologist who discovered the role of acetylcholine as an endogenous neurotransmitter. For this discovery, he was awarded the Nobel Prize in Physiology or Medicine in 1936, which he shared with Sir Henry Dale, who was a lifelong friend that helped to inspire the neurotransmitter experiment. Loewi met Dale in 1902 when spending some months in Ernest Starling's laboratory at University College, London.
A neuroeffector junction is a site where a motor neuron releases a neurotransmitter to affect a target—non-neuronal—cell. This junction functions like a synapse. However, unlike most neurons, somatic efferent motor neurons innervate skeletal muscle, and are always excitatory. Visceral efferent neurons innervate smooth muscle, cardiac muscle, and glands, and have the ability to be either excitatory or inhibitory in function. Neuroeffector junctions are known as neuromuscular junctions when the target cell is a muscle fiber.
Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibers in the parasympathetic nervous system.
In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell. The area in the axon that holds groups of vesicles is an axon terminal or "terminal bouton". Up to 130 vesicles can be released per bouton over a ten-minute period of stimulation at 0.2 Hz. In the visual cortex of the human brain, synaptic vesicles have an average diameter of 39.5 nanometers (nm) with a standard deviation of 5.1 nm.
In molecular biology and physiology, something is GABAergic or GABAnergic if it pertains to or affects the neurotransmitter gamma-aminobutyric acid (GABA). For example, a synapse is GABAergic if it uses GABA as its neurotransmitter, and a GABAergic neuron produces GABA. A substance is GABAergic if it produces its effects via interactions with the GABA system, such as by stimulating or blocking neurotransmission.
Neurotransmission is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron, and bind to and react with the receptors on the dendrites of another neuron a short distance away. A similar process occurs in retrograde neurotransmission, where the dendrites of the postsynaptic neuron release retrograde neurotransmitters that signal through receptors that are located on the axon terminal of the presynaptic neuron, mainly at GABAergic and glutamatergic synapses.
Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second messenger signaling cascade that induces a broad, long-lasting signal. This modulation can last for hundreds of milliseconds to several minutes. Some of the effects of neuromodulators include: altering intrinsic firing activity, increasing or decreasing voltage-dependent currents, altering synaptic efficacy, increasing bursting activity and reconfigurating synaptic connectivity.
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another neuron or to the target effector cell.
Marthe Louise Vogt was a German scientist recognized as one of the leading neuroscientists of the twentieth century. She is mainly remembered for her important contributions to the understanding of the role of neurotransmitters in the brain, especially epinephrine.
Axon terminals are distal terminations of the branches of an axon. An axon, also called a nerve fiber, is a long, slender projection of a nerve cell that conducts electrical impulses called action potentials away from the neuron's cell body in order to transmit those impulses to other neurons, muscle cells or glands. In the central nervous system, most presynaptic terminals are actually formed along the axons, not at their ends.
Victor Percy Whittaker was a British biochemist who pioneered studies on the subcellular fractionation of the brain. He did this by isolating synaptosomes and synaptic vesicles from the mammalian brain and demonstrating that synaptic vesicles store the neurotransmitter acetylcholine.
Tripartite synapse refers to the functional integration and physical proximity of the presynaptic membrane, postsynaptic membrane, and their intimate association with surrounding glia as well as the combined contributions of these three synaptic components to the production of activity at the chemical synapse. Tripartite synapses occur at a number of locations in the central nervous system with astrocytes and may also exist with Muller glia of retinal ganglion cells and Schwann cells at the neuromuscular junction. The term was first introduced in the late 1990s to account for a growing body of evidence that glia are not merely passive neuronal support cells but, instead, play an active role in the integration of synaptic information through bidirectional communication with the neuronal components of the synapse as mediated by neurotransmitters and gliotransmitters.