Can neurons be inhibited with electric current?

It is well known the electricity can be used to fire neurons. But can it be used to inhibit neuronal firing? This is in the context of extracellular stimulation. In extracellular stimulation, it is known that there is a threshold for stimulation and a threshold for damage(electroporation). Is there a threshold in between these two which inhibits neuron firing without any damage? Please provide reference for your answer.

Yes, but maybe not how you think.

It is important to recognize that voltages refer to potential differences. When we say the "a cell is at -65mV" for example, we mean "The potential difference across the cell's membrane to the extracellular space is -65mV." When you stimulate electrically, you create a transient electric field, whereby the extracellular space is no longer effectively isopotential.

Let's imagine for the sake of some neuron that this field strength is on the order of 40 mV across the membrane. If this electric field is perpendicular to some neuronal process, the voltage across the membrane will be about -105mV on one side, and -25mV on the other side. The -25mV side is now depolarized enough to open voltage gated sodium channels, and some current is flowing into the cell. Once the shock has passed, positive current will continue to flow through those open channels and open more channels. It doesn't matter much that the other side is transiently at -105mV, all that matters is that you opened a bunch of voltage gated sodium channels which starts a positive feedback loop.

Therefore, transient electrical simulation will almost always be excitatory. There are two exceptions:

1) Neurochemical inhibition. If you excite a particular brain region that is specifically inhabited by inhibitory projection neurons, you will primarily excite those inhibitory cells and therefore cause excitation elsewhere. Of course, in this case, the electrical stimulation itself is still directly exciting cells, they just happen to have inhibitory effects elsewhere.

2) Depolarization block. If you continually stimulate the same population of neurons with a high-frequency stimulation, you can put neurons in a state called "depolarization block." Voltage-gated sodium channels have a chance to inactivate whenever they are activated. If you inactivate enough channels, there aren't enough available to produce an action potential. Therefore, if you can keep a cell pretty much constantly depolarized by continually stimulating, you can prevent action potential propagation because too many of the voltage gated channels in the axon initial segment are inactivated.

In practice, focal electrical stimulation of the brain can be used to prevent or abrogate seizures. There is a device marketed for this.


NeuroPace's Responsive Neurostimulation System (RNS), an electrical-stimulation implant with two leads, each containing four electrodes, placed in the brain at the seizure focus. The RNS detects electrical activity that denotes the start of a seizure and delivers direct electrical stimulation to interrupt the activity and normalize the area.

It is not immediately obvious to me why this would work. The linked review describes how this was first observed empirically. My understanding is that the electrical stimulation causes polarization such that the nerve cannot immediately fire again as part of the epileptic focus. Sort of like a counter burn if you are fighting a wildfire.

Sun FT et al. Responsive cortical stimulation for the treatment of epilepsy.Neurotherapeutics. 2008 Jan;5(1):68-74.

In the 1990s, Durand and colleagues demonstrated success in suppressing spontaneous inter- ictal bursts in vitro by providing responsive stimulation directly in the epileptogenic region. Their result sug- gested that the mechanism for suppression is an inhibi- tory polarization caused by the transmembrane currents generated by the applied pulse. These trials in animals laid the groundwork for responsive stimulation therapy for epilepsy.

Short answer


Long answer

Neuron activity can indeed be inhibited with the correct type of electrical input stimulus.

In fact you can play around with various electrical signalling stimuli yourself, and observe the results not just for a single neuron but the entire network, yourself:

The link above is a simulation environment that tried to emulate neuronal activity based on user defined signalling stimuli. Not only can you inhibit signals, but you can totally control macroscopic behaviors: e.g. excitation of entire regions of a prototypical neuronal pathway.

Excitation and Inhibition: The Yin and Yang of the Brain

To make a working nervous system, only two forces are necessary: excitation and inhibition. Excitatory signaling from one cell to the next makes the latter cell more likely to fire. Inhibitory signaling makes the latter cell less likely to fire. At chemical synapses in the brain, glutamate and GABA (gamma-aminobutyric acid) are transmitters for excitation and inhibition, respectively. Admittedly, their names don’t quite evoke symmetry—one being evocative of cheap food seasoning and the other of a Swedish pop band. Yet, glutamate and GABA are the Yin and Yang of the brain. Dopamine, serotonin, norepinephrine, and other more celebrated brain chemicals have earned their fame as transmitters with much more specialized effects. But the bread and butter of the brain are unquestionably glutamate and GABA. In principle, a nervous system of only a handful of neurons and two transmitters—excitatory and inhibitory—is possible.

The balance between neural excitation and neural inhibition is crucial to healthy cognition and behavior. A brain dominated by glutamate would only be capable of exciting itself in repeated bursts of activity, similar to an epileptic seizure. Conversely, a brain dominated by GABA would only be capable of quiet whispers of activity, with little synchronization necessary for meaningful communication between brain areas. Healthy brain activity thrives in the middle area between these two extremes, where a balance between excitation and inhibition generates complex patterns of activity. Thus, a seemingly simple nervous system formed with only glutamate and GABA nonetheless results in highly complex activity.

Similarly, a seemingly simple mixture of chemicals in a Petri dish can give rise to highly complex chemical reaction patterns, such as oscillating spiral waves, when a chemical that excites the reaction and a chemical that inhibits the reaction are both present. This general type of reaction, called the Belousov–Zhabotinsky reaction, has even been studied as a model for how neural networks process information, since the reaction’s complexity is governed by similar principles.

Because complex patterns of brain activity are thought to underlie flexible behavior and cognition, the ratio between excitation and inhibition—referred to as E/I balance—is becoming increasingly recognized as a crucial measure for assessing the fitness of any brain. Schizophrenia, for example, has been associated with a low E/I ratio caused by weakly active glutamate receptors. Autism, on the other hand, has been associated with a high E/I ratio caused by weakly active GABA receptors. Even greater excesses of excitation or inhibition may result in epileptic seizures or brain coma, respectively. In fact, individuals with autism are far more likely to have epilepsy—a condition that causes seizures—than the average person, suggesting that both autism and epilepsy are rooted in a high E/I ratio.

How does the synergy between excitation and inhibition work? Both excitation and inhibition, acting alone, attract the brain toward distinct patterns of relatively simple activity. The balance of both creates a critical state, like the boundary between a gas and a liquid. Outside the brain, many critical states are unstable, like a pencil that is balanced vertically on its tip but falls over after any further change in its position. Yet surprisingly, critical states in the brain are often self-maintained and robust to further changes. For instance, after synaptic input to a neural network has generated a critical state, further synaptic input maintains the critical state rather than pushing the network into a simple, stable pattern. For this reason, the phenomenon is called self-organized criticality, or SOC, a term for the concept developed by physicists Per Bak, Chao Tang, and Kurt Wiesenfeld of the Brookhaven National Laboratory in New York.

SOC is thought to be important for brain function because it allows the brain a certain degree of flexibility. Just as a critical substance might flexibly switch between a gas and a liquid state, SOC might allow the brain to visit many different activity states. Wherever SOC is observed in nature, it seems to produce complex activity across many temporal and spatial scales as a result of a slow process that builds energy and a fast process that dissipates energy. This complexity can be described by a pattern called a scale-free distribution. Unlike the normal distribution or “bell curve” we know from statistics class, a scale-free distribution has no mean or average.

To better understand SOC, Bak and his colleagues imagined a familiar scenario: building a sandpile at the beach. The sandpile grows bigger until its slope reaches a certain steepness that results in a critical state. Adding more sand then triggers avalanches of various sizes. In fact, the critical state persists even as you add more sand—it is truly self-organized.

The two competing processes in this example are the slow process of adding sand, which builds energy, and the fast process resulting from the force of gravity overcoming the force friction, which dissipates energy. Perhaps this example feels far removed from the brain. But the slow process of adding sand is actually analogous to adding excitatory synaptic input in a neural network. Similarly, the fast process of gravity overcoming friction is analogous to neural excitation overcoming neural inhibition and triggering bursts of firing—neuronal avalanches. Sandpile avalanches follow the same scale-free distribution observed in electrical brain recordings: Activity is observed at all scales and frequencies, a result of delicate E/I balance.

In fact, we can alter the sandpile model to simulate disease states where excitation and inhibition are unbalanced. Imagine building a pile from glass beads rather than grains of sand. The smooth beads do not stick well, and the fragile pile collapses like a Jenga tower once it reaches a critical mass, never achieving true self-organized criticality. This is analogous to state of excessive neural excitation: synaptic inhibition is too weak to stop the storms of excitatory bursting that interrupt complex signaling and form seizures. Conversely, imagine building a sandpile using wet sand. The wet sand is sticky, resulting in few avalanches as the cohesiveness of the sand is too high. This is analogous to a state of excessive neural inhibition: Excitatory drive cannot overcome the suffocating grip of synaptic inhibition, hampering neural computations that depend on complex signaling.

Because electrical brain activity can easily be observed by placing electrodes on the scalp (EEG), it is possible for researchers and clinicians to infer E/I balance without directly probing cells in the brain. For example, epileptiform discharges—bursts of disruptive excitement—are clear signatures of a high E/I ratio. These discharges may indicate that the brain has been pushed past criticality to a supercritical state. Though traditionally associated with epilepsy, epileptiform discharges may also occur in the EEGs of patients who have never had a single seizure before. An emerging concept of epilepsy spectrum disorders seeks to frame mental illnesses, such as panic disorder, in the same context as epilepsy. Dr. Nash N. Boutros at the University of Missouri, Kansas City is exploring epileptiform discharges in patients with panic attacks as possible indicators of the same high E/I ratio that causes epilepsy. If panic disorders and epilepsy share a common cause, they might both be treatable with antiepileptic drugs. While such drugs generally treat seizures, they are believed to decrease neuronal excitability and have also been approved by the FDA to treat bipolar disorder, a psychiatric disorder where patients experience states of both elevated and lowered mood.

In the near future, drugs that alter neuronal excitability may show promise in guiding the diseased brain towards E/I balance. Indeed, just as many spiritual practices advocate for maintaining an “inner balance,” a physical balance between opposing forces appears central to maintaining a healthy brain. The synergy between opposites observed in the brain reminds us that complexity requires a balance. While empirical evidence has shown that brain size or brain mass is not the best measure of brain fitness, E/I balance might instead contend for that title. One day, a checkup at the doctor’s office might not just involve taking your pulse, height, and weight, but also an EEG reading of your E/I ratio.

Gruenert, Gerd, Peter Dittrich, and Klaus-Peter Zauner. "Artificial wet neuronal networks from compartmentalised excitable chemical media." ERCIM NEWS 85 (2011): 30-32.

Vanag, Vladimir K., and Irving R. Epstein. "Excitatory and inhibitory coupling in a one-dimensional array of Belousov-Zhabotinsky micro-oscillators: Theory." Physical Review E 84.6 (2011): 066209.

Buzsaki, Gyorgy. Rhythms of the Brain. Oxford University Press, 2006.

Bak, Per. "How nature works: the science of self-organized criticality." Nature 383.6603 (1996): 772-773.

Tetzlaff, Christian, et al. "Self-organized criticality in developing neuronal networks." PLoS Comput Biol 6.12 (2010): e1001013.

Boutros, Nash N., et al. "Epilepsy spectrum disorders: A concept in need of validation or refutation." Medical hypotheses 85.5 (2015): 656-663.

Boutros, Nash N., et al. "Predictive value of isolated epileptiform discharges for a favorable therapeutic response to antiepileptic drugs in nonepileptic psychiatric patients." Journal of Clinical Neurophysiology 31.1 (2014): 21-30.

Glucose-sensing neurons of the hypothalamus

Specialized subgroups of hypothalamic neurons exhibit specific excitatory or inhibitory electrical responses to changes in extracellular levels of glucose. Glucose-excited neurons were traditionally assumed to employ a 'beta-cell' glucose-sensing strategy, where glucose elevates cytosolic ATP, which closes KATP channels containing Kir6.2 subunits, causing depolarization and increased excitability. Recent findings indicate that although elements of this canonical model are functional in some hypothalamic cells, this pathway is not universally essential for excitation of glucose-sensing neurons by glucose. Thus glucose-induced excitation of arcuate nucleus neurons was recently reported in mice lacking Kir6.2, and no significant increases in cytosolic ATP levels could be detected in hypothalamic neurons after changes in extracellular glucose. Possible alternative glucose-sensing strategies include electrogenic glucose entry, glucose-induced release of glial lactate, and extracellular glucose receptors. Glucose-induced electrical inhibition is much less understood than excitation, and has been proposed to involve reduction in the depolarizing activity of the Na+/K+ pump, or activation of a hyperpolarizing Cl- current. Investigations of neurotransmitter identities of glucose-sensing neurons are beginning to provide detailed information about their physiological roles. In the mouse lateral hypothalamus, orexin/hypocretin neurons (which promote wakefulness, locomotor activity and foraging) are glucose-inhibited, whereas melanin-concentrating hormone neurons (which promote sleep and energy conservation) are glucose-excited. In the hypothalamic arcuate nucleus, excitatory actions of glucose on anorexigenic POMC neurons in mice have been reported, while the appetite-promoting NPY neurons may be directly inhibited by glucose. These results stress the fundamental importance of hypothalamic glucose-sensing neurons in orchestrating sleep-wake cycles, energy expenditure and feeding behaviour.


Model for how actions of glucose on neurons of the lateral hypothalamus may…

Multiple pathways are likely to…

Multiple pathways are likely to be involved in the modulation of the electrical…

Opinion: The Overlooked Power of Inhibitory Neurons

Lauren Aguirre
Jun 1, 2021


W hen we think about how the brain works—or how to fix it—we tend to think of neurotransmitters such as serotonin or dopamine. But the brain is an electric organ, its currency the impulses that fly across thousands of miles of neurons. As I describe in my new book, The Memory Thief and the Secrets Behind How We Remember: A Medical Mystery, more electrical activity is not always better. In fact, hyperactivity in the hippocampus—the brain’s memory center—is an early sign of Alzheimer’s disease that is gaining overdue interest as a therapeutic target.

Neurons come in two main “flavors,” excitatory and inhibitory. When an excitatory neuron receives enough input from other excitatory neurons, it fires, passing that signal along its axon to partners downstream. Inhibitory neurons usually tell other neurons not to fire. They are less plentiful than excitatory neurons but more diverse. In some ways, they are the real brains of the system, the machines in the background that pace and coordinate a ceaseless hum of electrical activity.

The best-studied inhibitory neuron is called a basket cell, so named because its axon splits into many filaments and wraps like a basket around the cell body of other neurons, the point where it can exert maximum control. Basket cells have a relatively simple job: they act as gatekeepers, allowing excitatory neurons to fire or preventing them from doing so. A single basket cell can control and synchronize the output of hundreds or even thousands of excitatory neurons, switching them on and off with precise timing and setting up a rhythmic tug-of-war that creates brain waves. Brain waves, in turn, allow information to be coordinated and transmitted across long distances. When inhibitory neurons stop working well, this delicate balance between excitation and inhibition degrades, and brain waves become less coherent.

When researchers first identified hippocampal hyperactivity as an early Alzheimer’s symptom, they assumed it was compensatory, a way to turn up the volume on weak communication between neurons. Researchers now understand that this loss of inhibition is like background static that interferes with memory retrieval, and clues point to inhibitory neurons as essential players in the chain of events that occurs as Alzheimer’s progresses. For example, even cognitively normal older adults have hyperactivity in the hippocampus and accumulation of tau protein along with it. In addition to sticky amyloid beta plaques, these toxic tau proteins are a defining feature of the disease. Another clue is that seizures, which occur when excitatory neurons fire uncontrollably, are more common in people with Alzheimer’s than without, are thought to accelerate its progression, and may appear in the early stages—perhaps even before other signs of disease. A third clue is that one type of brain wave, called gamma, is weaker in people with Alzheimer’s. These insights suggest that adjusting the balance between excitation and inhibition could improve memory and slow down the disease’s progression.

Researchers are investigating several approaches to recalibrating that balance. The furthest along is a Phase 3 clinical trial of a widely used anti-seizure drug called levetiracetam. The US company behind the trial, AgeneBio, is testing whether an extended-release, very low dose reduces background hyperactivity enough to improve memory in the earliest stages of Alzheimer’s. A second angle of attack is to manipulate the brain waves generated by inhibitory neurons. Researchers at a company called Cognito Therapeutics, at MIT, and elsewhere are running several independent trials that use external flickering lights and audio to entrain and strengthen gamma rhythms. A third tack, currently being tested in mice, is to transplant genetically enhanced inhibitory neurons into the brain.

Faulty electrical communication is also thought to play a role in other brain disorders and diseases, including epilepsy, schizophrenia, depression, and autism. Our understanding of inhibitory neurons is in its infancy compared to what we know about neurotransmitters. Because neurotransmitters play multiple roles and therefore have many side effects, they can act like a pharmacological blanket laid down over the whole brain’s delicate workings. Perhaps, if researchers figure out how to target the inhibitory neurons involved in each illness, they could develop more sophisticated ways of helping hundreds of millions of people around the world who suffer from these debilitating brain diseases.

Lauren Aguirre is a science journalist whose work has appeared in the PBS series NOVA, The Atlantic, Undark Magazine, and STAT. Read an excerpt from The Memory Thief here.

Recent Progress in the Discovery of Kv7 Modulators

Ismet Dorange , Britt-Marie Swahn , in Annual Reports in Medicinal Chemistry , 2011

3.1 Function

Subunits Kv7.2 and Kv7.3 coassemble and form a tetramer that underlies the M current [19] . It is noteworthy that other subunits (Kv7.4 and Kv7.5) are also associated, albeit to a lesser extent, with M current characteristics [20,21] . The M current which is activated at a lower-threshold membrane potential than would normally activate neuronal cells, hyperpolarizes the cell membrane, and consequently reduces the firing of action potential. In other words, modulation of these channels may control neuronal excitability. Recognizing that neuronal hyperexcitability is the cause of several clinical disorders such as epilepsy and pain, modulation of these channels represents an appealing approach for the treatment of such conditions.

Awakening Dormant Neurons Could Provide Disease-modifying Parkinson’s Treatment, Early Study Suggests

Together with dying nerve cells, dormant neurons also may be at the root cause of Parkinson’s disease, according to a recent study in animal models.

Reawakening these neurons by targeting a type of brain cells called astrocytes can restore dopamine production in the brain and reverse Parkinson’s motor symptoms, the study found. These findings could lead to a potential new disease-modifying treatment, especially at the early stages of Parkinson’s.

Despite its prevalence and debilitating consequences, current medical therapy for Parkinson’s relies on alleviating symptoms. Research investigating ways of modifying the disease or reversing its symptoms is scarce, based on the firm belief that Parkinson’s is caused by the irreversible death of nerve cells — also called neurons — in a region of the brain called the substantia nigra.

In this brain region, nerve cells known as dopaminergic neurons are responsible for producing the neurotransmitter dopamine, a chemical messenger that allows nerve cells to communicate. Dopamine plays a key role in motor function control and also is involved in behavior and cognition, memory and learning, sleep, and mood.

Levodopa, a mainstay of Parkinson’s treatment, works by supplying extra dopamine to the brain. However, it only alleviates motor symptoms and does not alter the disease course. Moreover, its long-term use can cause serious side effects, including involuntary, erratic, and writhing movements.

Now, a team of Korean researchers have discovered additional clues about the underlying mechanisms of Parkinson’s that may offer hope for the development of disease-modifying treatments that could reverse the condition.

Using mouse and rat models of Parkinson’s, they found that the motor abnormalities that mark the disease begin earlier than was previously thought. They are triggered when dopaminergic neurons in the substantia nigra are still alive but in a dormant state, unable to produce dopamine.

However, what holds the key to that dormant state is another type of cells called astrocytes, star-shaped cells present in the brain and spinal cord that play important roles in the protection and regulation of the nervous system.

When neurons die, nearby astrocytes react by proliferating, and start to release an inhibitory neurotransmitter called gamma-aminobutyric acid (GABA) at excessive levels. This puts neighboring neurons “on hold,” suspending their production of dopamine.

GABA prevents the neurons from firing electrical impulses and causes them to stop making an enzyme, called tyrosine hydroxylase, that’s essential for the production of dopamine. In effect, GABA puts the neurons into a dormant, or sleeping state.

One of the most important discoveries of the study was that surviving dormant neurons could actually be “awakened” from their “sleeping” state and rescued to alleviate motor symptoms.

“Everyone has been so trapped in the conventional idea of the neuronal death as the single cause of PD. That hampers efforts to investigate roles of other neuronal activities, such as surrounding astrocytes,” C. Justin Lee, PhD, the study’s corresponding author, said in a press release.

“The neuronal death ruled out any possibility to reverse PD. Since dormant neurons can be awakened to resume their production capability, this finding will allow us to give PD patients hopes to live a new life without PD,” Lee added.

Treatment with two different compounds that block GABA production in astrocytes, called monoamine oxidase-B, or MAO-B, inhibitors, was sufficient for neurons to recover the enzymatic machinery necessary to produce dopamine, the study found. This significantly alleviated Parkinson’s motor symptoms in the study animals.

In fact, the MAO-B inhibitors used for the study — selegiline (brand names Eldepryl, Carbex, Zelapar, among others), and safinamide (brand name Xadago) — are already prescribed to Parkinson’s patients as an add-on therapy to levodopa. They are believed to prevent the break down of dopamine in the brain.

Importantly, the existence of dormant neurons was observed in the brains of human patients. Analysis of postmortem brains of individuals with mild and severe Parkinson’s had a significant population of dormant neurons surrounded by numerous GABA-producing astrocytes.

The researchers hope that “awakening” neurons using MAO-B inhibition could be an effective disease-modifying therapeutic strategy for Parkinson’s, especially for patients in the early stages of the disease. At that time, inactive, yet live dopaminergic neurons are still present.

Although the results from several clinical trials have cast doubt on the therapeutic efficacy of traditional MAO-B inhibitors, researchers say they have recently developed a new inhibitor, KDS2010. KDS2010 effectively inhibits astrocytic GABA production with minimal side effects in Alzheimer’s animal models and also could be effective for alleviating Parkinson’s motor symptoms, the investigators said.

“This research refutes the common belief that there is no disease-modifying treatment for PD due to its basis on neuronal cell death,” said Hoon Ryu, PhD, a researcher at KIST Brain Science Institute, in South Korea, and one of the senior authors of the study.

“The significance of this study lies in its potential as the new form of treatment for patients in early stages of PD,” Ryu said.

The fact that inhibition of dopaminergic neurons by surrounding astrocytes is one of the core causes of Parkinson’s should be a “drastic turning point” in understanding and treating not only Parkinson’s but also other neurodegenerative diseases, added Sang Ryong Jeon, MD, PhD, also a researcher at KIST and a study co-author.


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Neurons are the primary components of the nervous system, along with the glial cells that give them structural and metabolic support. The nervous system is made up of the central nervous system, which includes the brain and spinal cord, and the peripheral nervous system, which includes the autonomic and somatic nervous systems. In vertebrates, the majority of neurons belong to the central nervous system, but some reside in peripheral ganglia, and many sensory neurons are situated in sensory organs such as the retina and cochlea.

Axons may bundle into fascicles that make up the nerves in the peripheral nervous system (like strands of wire make up cables). Bundles of axons in the central nervous system are called tracts.

Neurons are highly specialized for the processing and transmission of cellular signals. Given their diversity of functions performed in different parts of the nervous system, there is a wide variety in their shape, size, and electrochemical properties. For instance, the soma of a neuron can vary from 4 to 100 micrometers in diameter. [1]

  • The soma is the body of the neuron. As it contains the nucleus, most protein synthesis occurs here. The nucleus can range from 3 to 18 micrometers in diameter. [2]
  • The dendrites of a neuron are cellular extensions with many branches. This overall shape and structure is referred to metaphorically as a dendritic tree. This is where the majority of input to the neuron occurs via the dendritic spine.
  • The axon is a finer, cable-like projection that can extend tens, hundreds, or even tens of thousands of times the diameter of the soma in length. The axon primarily carries nerve signals away from the soma, and carries some types of information back to it. Many neurons have only one axon, but this axon may—and usually will—undergo extensive branching, enabling communication with many target cells. The part of the axon where it emerges from the soma is called the axon hillock. Besides being an anatomical structure, the axon hillock also has the greatest density of voltage-dependent sodium channels. This makes it the most easily excited part of the neuron and the spike initiation zone for the axon. In electrophysiological terms, it has the most negative threshold potential.
    • While the axon and axon hillock are generally involved in information outflow, this region can also receive input from other neurons.

    The accepted view of the neuron attributes dedicated functions to its various anatomical components however, dendrites and axons often act in ways contrary to their so-called main function. [ citation needed ]

    Axons and dendrites in the central nervous system are typically only about one micrometer thick, while some in the peripheral nervous system are much thicker. The soma is usually about 10–25 micrometers in diameter and often is not much larger than the cell nucleus it contains. The longest axon of a human motor neuron can be over a meter long, reaching from the base of the spine to the toes.

    Sensory neurons can have axons that run from the toes to the posterior column of the spinal cord, over 1.5 meters in adults. Giraffes have single axons several meters in length running along the entire length of their necks. Much of what is known about axonal function comes from studying the squid giant axon, an ideal experimental preparation because of its relatively immense size (0.5–1 millimeters thick, several centimeters long).

    Fully differentiated neurons are permanently postmitotic [3] however, stem cells present in the adult brain may regenerate functional neurons throughout the life of an organism (see neurogenesis). Astrocytes are star-shaped glial cells. They have been observed to turn into neurons by virtue of their stem cell-like characteristic of pluripotency.

    Membrane Edit

    Like all animal cells, the cell body of every neuron is enclosed by a plasma membrane, a bilayer of lipid molecules with many types of protein structures embedded in it. A lipid bilayer is a powerful electrical insulator, but in neurons, many of the protein structures embedded in the membrane are electrically active. These include ion channels that permit electrically charged ions to flow across the membrane and ion pumps that chemically transport ions from one side of the membrane to the other. Most ion channels are permeable only to specific types of ions. Some ion channels are voltage gated, meaning that they can be switched between open and closed states by altering the voltage difference across the membrane. Others are chemically gated, meaning that they can be switched between open and closed states by interactions with chemicals that diffuse through the extracellular fluid. The ion materials include sodium, potassium, chloride, and calcium. The interactions between ion channels and ion pumps produce a voltage difference across the membrane, typically a bit less than 1/10 of a volt at baseline. This voltage has two functions: first, it provides a power source for an assortment of voltage-dependent protein machinery that is embedded in the membrane second, it provides a basis for electrical signal transmission between different parts of the membrane.

    Histology and internal structure Edit

    Numerous microscopic clumps called Nissl bodies (or Nissl substance) are seen when nerve cell bodies are stained with a basophilic ("base-loving") dye. These structures consist of rough endoplasmic reticulum and associated ribosomal RNA. Named after German psychiatrist and neuropathologist Franz Nissl (1860–1919), they are involved in protein synthesis and their prominence can be explained by the fact that nerve cells are very metabolically active. Basophilic dyes such as aniline or (weakly) haematoxylin [4] highlight negatively charged components, and so bind to the phosphate backbone of the ribosomal RNA.

    The cell body of a neuron is supported by a complex mesh of structural proteins called neurofilaments, which together with neurotubules (neuronal microtubules) are assembled into larger neurofibrils. [5] Some neurons also contain pigment granules, such as neuromelanin (a brownish-black pigment that is byproduct of synthesis of catecholamines), and lipofuscin (a yellowish-brown pigment), both of which accumulate with age. [6] [7] [8] Other structural proteins that are important for neuronal function are actin and the tubulin of microtubules. Class III β-tubulin is found almost exclusively in neurons. Actin is predominately found at the tips of axons and dendrites during neuronal development. There the actin dynamics can be modulated via an interplay with microtubule. [9]

    There are different internal structural characteristics between axons and dendrites. Typical axons almost never contain ribosomes, except some in the initial segment. Dendrites contain granular endoplasmic reticulum or ribosomes, in diminishing amounts as the distance from the cell body increases.

    Neurons vary in shape and size and can be classified by their morphology and function. [11] The anatomist Camillo Golgi grouped neurons into two types type I with long axons used to move signals over long distances and type II with short axons, which can often be confused with dendrites. Type I cells can be further classified by the location of the soma. The basic morphology of type I neurons, represented by spinal motor neurons, consists of a cell body called the soma and a long thin axon covered by a myelin sheath. The dendritic tree wraps around the cell body and receives signals from other neurons. The end of the axon has branching axon terminals that release neurotransmitters into a gap called the synaptic cleft between the terminals and the dendrites of the next neuron.

    Structural classification Edit

    Polarity Edit

    Most neurons can be anatomically characterized as:

      : single process : 1 axon and 1 dendrite : 1 axon and 2 or more dendrites
        : neurons with long-projecting axonal processes examples are pyramidal cells, Purkinje cells, and anterior horn cells : neurons whose axonal process projects locally the best example is the granule cell

      Other Edit

      Some unique neuronal types can be identified according to their location in the nervous system and distinct shape. Some examples are:

        , interneurons that form a dense plexus of terminals around the soma of target cells, found in the cortex and cerebellum , large motor neurons , interneurons of the cerebellum , most neurons in the corpus striatum , huge neurons in the cerebellum, a type of Golgi I multipolar neuron , neurons with triangular soma, a type of Golgi I , neurons with both ends linked to alpha motor neurons , interneurons with unique dendrite ending in a brush-like tuft , a type of Golgi II neuron cells, motoneurons located in the spinal cord , interneurons that connect widely separated areas of the brain

      Functional classification Edit

      Direction Edit

        convey information from tissues and organs into the central nervous system and are also called sensory neurons. (motor neurons) transmit signals from the central nervous system to the effector cells. connect neurons within specific regions of the central nervous system.

      Afferent and efferent also refer generally to neurons that, respectively, bring information to or send information from the brain.

      Action on other neurons Edit

      A neuron affects other neurons by releasing a neurotransmitter that binds to chemical receptors. The effect upon the postsynaptic neuron is determined by the type of receptor that is activated, not by the presynaptic neuron or by the neurotransmitter. A neurotransmitter can be thought of as a key, and a receptor as a lock: the same neurotransmitter can activate multiple types of receptors. Receptors can be classified broadly as excitatory (causing an increase in firing rate), inhibitory (causing a decrease in firing rate), or modulatory (causing long-lasting effects not directly related to firing rate).

      The two most common (90%+) neurotransmitters in the brain, glutamate and GABA, have largely consistent actions. Glutamate acts on several types of receptors, and has effects that are excitatory at ionotropic receptors and a modulatory effect at metabotropic receptors. Similarly, GABA acts on several types of receptors, but all of them have inhibitory effects (in adult animals, at least). Because of this consistency, it is common for neuroscientists to refer to cells that release glutamate as "excitatory neurons", and cells that release GABA as "inhibitory neurons". Some other types of neurons have consistent effects, for example, "excitatory" motor neurons in the spinal cord that release acetylcholine, and "inhibitory" spinal neurons that release glycine.

      The distinction between excitatory and inhibitory neurotransmitters is not absolute. Rather, it depends on the class of chemical receptors present on the postsynaptic neuron. In principle, a single neuron, releasing a single neurotransmitter, can have excitatory effects on some targets, inhibitory effects on others, and modulatory effects on others still. For example, photoreceptor cells in the retina constantly release the neurotransmitter glutamate in the absence of light. So-called OFF bipolar cells are, like most neurons, excited by the released glutamate. However, neighboring target neurons called ON bipolar cells are instead inhibited by glutamate, because they lack typical ionotropic glutamate receptors and instead express a class of inhibitory metabotropic glutamate receptors. [12] When light is present, the photoreceptors cease releasing glutamate, which relieves the ON bipolar cells from inhibition, activating them this simultaneously removes the excitation from the OFF bipolar cells, silencing them.

      It is possible to identify the type of inhibitory effect a presynaptic neuron will have on a postsynaptic neuron, based on the proteins the presynaptic neuron expresses. Parvalbumin-expressing neurons typically dampen the output signal of the postsynaptic neuron in the visual cortex, whereas somatostatin-expressing neurons typically block dendritic inputs to the postsynaptic neuron. [13]

      Discharge patterns Edit

      Neurons have intrinsic electroresponsive properties like intrinsic transmembrane voltage oscillatory patterns. [14] So neurons can be classified according to their electrophysiological characteristics:

      • Tonic or regular spiking. Some neurons are typically constantly (tonically) active, typically firing at a constant frequency. Example: interneurons in neurostriatum.
      • Phasic or bursting. Neurons that fire in bursts are called phasic.
      • Fast spiking. Some neurons are notable for their high firing rates, for example some types of cortical inhibitory interneurons, cells in globus pallidus, retinal ganglion cells. [15][16]

      Neurotransmitter Edit

      • Cholinergic neurons—acetylcholine. Acetylcholine is released from presynaptic neurons into the synaptic cleft. It acts as a ligand for both ligand-gated ion channels and metabotropic (GPCRs) muscarinic receptors. Nicotinic receptors are pentameric ligand-gated ion channels composed of alpha and beta subunits that bind nicotine. Ligand binding opens the channel causing influx of Na + depolarization and increases the probability of presynaptic neurotransmitter release. Acetylcholine is synthesized from choline and acetyl coenzyme A.
      • Adrenergic neurons—noradrenaline. Noradrenaline (norepinephrine) is release from most postganglionic neurons in the sympathetic nervous system onto two sets of GPCRs: alpha adrenoceptors and beta adrenoceptors. Noradrenaline is one of the three common catecholamine neurotransmitter, and the most prevalent of them in the peripheral nervous system as with other catecholamines, it is synthesised from tyrosine.
      • GABAergic neurons—gamma aminobutyric acid. GABA is one of two neuroinhibitors in the central nervous system (CNS), along with glycine. GABA has a homologous function to ACh, gating anion channels that allow Cl − ions to enter the post synaptic neuron. Cl − causes hyperpolarization within the neuron, decreasing the probability of an action potential firing as the voltage becomes more negative (for an action potential to fire, a positive voltage threshold must be reached). GABA is synthesized from glutamate neurotransmitters by the enzyme glutamate decarboxylase.
      • Glutamatergic neurons—glutamate. Glutamate is one of two primary excitatory amino acid neurotransmitters, along with aspartate. Glutamate receptors are one of four categories, three of which are ligand-gated ion channels and one of which is a G-protein coupled receptor (often referred to as GPCR).
        and Kainate receptors function as cation channels permeable to Na + cation channels mediating fast excitatory synaptic transmission. receptors are another cation channel that is more permeable to Ca 2+ . The function of NMDA receptors depend on glycine receptor binding as a co-agonist within the channel pore. NMDA receptors do not function without both ligands present.
  • Metabotropic receptors, GPCRs modulate synaptic transmission and postsynaptic excitability.
    • Dopaminergic neurons—dopamine. Dopamine is a neurotransmitter that acts on D1 type (D1 and D5) Gs-coupled receptors, which increase cAMP and PKA, and D2 type (D2, D3, and D4) receptors, which activate Gi-coupled receptors that decrease cAMP and PKA. Dopamine is connected to mood and behavior and modulates both pre- and post-synaptic neurotransmission. Loss of dopamine neurons in the substantia nigra has been linked to Parkinson's disease. Dopamine is synthesized from the amino acid tyrosine. Tyrosine is catalyzed into levadopa (or L-DOPA) by tyrosine hydroxlase, and levadopa is then converted into dopamine by the aromatic amino acid decarboxylase.
    • Serotonergic neurons—serotonin. Serotonin (5-Hydroxytryptamine, 5-HT) can act as excitatory or inhibitory. Of its four 5-HT receptor classes, 3 are GPCR and 1 is a ligand-gated cation channel. Serotonin is synthesized from tryptophan by tryptophan hydroxylase, and then further by decarboxylase. A lack of 5-HT at postsynaptic neurons has been linked to depression. Drugs that block the presynaptic serotonin transporter are used for treatment, such as Prozac and Zoloft.
    • Purinergic neurons—ATP. ATP is a neurotransmitter acting at both ligand-gated ion channels (P2X receptors) and GPCRs (P2Y) receptors. ATP is, however, best known as a cotransmitter. Such purinergic signalling can also be mediated by other purines like adenosine, which particularly acts at P2Y receptors.
    • Histaminergic neurons—histamine. Histamine is a monoamine neurotransmitter and neuromodulator. Histamine-producing neurons are found in the tuberomammillary nucleus of the hypothalamus. [17] Histamine is involved in arousal and regulating sleep/wake behaviors.

    Multimodel Classification Edit

    Since 2012 there has been a push from the cellular and computational neuroscience community to come up with a universal classification of neurons that will apply to all neurons in the brain as well as across species. this is done by considering the 3 essential qualities of all neurons: electrophysiology, morphology, and the individual transcriptome of the cells. besides being universal this classification has the advantage of being able to classify astrocytes as well. A method called Patch-Seq in which all 3 qualities can be measured at once is used extensively by the Allen Institute for Brain Science. [18]

    Neurons communicate with each other via synapses, where either the axon terminal of one cell contacts another neuron's dendrite, soma or, less commonly, axon. Neurons such as Purkinje cells in the cerebellum can have over 1000 dendritic branches, making connections with tens of thousands of other cells other neurons, such as the magnocellular neurons of the supraoptic nucleus, have only one or two dendrites, each of which receives thousands of synapses.

    Synapses can be excitatory or inhibitory, either increasing or decreasing activity in the target neuron, respectively. Some neurons also communicate via electrical synapses, which are direct, electrically conductive junctions between cells. [19]

    When an action potential reaches the axon terminal, it opens voltage-gated calcium channels, allowing calcium ions to enter the terminal. Calcium causes synaptic vesicles filled with neurotransmitter molecules to fuse with the membrane, releasing their contents into the synaptic cleft. The neurotransmitters diffuse across the synaptic cleft and activate receptors on the postsynaptic neuron. High cytosolic calcium in the axon terminal triggers mitochondrial calcium uptake, which, in turn, activates mitochondrial energy metabolism to produce ATP to support continuous neurotransmission. [20]

    An autapse is a synapse in which a neuron's axon connects to its own dendrites.

    The human brain has some 8.6 x 10 10 (eighty six billion) neurons. [21] Each neuron has on average 7,000 synaptic connections to other neurons. It has been estimated that the brain of a three-year-old child has about 10 15 synapses (1 quadrillion). This number declines with age, stabilizing by adulthood. Estimates vary for an adult, ranging from 10 14 to 5 x 10 14 synapses (100 to 500 trillion). [22]

    In 1937 John Zachary Young suggested that the squid giant axon could be used to study neuronal electrical properties. [23] It is larger than but similar to human neurons, making it easier to study. By inserting electrodes into the squid giant axons, accurate measurements were made of the membrane potential.

    The cell membrane of the axon and soma contain voltage-gated ion channels that allow the neuron to generate and propagate an electrical signal (an action potential). Some neurons also generate subthreshold membrane potential oscillations. These signals are generated and propagated by charge-carrying ions including sodium (Na + ), potassium (K + ), chloride (Cl − ), and calcium (Ca 2+ ).

    Several stimuli can activate a neuron leading to electrical activity, including pressure, stretch, chemical transmitters, and changes of the electric potential across the cell membrane. [24] Stimuli cause specific ion-channels within the cell membrane to open, leading to a flow of ions through the cell membrane, changing the membrane potential. Neurons must maintain the specific electrical properties that define their neuron type. [25]

    Thin neurons and axons require less metabolic expense to produce and carry action potentials, but thicker axons convey impulses more rapidly. To minimize metabolic expense while maintaining rapid conduction, many neurons have insulating sheaths of myelin around their axons. The sheaths are formed by glial cells: oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. The sheath enables action potentials to travel faster than in unmyelinated axons of the same diameter, whilst using less energy. The myelin sheath in peripheral nerves normally runs along the axon in sections about 1 mm long, punctuated by unsheathed nodes of Ranvier, which contain a high density of voltage-gated ion channels. Multiple sclerosis is a neurological disorder that results from demyelination of axons in the central nervous system.

    Some neurons do not generate action potentials, but instead generate a graded electrical signal, which in turn causes graded neurotransmitter release. Such non-spiking neurons tend to be sensory neurons or interneurons, because they cannot carry signals long distances.

    Neural coding is concerned with how sensory and other information is represented in the brain by neurons. The main goal of studying neural coding is to characterize the relationship between the stimulus and the individual or ensemble neuronal responses, and the relationships among the electrical activities of the neurons within the ensemble. [26] It is thought that neurons can encode both digital and analog information. [27]

    The conduction of nerve impulses is an example of an all-or-none response. In other words, if a neuron responds at all, then it must respond completely. Greater intensity of stimulation, like brighter image/louder sound, does not produce a stronger signal, but can increase firing frequency. [28] : 31 Receptors respond in different ways to stimuli. Slowly adapting or tonic receptors respond to steady stimulus and produce a steady rate of firing. Tonic receptors most often respond to increased intensity of stimulus by increasing their firing frequency, usually as a power function of stimulus plotted against impulses per second. This can be likened to an intrinsic property of light where greater intensity of a specific frequency (color) requires more photons, as the photons can't become "stronger" for a specific frequency.

    Other receptor types include quickly adapting or phasic receptors, where firing decreases or stops with steady stimulus examples include skin which, when touched causes neurons to fire, but if the object maintains even pressure, the neurons stop firing. The neurons of the skin and muscles that are responsive to pressure and vibration have filtering accessory structures that aid their function.

    The pacinian corpuscle is one such structure. It has concentric layers like an onion, which form around the axon terminal. When pressure is applied and the corpuscle is deformed, mechanical stimulus is transferred to the axon, which fires. If the pressure is steady, stimulus ends thus, typically these neurons respond with a transient depolarization during the initial deformation and again when the pressure is removed, which causes the corpuscle to change shape again. Other types of adaptation are important in extending the function of a number of other neurons. [29]

    The German anatomist Heinrich Wilhelm Waldeyer introduced the term neuron in 1891, [30] based on the ancient Greek νεῦρον neuron 'sinew, cord, nerve'. [31]

    The word was adopted in French with the spelling neurone. That spelling was also used by many writers in English, [32] but has now become rare in American usage and uncommon in British usage. [33] [31]

    The inhibition of high-voltage-activated calcium current by activation of MrgC11 involves phospholipase C-dependent mechanisms

    High-voltage-activated (HVA) calcium channels play an important role in synaptic transmission. Activation of Mas-related G-protein-coupled receptor subtype C (MrgC mouse MrgC11, rat homolog rMrgC) inhibits HVA calcium current (ICa) in small-diameter dorsal root ganglion (DRG) neurons, but the intracellular signaling cascade underlying MrgC agonist-induced inhibition of HVA ICa in native DRG neurons remains unclear. To address this question, we conducted patch-clamp recordings in MrgA3-eGFP-wild-type mice, in which most MrgA3-eGFP(+) DRG neurons co-express MrgC11 and can be identified for recording. We found that the inhibition of HVA ICa by JHU58 (0.001-100nM, a dipeptide, MrgC-selective agonist) was significantly reduced by pretreatment with a phospholipase C (PLC) inhibitor (U73122, 1μM), but not by its inactive analog (U73343) or vehicle. Further, in rats that had undergone spinal nerve injury, pretreatment with intrathecal U73122 nearly abolished the inhibition of mechanical hypersensitivity by intrathecal JHU58. The inhibition of HVA ICa in MrgA3-eGFP(+) neurons by JHU58 (100nM) was partially reduced by pretreatment with a Gβγ blocker (gallein, 100μM). However, applying a depolarizing prepulse and blocking the Gαi and Gαs pathways with pertussis toxin (PTX) (0.5μg/mL) and cholera toxin (CTX) (0.5μg/mL), respectively, had no effect. These findings suggest that activation of MrgC11 may inhibit HVA ICa in mouse DRG neurons through a voltage-independent mechanism that involves activation of the PLC, but not Gαi or Gαs, pathway.

    Keywords: MrgC PLC calcium channel dorsal root ganglion pain.

    Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.


    Fig. 1. Pertussis toxin (PTX) does not…

    Fig. 1. Pertussis toxin (PTX) does not block JHU58-induced inhibition of high-voltage-activated (HVA) calcium currents…

    Fig. 2. Pertussis toxin (PTX) does not…

    Fig. 2. Pertussis toxin (PTX) does not reduce BAM8-22–induced inhibition of high-voltage-activated (HVA) calcium currents…

    Fig. 3. JHU58-induced inhibition of high-voltage-activated (HVA)…

    Fig. 3. JHU58-induced inhibition of high-voltage-activated (HVA) calcium currents ( I Ca ) in MrgA3-eGFP…

    Fig. 4. Effects of gallein and prepulse…

    Fig. 4. Effects of gallein and prepulse stimulation on JHU58-induced inhibition of high-voltage-activated (HVA) calcium…

    Fig. 5. Cholera toxin (CTX) does not…

    Fig. 5. Cholera toxin (CTX) does not block JHU58-induced inhibition of high-voltage-activated (HVA) calcium currents…

    Fig. 6. U73122 reduces JHU58-induced inhibition of…

    Fig. 6. U73122 reduces JHU58-induced inhibition of neuropathic mechanical hypersensitivity

    Songbird neurons for advanced cognition mirror the physiology of mammalian counterparts

    University of Massachusetts Amherst neuroscientists examining genetically identified neurons in a songbird's forebrain discovered a remarkable landscape of physiology, auditory coding and network roles that mirrored those in the brains of mammals.

    The research, published May 13 in Current Biology, advances insight into the fundamental operation of complex brain circuits. It suggests that ancient cell types in the pallium -- the outer regions of the brain that include cortex -- most likely retained features over millions of years that are the building blocks for advanced cognition in birds and mammals.

    "We as neuroscientists are catching on that birds can do sophisticated things and they have sophisticated circuits to do those things," says behavioral neuroscientist Luke Remage-Healey, associate professor of psychological and brain sciences and senior author of the paper.

    For the first time, the team of neuroscientists, including lead author Jeremy Spool, who worked as a National Institutes of Health (NIH) postdoctoral fellow in Remage-Healey's lab, used viral optogenetics to define the molecular identities of excitatory and inhibitory cell types in zebra finches (Taeniopygia guttata) and match them to their physiological properties.

    "In the songbird community, we've had a hunch for a long time that when we record the electrical signatures of these two cell types, we say -- 'that's a putative excitatory neuron, that's a putative inhibitory neuron.' Now we know that these features are grounded in molecular truth," Remage-Healey says. "Without being able to pinpoint the cell types with these viruses, we wouldn't be able to learn how the cell and network features bear resemblance to those in mammals, because the brain architectures are so different."

    The research team used viruses from a collection curated by co-author Yoko Yazaki-Sugiyama at the Okinawa Institute of Science and Technology in Japan to conduct viral optogenetic experiments in the brain. With optogenetics, the team used flashes of light to manipulate one cell type independent of the other. The team targeted excitatory vs. inhibitory neurons (using CaMKII? and GAD1 promoters, respectively) in the zebra finch auditory pallium to test predictions based on the mammalian pallium.

    "There's so much work out there on the physiology of these different cell types in the mammalian cortex that we were able to line up a series of predictions about what features birds may or may not have," Spool says.

    The CaMKII? and GAD1 populations in the songbird were distinct "in exactly the proportions you would expect from the mammalian brain," Spool says. With the cell type populations isolated, the researchers then examined systematically whether each population would correspond to the physiology of their mammalian counterparts.

    "As we kept moving forward, again and again these cell populations were acting as if they were essentially from the mammalian cortex in a lot of physiological ways," Spool says.

    Remage-Healey adds, "The correspondence between the cortex in mammals and what we're pulling out with molecularly identified cell types in birds is pretty striking."

    In both birds and mammals, these neurons are thought to support advanced cognitive functions, such as memory, individual recognition and associative learning, Spool says.

    Remage-Healey says the research, supported by NIH grants, helps delineate "the basic nuts and bolts of how the brain operates." Knowing the nuts and bolts builds foundations necessary to develop breakthroughs that could lead to neurological interventions for brain disorders.

    "This can help us figure out what brain diversity is out there by unpacking these circuits and the ways they can go awry," Remage-Healey says.

    Watch the video: Νευρικό Σύστημα. Μέρος Ε: Ανώτερες Πνευματικές Λειτουργίες. Μνήμη-Μάθηση-Συμπεριφορά (January 2022).