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Are there any neurotransmitters that trigger all neurons?

Are there any neurotransmitters that trigger all neurons?


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I'm reading into the basics of the nervous system, and am intrigued by neurotransmitters. I understand that certain neurotransmitters can trigger more than one neuron type, and may be used as inhibitors or regulators (antagonists). Conversely, are there any types of agonists that trigger excitation in all neurons, regardless of type? If so, what functions do these play?


There is no such promiscuous neurotransmitter. There is always some difference between central and peripheral nervous system w.r.t neurotransmitter usage.

Glutamate is one neurotransmitter which acts as an excitatory agonist in most neurons (but still… not ALL neurons)


Equine Behavior of Sensory and Neural Origin

Neurotransmitters

Neurotransmitters are responsible for sending the messages from one neuron to the next. While they exist throughout the body, they are most prevalent in the brain. Understanding brain function and responses to various psychopharmacological agents depends on a basic understanding of these internal chemicals. Classifying neurotransmitters is complicated because there are over 100 different ones. Fortunately, the seven “small molecule” neurotransmitters (acetylcholine, dopamine, gamma-aminobutyric acid (GABA), glutamate, histamine, norepinephrine, and serotonin) do the majority of the work. Another complicating factor is that neurotransmitters may have a number of subtypes, serotonin having 15, as an example. 157 Endorphins and oxytocin are neuropeptides that are sometimes considered to be neurotransmitters, and β-endorphin is associated with the feeling of pleasure in humans. Exercise causes β-endorphin and serotonin levels to significantly increase in horses. 158 This is likely to happen in human runners too. It is also thought some neurotransmitters may play a role in stereotypies. 159 Neurotransmitters do have general functions that hold true even across species, as will be described later in the book.

The equine brain has not been well studied relative to which neurotransmitters are associated with which nuclei or specific functions. Each nucleus may have multiple neurotransmitters, and there can be considerable differences in their proportions between species. This explains why a drug that works in one species may not be as effective for a similar problem in another. It is important to understand that the choice of a psychopharmacological drug is based on empirical data, so depending on the patient’s response, it might be necessary to modify doses or drugs used.


What Is A Neuron?

In order to answer how a neuronal action potential works, we need to first review the basics of what a neuron is. This section will show that a neuron is essentially just like any other cell of the body. However, it will also reveal the striking differences in shape and structure compared to other cell types, features crucial to their unique functions.

A Cell Like Any Other

To begin, a neuron is made of all the same stuff as the cells of your kidneys, muscles, skin, blood vessels, bones, and every other organ in your body. The basic components of all such cells are: the membrane (the cell’s container), the cytoplasm (a watery substance that fills the membrane), the organelles (tiny organs that accomplish the individual tasks necessary to a cell’s survival and proper functioning), the cytoskeleton (structural components of the cell), and functional molecules (which cause key chemical reactions to occur) (6, 7).

In addition to these structural similarities, neurons share a few other properties with bodily cells: they have access to the bloodstream they are sensitive to hormones they need water, glucose, and other nutrients they exchange molecules with their immediate environment they each contain all the DNA of their owner’s genome and they are formed from the very same progenitor cells during fetal development (6, 7).

A Cell Like No Other

So what’s the big deal? Why are neurons so special? Part of the answer to that question comes from their unique shape and functional arrangement. Neurons (sometimes also called “nerve cells”) have three main parts: the cell body, the dendrites, and the axon (1, 6).

The cell body is the hub of the neuron, the central core, with a roughly spherical shape. It holds many of the components listed above and is largely responsible for both the basic life processes that allow the neuron to survive and do its thing, as well as the consolidation of signals from other neurons.

Growing out from various locations on the surface of the cell body are tree-like structures (without the leaves) called “dendrites”. Dendrites are the receivers they are responsible for taking in messages from other neurons. And they are indeed very tree-like in appearance, which explains why neuroscientists refer to their branching patterns as “arborization”.

Also growing out from the cell body is a single, sturdy cable called the “axon”. At the end of this cable, the axon also has an interesting and somewhat extensive branching pattern. The axon is the sender its function is to transmit signals to the dendrites of nearby neurons.

A final point concerns the diversity of forms exhibited by various types of neurons (the names of which we won’t bother with here). They can be anywhere on the spectrum of uniform and compact to asymmetrical and extended (1, 6, 8). For example, the cortex of the brain houses neurons that can appear like a static, elongated image of those “plasma globe” things you find at gift shops, with the central electrode corresponding to the cell body and the filaments of electricity corresponding to the dendrites and axon. On the other hand, the spinal cord is composed of neurons with axons (the sender cables) extending a few feet from their cell body (1), giving them a cord-like appearance.


Biology of Depression - Neurotransmitters

Lots of research has been done on the causes of depression. We are now going to have a brief discussion of the many biological, psychological and social factors that have been identified as being related to major depressive disorder.

Biology of Depressive Disorders

You may have heard that depression is the result of a simple imbalance of brain chemicals. Although brain chemicals are certainly part of the cause, this explanation is too simple. Even just considering the biological dimension of depression, the brain has multiple layers of issues that are involved.

Neurochemistry

The brain uses a number of chemicals as messengers to communicate with other parts of itself and within the nervous system. Nerve cells are the major type of cell in the nervous system. These are called neurons. They communicate through chemical messengers, called neurotransmitters. These messengers are released and received by the brain's many neurons. Neurons are constantly communicating with each other by exchanging neurotransmitters. This communication system is essential to all of the brain's functions.

A neuron has a cell body and a tail-like structure called an axon. Neurons are spaced apart by a tiny space called a synapse. In a simple scenario, one neuron (the sender) sends a neurotransmitter message across the synapse to the next neuron (the receiver). The receiver neuron is activated by whatever chemical it just received and communicates the signal down the chain to the next neuron. The receiving end of a neuron has receptors, which receive the chemical signals. When the perfect matching signal or neurotransmitter reaches its receptor across the tiny space, the receptor is activated. It then sends the message along to the next neuron by way of a neurotransmitter. For example, if someone has to go through many locked doors with each door being behind another locked door, the right key is needed. If the first door is opened with the right key, then the person can proceed to the next door with the next key and so on.

In music, it's not just the notes that make up a melody. It is also the spaces or rests between the notes that make each note stand out and be distinct. It's exactly the same with regard to neurotransmitters and synapses. There needs to be some quiet time between neurotransmitter messages for those messages to have any meaning. It is important that receptors be allowed to reset and deactivate between messages so that they can become ready to receive the next burst of neurotransmitters. In order to achieve this "resetting", the receptors relax and release their captured neurotransmitters back into the tiny space where about 90% of them get taken up again (in a process called reuptake) by the original sending neuron. The neurotransmitters are then repackaged and reused the next time a message needs to be sent across the synapse. Even though this seems like a complicated set of steps, this entire information transmission cycle occurs in the brain within in a matter of seconds. Any problem that interrupts the smooth functioning of this chain of chemical events can negatively impact both the brain and nervous system.

Depression has been linked to problems or imbalances in the brain, specifically with the neurotransmitters serotonin, norepinephrine, and dopamine. It is very difficult to actually measure the level of neurotransmitters in a person's brain and their activity. What we do know is that antidepressant medications, which are used to treat the symptoms of depression, are known to act upon these particular neurotransmitters and their receptors. We'll talk more about antidepressant medications in the treatment section of this center.

The neurotransmitter serotonin is involved in controlling many important bodily functions, including sleep, aggression, eating, sexual behavior, and mood. Serotonin is produced by serotonergic neurons. Current research suggests that a decrease in the production of serotonin by these neurons can cause depression in some people, and more specifically, a mood state that can cause some people to feel suicidal.

In the 1960s, the "catecholamine hypothesis" was a popular explanation for why people developed depression. This hypothesis suggested that a deficiency of the neurotransmitter norepinephrine (also known as noradrenaline) in certain areas of the brain was responsible for creating depressed mood. More recent research suggests that there is a group of people with depression who have low levels of norepinephrine. Autopsy studies show that people who have experienced multiple depressive episodes have fewer norepinephrinergic neurons than people who have no depressive history. However, research results also tell us that not all people experience mood changes in response to decreased norepinephrine levels. Some people who are depressed actually show more than normal within the neurons that produce norepinephrine. More current studies suggest that in some people, low levels of serotonin trigger a drop in norepinephrine levels, which then leads to depression.

Another line of research has investigated linkages between stress, depression, and norepinephrine. Norepinephrine helps our bodies to recognize and respond to stressful situations. Researchers suggest that people who are vulnerable to depression may have a norepinephrinergic system that doesn't handle the effects of stress very efficiently.

The neurotransmitter dopamine is also linked to depression. Dopamine plays an important role in controlling our drive to seek out rewards, as well as our ability to obtain a sense of pleasure. Low dopamine levels may, in part, explain why people with depression don't get the same sense of pleasure out of activities or people that they did before becoming depressed.

In addition, new studies are showing that other neurotransmitters such as acetylcholine, glutamate, and Gamma-aminobutyric acid (GABA) can also play a role in depressive disorders. More research is necessary to understand their role in depression's brain chemistry.


Biology of Depression - Neurotransmitters

Lots of research has been done on the causes of depression. We are now going to have a brief discussion of the many biological, psychological and social factors that have been identified as being related to major depressive disorder.

Biology of Depressive Disorders

You may have heard that depression is the result of a simple imbalance of brain chemicals. Although brain chemicals are certainly part of the cause, this explanation is too simple. Even just considering the biological dimension of depression, the brain has multiple layers of issues that are involved.

Neurochemistry

The brain uses a number of chemicals as messengers to communicate with other parts of itself and within the nervous system. Nerve cells are the major type of cell in the nervous system. These are called neurons. They communicate through chemical messengers, called neurotransmitters. These messengers are released and received by the brain's many neurons. Neurons are constantly communicating with each other by exchanging neurotransmitters. This communication system is essential to all of the brain's functions.

A neuron has a cell body and a tail-like structure called an axon. Neurons are spaced apart by a tiny space called a synapse. In a simple scenario, one neuron (the sender) sends a neurotransmitter message across the synapse to the next neuron (the receiver). The receiver neuron is activated by whatever chemical it just received and communicates the signal down the chain to the next neuron. The receiving end of a neuron has receptors, which receive the chemical signals. When the perfect matching signal or neurotransmitter reaches its receptor across the tiny space, the receptor is activated. It then sends the message along to the next neuron by way of a neurotransmitter. For example, if someone has to go through many locked doors with each door being behind another locked door, the right key is needed. If the first door is opened with the right key, then the person can proceed to the next door with the next key and so on.

In music, it's not just the notes that make up a melody. It is also the spaces or rests between the notes that make each note stand out and be distinct. It's exactly the same with regard to neurotransmitters and synapses. There needs to be some quiet time between neurotransmitter messages for those messages to have any meaning. It is important that receptors be allowed to reset and deactivate between messages so that they can become ready to receive the next burst of neurotransmitters. In order to achieve this "resetting", the receptors relax and release their captured neurotransmitters back into the tiny space where about 90% of them get taken up again (in a process called reuptake) by the original sending neuron. The neurotransmitters are then repackaged and reused the next time a message needs to be sent across the synapse. Even though this seems like a complicated set of steps, this entire information transmission cycle occurs in the brain within in a matter of seconds. Any problem that interrupts the smooth functioning of this chain of chemical events can negatively impact both the brain and nervous system.

Depression has been linked to problems or imbalances in the brain, specifically with the neurotransmitters serotonin, norepinephrine, and dopamine. It is very difficult to actually measure the level of neurotransmitters in a person's brain and their activity. What we do know is that antidepressant medications, which are used to treat the symptoms of depression, are known to act upon these particular neurotransmitters and their receptors. We'll talk more about antidepressant medications in the treatment section of this center.

The neurotransmitter serotonin is involved in controlling many important bodily functions, including sleep, aggression, eating, sexual behavior, and mood. Serotonin is produced by serotonergic neurons. Current research suggests that a decrease in the production of serotonin by these neurons can cause depression in some people, and more specifically, a mood state that can cause some people to feel suicidal.

In the 1960s, the "catecholamine hypothesis" was a popular explanation for why people developed depression. This hypothesis suggested that a deficiency of the neurotransmitter norepinephrine (also known as noradrenaline) in certain areas of the brain was responsible for creating depressed mood. More recent research suggests that there is a group of people with depression who have low levels of norepinephrine. Autopsy studies show that people who have experienced multiple depressive episodes have fewer norepinephrinergic neurons than people who have no depressive history. However, research results also tell us that not all people experience mood changes in response to decreased norepinephrine levels. Some people who are depressed actually show more than normal within the neurons that produce norepinephrine. More current studies suggest that in some people, low levels of serotonin trigger a drop in norepinephrine levels, which then leads to depression.

Another line of research has investigated linkages between stress, depression, and norepinephrine. Norepinephrine helps our bodies to recognize and respond to stressful situations. Researchers suggest that people who are vulnerable to depression may have a norepinephrinergic system that doesn't handle the effects of stress very efficiently.

The neurotransmitter dopamine is also linked to depression. Dopamine plays an important role in controlling our drive to seek out rewards, as well as our ability to obtain a sense of pleasure. Low dopamine levels may, in part, explain why people with depression don't get the same sense of pleasure out of activities or people that they did before becoming depressed.

In addition, new studies are showing that other neurotransmitters such as acetylcholine, glutamate, and Gamma-aminobutyric acid (GABA) can also play a role in depressive disorders. More research is necessary to understand their role in depression's brain chemistry.


Loss Of Two Types Of Neurons Triggers Parkinson's Symptoms, Study Suggests

New evidence indicates that the loss of two types of brain cells--not just one as previously thought--may trigger the onset of symptoms associated with Parkinson's disease.

The evidence, based on mouse models, shows a link between the loss of both norepinephrine and dopamine neurons and the delayed onset of symptoms associated with Parkinson's disease. It was originally thought that the loss of only dopamine neurons triggered symptoms. Dopamine is a neurotransmitter critical for coordinating movement.

The research was conducted by Karen Rommelfanger, graduate student in the laboratory of David Weinshenker, PhD, assistant professor of human genetics in Emory University School of Medicine and Gary Miller, PhD, associate professor in Emory's Rollins School of Public Health. The team also included Gaylen Edwards and Kimberly Freeman at the University of Georgia.

Parkinson's disease affects motor coordination and is characterized by symptoms such as tremors of hands, arms, legs, jaw and face rigidity or stiffness of limbs and trunk bradykinesia, or slowness of movement and postural instability. The disease most often occurs in those over 50.

"People don't start showing symptoms of Parkinson's disease until about 80 percent of their dopamine neurons are gone, which is when you cross some sort of threshold. Our study looked at what happens while the dopamine neurons are dying and people still appear fine, says Dr. Weinshenker. "The lack of symptoms until the death of most of the dopamine neurons suggested the existence of a system that can temporarily compensate for the loss of the dopamine."

"The dogma in the field is that Parkinson's disease involves a selective loss of dopamine neurons. The truth is, if you look at postmortem Parkinson's disease brains, you will see that both dopamine and norepinephrine neurons are gone," Dr. Weinshenker explains. "We know that norepinephrine is important for regulating the activity of dopamine neurons, so we suspected that the dopamine neurons and the norepinephrine neurons function in concert. As the dopamine neurons start dying, the norepinephrine neurons compensate by signaling the surviving dopamine cells to dramatically increase their activity and the output of dopamine. Eventually, the norepineprhine neurons die, the surviving dopamine neurons lose their ability to release extra dopamine, and symptoms start to appear."

To test their hypothesis, the researchers gave healthy, one-year-old mice the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) at a dose that kills about 80 percent of the dopamine cells, but observed no motor impairments in the mice. Surprisingly, when they tested mice unable to synthesize norepinephrine and that have trouble releasing dopamine properly, they observed symptoms of Parkinson's disease including resting tremor, hunched posture and deficits in coordinated movement. These results indicate that having a normal complement of dopamine neurons is not enough for normal motor function norepinephrine also needs to be present to ensure proper dopamine release.

"Although there are no cures for Parkinson's disease, some moderately effective treatments are available, but most target the dopamine neurons only and are effective for only a limited amount of time. In light of this study, it's quite possible that simultaneously treating both the dopamine and norepinephrine loss could further ameliorate the symptoms of Parkinson's disease,Ó says Dr. Weinshenker.

Results of the study by Emory scientists, along with the University of Georgia, will appear in the Proceedings of the National Academy of Sciences, Early Edition online during the week of Aug. 13-17 and in the Aug. 21 print edition.

The work was funded in part by the National Institutes of Health.

Story Source:

Materials provided by Emory University. Note: Content may be edited for style and length.


Molecular Basis of Rare Neurological Disorder Reveals Potential Treatment

Edwin Chapman has long studied how one protein triggers the release of neurotransmitters, allowing neurons to communicate. A mother’s email prompted him to investigate what happens when this protein malfunctions.

Like people, neurons need to talk to one another. But instead of turning thoughts into words, these cells convert electrical signals into chemical ones. For nearly 30 years, biochemist Edwin Chapman has studied how one protein triggers this crucial conversion.

Now, his team has figured out how mutations in this protein, called synaptotagmin-1 or syt1, can lead to a rare condition known as syt1-associated neurodevelopmental disorder. The scientists’ discovery led them to identify a possible treatment, Chapman and his colleagues report May 1, 2020, in the journal Neuron.

An email prompted the team’s investigation. In 2015, Chapman, a Howard Hughes Medical Institute (HHMI) Investigator at the University of Wisconsin–Madison, received a message from the mother of a two-year-old girl who had learned to walk only with intensive physical therapy, and who could not yet speak or play like a typical child her age.

After testing her daughter, doctors told the mother that a mutation in the SYT1 gene could be the cause. The woman later introduced Chapman to another family who had a child with a similar disorder.

“What was remarkable for me at a personal level was how keen they were to find out exactly what had happened,” Chapman says. “I knew we could figure out the precise problem, and with the support of the parents, we delved into it.”

Syt1-associated neurodevelopmental disorder is extremely rare, with only 11 confirmed cases. These patients suffer from a constellation of difficulties, including developmental delays, eye abnormalities, involuntary movements, and agitation that can cause them to hurt themselves.

Chapman and MD/PhD student Mazdak Bradberry’s study of the disorder relied on their research on neurons. Within these cells, information travels as an electrical pulse. When the pulse reaches the end of a neuron, it triggers an influx of calcium ions. Syt1’s job, Chapman’s team had previously shown, is to detect and grab calcium. Then, the protein inserts itself into the neuron’s membrane, and sparks the release of chemicals known as neurotransmitters. These chemicals carry information to the next neuron.

Scientists have studied this process thoroughly, but they know much less about how mutations in the syt1 protein can interfere with neuron-to-neuron communication. Chapman, Bradberry, and their colleagues took a close look at the mutated proteins made by the girl and two other patients.

Lab experiments with neurons in culture dishes showed that each patient’s mutation interfered with neurotransmitter release, but to different degrees. In all cases, however, the altered syt1 protein became less responsive to calcium — in other words, it had a hard time detecting the signal to send out neurotransmitters, the researchers say.

“That made us think that if there was some way we could enhance calcium signaling, we might be able to help compensate for the protein’s defects,” Bradberry says.

He learned that a familiar drug, known as 4-AP, was already approved to treat the disorder multiple sclerosis. Because 4-AP prompts a greater-than-normal influx of calcium into neurons, Bradberry suspected it could help patients with SYT1 mutations.

In preliminary experiments to test the drug’s potential, the researchers used a technique devised by Loren Looger, a group leader at HHMI’s Janelia Research Campus, to make neurons in culture fluoresce when they release neurotransmitters. Neurons containing mutated syt1 proteins flashed only dimly under the microscope. But adding 4-AP boosted their fluorescence.

Because the drug has already been approved by the U.S. Food and Drug Administration, doctors for the three patients should be able to quickly get permission to treat them with it, says Hugo Bellen, an HHMI Investigator at Baylor College of Medicine who was not involved with the study. The new work helps explain how certain genetic errors can disrupt neurotransmitter release and lead to a neurological disorder, he says.

Bradberry has cautiously shared the results of the team’s 4-AP experiments with the patients and their doctors, so they can decide if they want to try it. He and Chapman emphasize that a drug like 4-AP will not cure patients like the three in the study, because it cannot reverse changes that have already occurred in the developing brain. However, it might reduce symptoms.

“Behaviors seen in this condition, like self-injurious hitting, impact patients’ and caregivers' lives, and it’s possible these could be addressed by whatever treatment we are able to offer,” Bradberry says.

Chapman agrees. “If it brings any relief at all, it will be incredibly satisfying for us.”


Brain Factors that Stimulate or Block New Neurons

There are many other factors that influence BDNF and the production of new neurons. Lack of appropriate sleep appears to decrease the production of new brain cells through a pathway involving the hormone glucocorticoids. Chronic stress and aging also seem to influence BDNF to decrease new cells.

Microbes in the gut also influence hippocampal levels of BDNF. In gastrointestinal disorders BDNF can be influenced to stimulate depression. The mechanism of the microbe effect on BDNF and the brain did not occur through the autonomic nervous system, GI neurotransmitters, and inflammation. It appears to be a direct blood signal to the brain from the microbes.

Another dramatic finding about BDNF involves the HIV virus. HIV doesn’t infect neurons directly but it dramatically affects them, destroying many neurons and causing dementia. The mechanism of this dementia has just been discovered. HIV has a hook on its surface called the gp120 envelope protein, which is used to grab onto blood and glia cells to infect them. This same hook also grabs onto the precursor to BDNF, called proBDNF. By grabbing onto this molecule it stops the creation of the active BDNF, which is necessary for new brain cells, and new connections between neurons. By stopping BDNF it actually kills neurons and causes dementia.


ABBREVIATIONS:

MRS is a rapidly developing noninvasive technique that allows the clinician to assess the intact brain for neurochemical changes in a given brain region of interest. In the past 25 years, MRS has been an important clinically productive diagnostic tool. The detection of these molecules has been valuable in understanding the presence of neuronal elements (NAA), cell proliferation and degradation (choline), glial disease (myo-inositol), and energy states (Cr) but most changes in metabolite concentrations tend to be rather nonspecific.

The 2 most abundant neurotransmitters in the human brain are glutamate and GABA. More recently, there is emerging scientific interest in understanding the role of NAAG in neurologic diseases. A variety of pathologic alterations may arise from changes in the concentration of these neurotransmitters. These may occur due to alterations at several levels, including their synthesis, metabolism, and interaction with receptors. At present, neurologists have access to a vast repertoire of drugs that modulate neurotransmitter activity in the brain for the treatment of diseases such as epilepsy, motor neuron diseases, and several chronic neurodegenerative disorders. However, complete remission of signs and symptoms is not consistently achieved.

Glutamate, GABA, and NAAG are “visible” in 1 H-MR spectroscopy. However, routine 1 H-MR spectroscopy sequences do not allow the unequivocal detection of these neurotransmitters for several reasons: low spectral resolution, relatively low concentrations, and spectral contamination from other more dominant metabolites. To overcome these hurdles, specific “editing” methods at high magnetic fields (>1.5T) are being developed and applied in clinical research, which provide a more reliable way for quantifying neurotransmitter levels in pathologic conditions. Because most acute and chronic neurologic disorders are associated with an imbalance of excitatory and inhibitory neurotransmission, it is exciting to consider a future role of 1 H-MR spectroscopy in providing a possible “biomarker” of disease and response to treatment.

The aim of this review is the following: 1) to highlight the essential biology of 3 major neurotransmitters: glutamate, GABA, and NAAG and 2) to illustrate possible applications of editing 1 H-MR spectroscopy techniques in neurologic diseases, which can aid clinical practice, clinical trials, and neuroscience research.


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  2. Luo G, et al. Absence of anti-hypocretin receptor 2 autoantibodies in post Pandemrix narcolepsy cases. PLoS One. 201712:e0187305. Cogswell AC, et al. Children with narcolepsy type 1 have increased T-cell responses to orexins. Ann Clin Transl Neurol. 2019 6:2566-72.

This content was last reviewed on February 21, 2018

A resource from the Division of Sleep Medicine at
Harvard Medical School



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