LO2 What Are Neurons and Glial Cells

LO2 What Are Neurons and Glial Cells? All of your experiences arise from the complex interaction of cells in your brain. There are two major classes of cells in the nervous system: the neuron and the glial cell. Neurons are in the business of conveying information. They do this through a combination of electrical and chemical signals that are used to convey information quickly from one neuron to another at speeds that can reach up to 530 kilometres per hour (approximately 150 m/s). As a result, if you accidentally touch a hot stove, your brain receives this information in a matter of milliseconds. Just how fast is 530 kilometres per hour? Consider that the NASCAR speed record is 342.5 kilometres per hour. The new Cessna Denali turboprop passenger plane has a cruising speed of 530 kilometres per hour. Besides neurons, the brain is also made up of glial cells. Compared to neurons neuroscientists know far less about the function of glial cells, but a growing literature is shedding light on ways in which glial cells are critical to brain function (Edgar & Sibille, 2012; Gundersen et al., 2015). Glial cells or glia provide support, nutritional benefits, protection, and other functions in the nervous system (Allen & Lyons, 2018; Jäkel & Dimou, 2017; Trevisiol & Nave, 2015). They are much smaller than neurons, but have different structural features. Although it was once believed that glial cells were more numerous than neurons (a ratio of about 10 to 50 glial cells per 1 neuron), this view has been challenged and the number of glial cells and neurons are roughly the same (von Bartheld et al., 2016). Glial cells can be thought of as a type of “glue” that holds the nervous system together by providing structural and functional support to keep neurons running faster and more efficiently. In fact, the word glia comes from the Greek word for glue. You might think of the glial cells as a combination of the pit crew in a raceway and the parents of an active child. They are like a pit crew in making sure that the neurons can perform at a high level of speed and efficiency, and they are like parents in making sure that the neurons are well fed and protected. Page 75 Until recently, researchers believed that glial cells were not specialized to process information and that they were just spectators to information processing going on in the nervous system. This was based on the presumption that glial cells do not have synapses or release neurotransmitters, both of which are crucial for neural transmission. However, research now shows that this view is wrong and that glial cells are more than just passive spectators to neural transmission. We now know that glial cells can actively detect neural impulses and send signals to other glial cells (Fields et al., 2015) and even neurons (Harada et al., 2016; Igelhorst et al., 2015). When glial cells do not function properly, it can be extremely disastrous to brain function. In fact, glial cells may play a critical role in the development of several brain disorders, including Alzheimer’s disease (Melo et al., 2011), chronic pain (Hanani, 2015), epilepsy (Vezzani et al., 2022), and psychological disorders (Noda, 2015; Rurak et al., 2021; Simard et al., 2018). Taken together, these findings showcase how scientific knowledge is always evolving and challenge earlier views that the functions of glial cells are unexciting compared to those of neurons. Glial cells are now receiving the credit they deserve as being critical participants in almost every aspect of brain function. What Is the Structure of a Neuron? Individual neurons are the basic structural and functional unit of the nervous system. The human brain contains a large number of neurons, on the order of around 86 billion neurons. They can exhibit a wide range of different forms, sizes, and functions, but all neurons share five common features: (1) a cell body, (2) dendrites, (3) an axon, (4) axon terminals (or synaptic boutons), and (5) a cell membrane ( Figure 3.2). Figure 3.2 The Neuron The drawing shows the parts of a neuron and the connection between one neuron and another. Note the cell body, the branching of dendrites, and the axon with a myelin sheath. The cell body (or soma) is the metabolic and genetic hub of the neuron. Like all cells, the cell body contains the machinery necessary for maintaining the neuron’s function and integrity over its lifetime. This includes energy production and synthesizing critical components such as structural proteins, enzymes, and some chemical messengers. The cell body also houses the nucleus, which contains 46 chromosomes made from DNA (deoxyribonucleic acid) and some proteins. These chromosomes contain sequences of DNA called genes that ultimately determine the structural and functional properties of the neuron. The cell body, as well as other components of the neuron such as its dendrites, also contains large clumps of ribosomes, which enable neurons to synthesize large quantities of proteins. The creation of new proteins is a critical part of the ability of neurons to change, adapt, and store new information such as memories. Factors that can adversely affect Dynamic Figure The Neuron The basic component of our brain and the rest of our nervous system is known as a neuron. A neuron is a type of cell that communicates information by sending signals via chemicals to other neurons. Each aspect of the neuron plays a role in the transmission of the signal, from collecting the information from other cells via the dendrites, speeding up the process with myelin, and then sending out the signal in the form of chemicals from the terminal buttons. protein synthesis, such as sleep deprivation, stress, and even alcohol consumption (that’s right!) can impair the ability to form and store new memories. Page 76 Dendrites are specialized branch-like processes that extend off the neuron’s cell body and form a tree-like structure called the dendritic arbor. The dendritic arbor can be extremely complex and quite elaborate, with many dendrites branching into smaller and smaller dendrites. Many dendrites are also covered with tiny protuberances called spines. These dendritic spines dramatically increase the surface area of the neuron, providing multiple sites for synaptic contact. Dendritic spines are also quite dynamic and can grow in response to various types of experiences. For example, young rats reared in a complex environment with opportunities to explore and interact with objects, toys, and other rats have measurable increases in the thickness of certain brain regions, which is a result of an expansion in the size of the neurons, an increase in dendritic length and branching, and a rise in the number of dendritic spines and synapses per neuron (Bennett et al., 1964; Connor et al., 1982; Diamond et al., 1964, 1966). It is believed that changes in dendritic spine numbers represent the microstructural changes in the brain that occur when we learn new information and form new memories. In other words, learning encourages the physical growth of new dendritic spines and synaptic contacts made between neurons. Several neurodevelopmental, neuropsychiatric, and neurodegenerative conditions, including Down syndrome, fetal alcohol syndrome, autism spectrum disorder, epilepsy, Alzheimer’s disease, and schizophrenia, are associated with alterations in dendrite shape, size, or number (Kulkarni & Firestein, 2012; Penzes et al., 2011; Rossini et al., 2021). These structural changes can lead to defects in the neural circuit, which can contribute to cognitive and behavioural symptoms associated with these conditions; see Figure 3.3. The axon is a single long cylindrical projection from the cell body that carries information away from the cell body toward the ends of the cells. (Remember that axon and away both start with the letter a.) Most neurons have only one axon, but the axon can branch into several terminals. Although extremely thin (one-tenth the thickness of a human hair), an axon can be very long. In fact, some extend about a metre—all the way from the top of the brain to the base of the spinal cord. The axon is specialized for the transmission of coded information in the form of electrical perturbations known as the action potentials. At the end of the axon are the synaptic boutons (also known as “axon terminals” or “synaptic terminals”), which are specialized enlarged bulb-shaped regions of the axon that usually terminate in close vicinity of the dendritic spines of another neuron. This tiny junction between the two neurons is referred to as the synapse or synaptic cleft. The axon of a single neuron may provide only a few synapses or can provide Figure 3.3 How Dendrites Can Be Affected in Various Brain Disorders In various clinical conditions, dendritic structure can be adversely affected. This can involve a reduction in the overall length of the dendrites, a decrease in the number of branches, along with a reduction in the number of dendritic spines. However, sometimes there can be a decrease in dendritic branching but an increase in the number of dendritic spines, as can be seen in autism spectrum disorder (ASD). In addition, sometimes these changes occur across the entire dendritic field of the neuron, or can be restricted to either top or bottom dendrites of the neurons. Identifying and understanding these changes in dendrite anatomy is critical for understanding brain function in healthy and disease states. thousands of synaptic inputs to other neurons. As a result, a single neuron can receive information from thousands of different neurons. The axon terminals contain the specialized machinery that stores and releases chemical substances or neurotransmitters. Finally, covering all cells, including neurons, is a double-layered barrier called the cell membrane. The cell membrane is like your skin: it is very thin, covers the entire surface of the cell, and keeps the inside in and the outside out. Due to the unique composition of the cell membrane, it acts as a barrier to the movement of chemicals and molecules dissolved in water. Because of this many of the substances that are central to electrical signalling in neurons must find a way to bypass the neuron’s membrane. As we will see in a moment, nature has come up with an interesting solution to this problem. Page 77 How Does Information Travel Inside a Neuron? As you reach out to turn this page, hundreds of these impulses stream down the axons in your arm to tell your muscles when to flex or extend and how quickly. Similarly, when you feel the touch of the page with your fingertips, hundreds of these impulses along a different set of axons alert your brain to the fact that you are touching paper. The transmission of this information through the brain occurs as brief electrochemical impulses that travel along the length of the neuron’s axon. How does a neuron—a living cell—generate this electricity? To answer this question, we need to take a moment to examine the neuron and the cell membrane that surrounds it. The Art of Relaxation: How Do Neurons Rest? As we recently discussed, all neurons possess a thin, double-layered cell membrane that serves as a barrier between its interior and the surrounding environment. There is fluid found both inside the neuron and in the space residing outside the neuron. This fluid is composed mainly of water, but dissolved within it are various electrically charged particles called ions. Ions are particles that come from atoms that have either gained (negatively charged) or lost (positively charged) one or more electrons. Some of these ions, notably sodium (Na+) and potassium (K+), carry positive charges, while other ions, such as chloride (Cl−) and some amino acids and proteins (A−), are negatively charged. Because these ions, as well as other dissolved molecules, are distributed unevenly across the inner and outer sides of the cell membrane, they will want to move from regions of high concentration to regions of low concentration. This process is called diffusion. The membrane restricts these substances from simply flowing randomly into and out of the neuron. Instead, the membrane possesses the characteristics of selective permeability, meaning that it will selectively allow for certain molecules and ions to pass while restricting the movement of others. This feature of the membrane is crucial for establishing the unique inner chemistry of all living cells, including neurons. To achieve this selective permeability, special proteins made by the cell are embedded in the membrane. These proteins form tiny passageways or gates called channels that can recognize and select for specific ions and other molecules to travel across the membrane. In fact, the neuron creates electrical signals through the movement of positive and negative ions in these ion channels. When the neuron is not transmitting information, it is in a resting state. However, even though the neuron may be at rest, it is still a charged cell. During this time, a slight negative charge is present along the inside of the cell membrane. On the outside of the cell membrane, the charge is positive. Because of the separation of charges (ions) across the membrane, the cell is said to be electrically polarized. This potential difference across the membrane creates a voltage ( Figure 3.4), and it is found in almost all living cells including neurons. That voltage, called the neuron’s resting potential, can be measured in some unit of volts and it is usually between −60 and −75 millivolts. A millivolt (mV) is 1/1000th of a volt. The reason why we assign a negative sign (−) is that by convention the outside of the membrane is given a charge of zero. Figure 3.4 The Resting Potential An oscilloscope measures the difference in electrical potential between two electrodes. When one electrode is placed inside an axon at rest and one is placed outside, the electrical potential inside the cell is −70 millivolts (mV) relative to the outside. This potential difference is due to the unequal distribution of positive (+) and negative (−) ions along the cell membrane. What Produces the Neuron ’ s Resting Potential? The resting potential of the neuron can be accounted for by the unequal distribution of ions across the two sides of the membrane. The fluid outside the neuron is rich in sodium (Na+) ions and relatively low in potassium (K+), whereas the fluid inside the neuron is high in K+ content and very low in Na+. The inside of the neuron also contains a large amount of negatively charged amino acids/proteins (A−), but these molecules are too big to move across the membrane. At rest the neuron’s membrane is more selectively permeable to potassium, allowing it to flow out of the neuron along its concentration gradient with relative ease. This movement of K+ leaves a small negative charge behind due to the presence of the negatively charged amino acids/proteins (A−). At the same time, the membrane also shows a slight permeability to Na+. Because Na+ ions are present at high concentration on the outside of the neuron and the inside membrane now has a slight negative charge, Na+ ions flow inwardly (remember, opposite charges attract). Other ions, such as chloride (Cl−), tend to contribute very little to the overall resting potential of the neuron. Page 78 While the resting membrane potential is achieved through a balance of Na+, K+, and to a lesser extent Cl− ions flowing in and out of the neuron, it turns out that potassium seems to be one of its largest contributors. For example, drugs that block potassium channels seriously disrupt the establishment of the resting potential. Blockers of Na+ and Cl− tend to have only a modest effect. You might wonder whether the constant movement of Na+ and K+ across the membrane eventually causes the inside of the neuron to now have more Na+ and the outside more K+. To maintain the proper ion concentrations, the cell membrane has special pumps known as the sodium–potassium pump. These pumps move in two K+ ions while ejecting three Na+ ions out of the cell. This process requires energy, which tells us that even when a neuron is “at rest” it still requires a significant expenditure of energy in order to maintain its operations. About 20 percent of your brain’s total energy budget is spent on maintaining the resting potential of its neurons (Howarth et al., 2012). When neurons are not in the resting state, they are communicating information over long distances through a series of electrical impulses called action potentials. These impulses travel down the length of the axon causing powerful changes in membrane voltage until reaching the axon terminals. From there, the impulses cause the release of small packages of chemicals stored within these terminals. These chemicals are called neurotransmitters. What Sets Off the Action Potentials? Action potentials are the signals that transmit information between neurons. But how are they generated? Before the generation of the action potential, the axon’s membrane is at rest with a voltage of around −70 mV. But along the entire length of the axon are special voltage-sensing Na+ and K+ channels. These channels have a gate that is normally closed. When a change in voltage occurs the gate opens, allowing Na+ and K+ ions to pass through the channel. This change in ion flow results in a change in the voltage across the membrane. Page 79 The opening of the voltage-gated Na+ and K+ channels in the axon is the first step that causes the action potential to be triggered. But how do these channels know when to open? Recall that the dendrites and soma of a single neuron receive synaptic inputs from hundreds or even thousands of other neurons. These inputs produce small voltage fluctuations in the receiving neuron called postsynaptic potentials that can be either excitatory or inhibitory in nature. These potentials either increase or decrease the likelihood that the neuron will generate an action potential. Once generated the excitatory and inhibitory potentials spread from the dendrites or soma to the axon. Each individual potential contributes to a small voltage fluctuation, which can be added together. If the sum of excitatory inputs exceeds the sum of inhibitory inputs, the voltage fluctuation and currents generated within the axon might be sufficient to change its resting potential and generate an action potential. The action potential is generated through a series of steps ( Figure 3.5). First, the axon must become more positive, and its resting potential must be reduced to a less negative value. This is called depolarization. When the axon’s resting potential has been reduced (depolarized) beyond a critical threshold, an explosive self-limiting process, namely the action potential, occurs. It turns out that for an action potential to be triggered, a threshold voltage of around −50 mV must be reached. In other words, if the resting potential was −70 mV, then the axon must be depolarized by at least 20 mV to reach this threshold. If the axon’s membrane is not sufficiently depolarized beyond this critical threshold, then no action potential is generated. Once the threshold is reached, the action potential is generated and travels down the axon as a wave of activity. The action potential is generated at the spot where the axon emerges from the neuron’s cell body. This region is called the axon hillock or trigger zone and it conveniently has a higher concentration of voltage-gated Na+ and K+ channels than anywhere else along the length of the axon. When the arriving synaptic potential depolarizes this zone beyond the threshold, the voltage-gated channels open and cause a drastic change in the membrane voltage. When a neuron generates an action potential, it is commonly said to be “firing.” However, during the generation of the action potential, there are also “time out” periods known as a refractory period. This time out period is important because it ensures that a neuron is not generating another action potential too quickly after a previous one has occurred. This helps to make neurons fire in a controlled and coordinated manner. For example, when the refractory period is compromised it can contribute to excessive and out of control neuronal firing, which often occurs during Figure 3.5 The Action Potential An action potential is a brief wave of positive electrical charge that sweeps down the axon as the sodium channels in the axon membrane open and close. (a) The action potential causes a change in electrical potential as it moves along the axon. (b) The movements of sodium ions (Na+ ) and potassium ions (K+) into and out of the axon cause the electrical changes. epileptic seizures (Dorn & Witte, 1995). Refractory periods also help ensure that action potential once generated travels away from the cell body and along the axon toward its terminals. Page 80 Once the axon has been sufficiently depolarized to reach threshold for an action potential, the wave of activity travels down the axon at a constant speed. For this to occur, the action potential must be constantly regenerated along the entire axon. This can be a challenging concept to grasp, but think of a line of dominoes: The first domino will not fall unless it is pushed. However, once the first domino falls, it will knock over its neighbour, which sets off a chain reaction with each subsequent domino falling in succession. This chain of falling dominoes travels in one direction without a loss of energy and is similar to what occurs during an action potential. Once the critical threshold has been reached in a segment of axon membrane, the opening of voltage-activated channels is sufficient to produce a voltage change that triggers the channels in the adjacent membrane to open, just as one domino falling causes its neighbour to fall. As you probably guessed, if the axon is not sufficiently depolarized beyond the critical threshold, then no action potential is generated. This means that the action potential follows an all-or-none principle. In other words, if the threshold has been met, an action potential always will occur and will move all the way down the axon at full strength without losing any of its intensity. The impulse travelling down an axon is comparable to the burning fuse of a firecracker. Whether you use a match or a blowtorch to light the fuse, once the fuse has been lit, the spark travels quickly and with the same intensity down the fuse. However, the all-or-nothing principle creates a bit of a puzzle. If there are no differences in the intensity of the action potentials, how can we detect differences in the intensity of a stimulus? How can we tell the difference between bright and dim light, or mild and hot salsa? The answer has to do with the frequency of the action potentials. As the rate of action potentials increases, we can perceive increases in the intensity of a stimulus. In short, the electrical activity of neurons can be summarized as involving three steps: So far we have been discussing only voltage-gated channels; that is, channels that will open or close in response to change in voltage across the cell’s membrane. However, in some non-mammalian species there are ion channels that do not respond to voltage but instead to light. Read more about how green slime has led to one of the biggest advances in neuroscience in the Intersection. Page 81 1. Resting Potential: the neuron maintains a small negative charge of −70 mV. This charge is created by the cell using energy to create an uneven distribution of ions across its cell membrane. 2. Action Potential: when the neuron is sufficiently stimulated by the release of neurotransmitters from thousands of other cells, it fires. During this firing, tiny channels open up and sodium ions rush into the neuron, reversing the polarity (the cell goes from having a negative charge to a positive charge). This activity races down the length of the axon as the channels open and then close. 3. Refractory Period: the cell now has a “time out” period where it has to regain its resting potential before it can fire again. During this time out, sodium ions are expelled out of the cell until it again reaches the −70 mV resting potential. INTERSECTION Optogenetics: Can We Use Light to Learn About Brain Function? Many behaviours we engage in depend on the precise interaction between neurons. Traditionally, the study of the brain has relied on scientists either zapping it with electricity or injecting drugs directly into it. While important findings have come from using these methods, they are way too crude. Neuroscientists needed a technology that would allow them to carefully control only one type of cell at a time while leaving others unaltered. Essentially, they needed a kind of neuron “light switch.” Biologists knew for some time that certain types of bacteria and algae possess unique light-sensitive proteins that help them respond to their environment and produce energy. These naturally occurring proteins are called opsins, and they function like the gated ion channels we discussed. However, instead of responding to voltage changes, these protein channels respond to light. When light hits the opsin proteins, the channels respond by either opening or closing, which allows for ions to flow into or out of the cell. In 2005, Edward Boyden, Feng Zhang, and Karl Deisseroth got the idea that perhaps they could insert this same bacterial opsin gene into mammalian neurons and make them sensitive to light (Boyden et al., 2005). To do this, they smuggled the opsin gene into rat neurons by using a virus at a concentration that would not kill them. They plated these neurons onto a dish, and when they flashed blue light it caused the modified cells with the opsin genes to produce a rapid flurry of action potentials. This discovery ushered in the era of optogenetics, which combines genetics and light to control the function of cells in highly specific ways. One important opsin is channelrhodopsin (ChR2), which is found in green algae. ChR2 responds only to blue light, and when exposed to it will allow for positively charged ions (Na+ and K+) to rapidly enter into the cell, resulting in depolarization and action potential firing. In effect the ChR2 functions as a sort of neuron “on switch.” Another important opsin discovered is halorhodopsin (NpHR), shown to function as a neuron “off switch.” By combining these two opsins researchers can manipulate the neural circuit much like a conductor of a symphony, turning brain activity on and off at the speeds that neurons naturally communicate with each other. This provides an unprecedented level of control to experiments seeking to understand how the brain processes information and influences behaviour. Optogenetics in rodents can help shed light on how specific brain circuits work together. The left image (a) displays a thin ribbon with electrodes, sensors, and a light-emitting diode (LED) that can be implanted deep within the mouse brain. The right image (b) demonstrates how the device’s light can stimulate precise neural pathways. (a) (b) (a) and (b): Professor John Rogers, University of Illinois/Science Source How Does Myelin Enhance Neuronal Transmission? Action potentials travel at a speed that is directly proportional to the diameter of the axon. In other words, the action potential will travel much faster and more quickly along a larger axon than a smaller axon. Large axons are typically found in invertebrate animals, such as the giant axons of the squid. These axons, which are important for mediating rapid swimming for escape, can be as large as 1 millimetre and conduct signals as fast as 25 metres per second. However, such large axons would take up a lot of space, which would seriously limit the number of neurons and connections we could have. Instead, vertebrates have evolved a different strategy to help increase the speed of action potentials. The speed of an action potential can be dramatically accelerated by the presence of myelin sheaths. A myelin sheath is a fatty substance that surrounds some axons similar to the way a shirt sleeve encases your arm. Being largely fat, myelin is a poor conductor of electricity; so, it insulates the axon and prevents electrical currents generated from the movement of ions from leaking out. Myelin occurs in a repeating pattern, with long wrapped regions of the axon covered with myelin that are interrupted by a very short bare region of no myelin. These non-myelinated areas along the axon are called nodes and contain a very high concentration of voltagegated Na+ and K+ channels. It is only at these nodes where the membrane needs to be depolarized to generate the action potential. This allows myelinated axons to transmit action potential up to 15 times faster than axons not covered with myelin (Whalley, 2015) and thus to carry and transmit information much more rapidly (D. J. Miller et al., 2012). This means that rather than having action potentials creep along each tiny segment of a non-myelinated axon, the action potentials in myelinated axons can move much more rapidly down the axon by leaping from node to node. Since the action potential is regenerated only at these nodes, it requires significantly less metabolic energy to produce these events than action potentials generated by non-myelinated axons. Numerous disorders are associated with problems in either the creation or the maintenance of myelin. One of these disorders is multiple sclerosis (MS), which is thought to be an autoimmune disease where a person’s immune system attacks their myelin. MS is a degenerative disease of the nervous system in which myelin tissue hardens, disrupting neuronal communication. In MS, scar tissue replaces the myelin sheath. Symptoms of the disease include blurry and double vision, tingling sensations throughout the body, and general weakness. Unfortunately, for reasons that still remain unclear, Canada has one of the world’s highest rates of MS ( Figure 3.6). Page 82 Figure 3.6 Distribution of Multiple Sclerosis Cases A world map shows the uneven distribution of cases of multiple sclerosis, with particularly high numbers of cases in northern regions, including Canada. GBD 2016 Multiple Sclerosis Collaborators. Global, regional, and national burden of multiple sclerosis 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet Neurology. 21 Jan 2019. doi:10.1016/ S1474-4422(18)30443-5. How Does Information Travel Between Neurons? The movement of an action potential along the length of an axon may be compared to a crowd “doing the wave” in a stadium. With the wave, there is a problem, however—the aisles. How does the wave get across each aisle? A similar problem arises for neurons, because they do not touch one another directly, and electricity cannot cross the space between them. Here is where the chemical part of electrochemical transmission comes in. Though communication inside neurons is electrical, communication between neurons is chemical. The communication between neurons is one of the most intriguing and highly researched areas of contemporary neuroscience (Herman & Rosenmund, 2015). Figure 3.7 gives an overview of how this communication between neurons takes place. Figure 3.7 How Synapses and Neurotransmitters Work (A) The axon of the presynaptic (sending) neuron meets dendrites of the postsynaptic (receiving) neuron. (B) This is an enlargement of one synapse, showing the synaptic gap between the two neurons, the terminal boutons, and the synaptic vesicles containing a neurotransmitter. (C) This is an enlargement of the receptor site. Note how the neurotransmitter opens the channel on the receptor site, triggering the neuron to fire. How Does Synaptic Transmission Work? Neurons don’t actually touch each other. The region defined by the end of one neuron (the presynaptic membrane) and the beginning of the next neuron (the postsynaptic membrane) is called the synapse. The synaptic gap is the tiny space between the terminal bouton of the presynaptic neuron and the receptor site on the dendrite of the postsynaptic neuron (the aisle in our stadium analogy). Most synapses lie between the end of the axon of one neuron and the dendrites or cell body of another neuron (Chapeton et al., 2012). Because the action potential cannot cross this synaptic gap, it must be converted into a chemical signal. Page 83 Figure 3.8 Synaptic Transmission There are 10 steps involved with synaptic transmission. (1) Action potential arrives at the presynaptic terminal. (2) Neurotransmitters are synthesized and stored into vesicles. (3) The depolarization from action potential opens voltage-gated Ca2+ channels allowing for Ca2+ influx. (4) Entry of Ca2+ mobilizes vesicle docking and causes neurotransmitter release. (5) Neurotransmitter binds to receptors, causing channels to open (or close). (5) Reuptake transporters bring neurotransmitter from synapse back into presynaptic terminal. (7) Neurotransmitter can be recycled back into vesicle for re-release. Enzymes present in the presynaptic terminal (8) or (9) in synaptic cleft breakdown neurotransmitter. (10). Excessive neurotransmitter release may spill over and activate autoreceptors, which causes the neuron to stop firing. The chemical communication between neurons is called synaptic transmission (see Figure 3.8). The steps in this process are: Page 84 Several inactivation procedures are available. For example, enzymes present within the synaptic cleft will chemically break down the neurotransmitter. This reduces the amount of neurotransmitter available. For the neurotransmitter to be protected from these enzymes it quickly crosses the synapse and physically binds to its receptor located on the membrane of the postsynaptic neuron. Another method involves the action of transporters, which are located on the membrane of the presynaptic axon. Following the release of the neurotransmitter these transporters operate like vacuums to bring the neurotransmitter back inside the axon terminal so that it can be recycled. This process is called reuptake and there are transporters for all major 1. Neurotransmitters are synthesized in the presynaptic axon terminal boutons and stored in tiny vesicles (sacs) within these terminals. The neurotransmitters need to be immediately taken up into the vesicles otherwise they will be chemically digested by enzymes that are present in the terminals. The action of this enzyme ensures that only an appropriate amount of neurotransmitter is present in the terminals at any given moment. 2. The neurotransmitter binds to the receptor of the next neuron causing the channels to open or close. This can cause a variety of effects on the receiving neuron, which depends on the type of receptor that is present. For example, the neurotransmitter might bind to a type of receptor that produces a rapid depolarization effect and can bring the postsynaptic neuron membrane closer to its threshold to generate an action potential if enough of these receptors were stimulated. Alternatively, it may produce a hyperpolarizing response that brings the membrane farther away from its threshold. 3. There must also be mechanisms present that can limit the duration of the neurotransmitter’s effect, otherwise it would not be a very effective method of communication. After all, as much as it is necessary to start a car, it would be impractical to not also have some way of turning off a car’s engine. neurotransmitters, including serotonin, dopamine, and norepinephrine. In fact, transporters are often sites that targeted by various drugs and thus through the process of blocking reuptake these drugs can have powerful effects on synaptic transmission. For example, many antidepressant drugs, such as Prozac, work by blocking the action of the serotonin transporter. This causes levels of serotonin in the synapse to increase, which is important given that lower serotonin is linked to depressed mood. What Are Neurochemical Messengers? The released chemicals by neurons are called neurotransmitters. By definition, a neurotransmitter is any substance that is released at a synapse by a neuron and can affect another neuron or some other effector cell, like a muscle or gland. Neurotransmitters are like pieces of a puzzle, and the receptor sites on the next neuron are differently shaped spaces. If the shape of a receptor site corresponds to the shape of a neurotransmitter molecule, the neurotransmitter fits into the receptor site so that the neuron receives the signals coming from the previous neuron. You might think of the receptor site as a keyhole in a lock and the neurotransmitter as the key that fits that lock. Page 85 There are many different neurotransmitters. Each play specific roles and functions in a specific pathway. Scientists do not know exactly how many neurotransmitters exist, and more are being discovered. In organisms ranging from snails to whales, neuroscientists have found the same neurotransmitter molecules that our own brains use. Because distribution of neurotransmitters ultimately determines the impact they have on brain processes, such as cognition and mood, let’s consider eight that have major effects on behaviour. What Is Acetylcholine? Acetylcholine (ACh) is involved in muscle contractions, learning, memory, and attention (Ferreira-Vieira et al., 2016). The synthesis of ACh requires choline, which is a vital component of the plasma membrane and is an essential nutrient (choline is enriched in foods such as egg yolks, beans, and rice). ACh is found throughout the central and peripheral nervous systems, but most of the ACh is concentrated within the synaptic contacts made between spinal cord motor neurons and muscles. Many toxins, such as some venoms and nerve gas agents, work by affecting ACh activity. For example, the venom from the bite of the black widow spider causes ACh to gush into the synaptic gaps between the spinal motor neurons and muscles, producing violent muscle spasms and weakness. Botox treatments for fine lines and wrinkles in the face also affect ACh activity. Botox is a brand-name product made from a bacterial poison called botulinum toxin. Botulinum destroys ACh so that when someone gets an injection of Botox, their facial muscles—which are activated by ACh —are prevented from contracting, with the result that wrinkles do not form. Individuals with Alzheimer’s disease, a degenerative brain disorder that gradually impairs memory, have an acetylcholine deficiency (Hachisu et al., 2015). Some of the drugs being developed to alleviate Alzheimer’s symptoms are designed to The neurotransmitter-like venom of the black widow spider does its harm by disturbing neurotransmission. Centers for Disease Control compensate for this deficiency. In fact, one of the most common treatments for Alzheimer’s disease, donepezil (Aricept), works by blocking the enzymes present in the synaptic cleft that break down ACh. By inhibiting this enzyme ACh levels build up in the synapse, which helps to slow the worsening of symptoms in people with Alzheimer’s disease. What Is GABA? GABA (gamma aminobutyric acid) is an amino acid found throughout the central nervous system. It is believed to be present in as many as one-third of the brain’s synapses. GABA plays a key function in the brain by inhibiting many neurons from firing (Purkayastha et al., 2015). You can consider that GABA acts like the brain’s brake pedal, helping to regulate neuron firing and control the precision of the signal being carried from one neuron to the next. Low levels of GABA are linked with anxiety (X. Li et al., 2015b). Valium and other anti-anxiety drugs increase the inhibiting effects of GABA. Drugs such as alcohol also work by binding to the same receptors as GABA. As a result one needs to be extremely careful if they are taking anti-anxiety medication such as Valium and drinking alcohol, as the presence of both drugs in the brain can increase the risk for toxic side effects. What Is Glutamate? Glutamate is the most prevalent neurotransmitter. In fact, 90 percent of all excitatory synapses will contain glutamate. If GABA is the brain’s brake pedal, glutamate is the accelerator. Glutamate has a key role in stimulating neurons to fire and is especially involved in learning and memory (Purkayastha et al., 2015). However, too much glutamate can overstimulate neurons, triggering migraine headaches or even seizures. Glutamate is also thought to be a factor in anxiety, depression, schizophrenia, Alzheimer’s disease, and Parkinson’s disease (Volk et al., 2015). Because of the widespread expression of glutamate in the brain, glutamate receptors have increasingly become the targets of drug treatment for a number of neurological and psychological disorders (Bishop et al., 2015). Page 86 What Is Norepinephrine? Stress stimulates the release of another neurotransmitter—norepinephrine (Sun et al., 2015). When we respond to stress, multiple things must happen at once, and so it is not surprising that norepinephrine (also called noradrenaline) has a number of effects on the body. If you think of all the things your body does when you experience extreme fear, for instance, you can begin to appreciate some of the ways norepinephrine affects your body. It can inhibit the firing of some neurons in the central nervous system, but it can simultaneously excite the heart muscle, intestines, and urinary tract. This neurotransmitter also helps to control alertness. Too much norepinephrine triggers agitation or jumpiness. For example, amphetamines and cocaine cause hyperactive, manic states of behaviour by rapidly increasing norepinephrine levels in the brain (Shorter et al., 2015). However, too little norepinephrine is associated with depression. In fact, one of the most common postmortem observations in depressed patients is evidence of a decrease in the number of brain stem neurons that synthesize norepinephrine (Arango et al., 1996; Ordway, 1997). Recall from the beginning of the chapter that one of the most important characteristics of the brain and nervous system is integration. In the case of neurotransmitters, they may work in teams of two or more. For example, norepinephrine also works with acetylcholine to regulate states of sleep and wakefulness. What Is Dopamine? Dopamine helps to control voluntary movement and affects sleep, mood, attention, learning, motivation, and the ability to recognize opportunities for rewarding experiences in the environment (Berke, 2018; Meyer, 2012). Stimulant drugs often act by increasing dopamine in the synapse. For example, cocaine and amphetamines produce excitement, alertness, elevated mood, decreased fatigue, and sometimes increased motor activity mainly by increasing levels of dopamine in the synapse (M. H. Cheng et al., 2015). Dopamine is also related to some personality traits such as extroversion (being outgoing and gregarious) (Wacker & Smillie, 2015). Problems in regulating dopamine levels are associated with a variety of psychological disorders, especially schizophrenia (Whitton et al., 2015), a severe disorder we will examine in Chapter 14. Low levels of dopamine are associated with Parkinson’s disease, a degenerative neurological disorder in which a person develops a type of “shaking palsy” that is characterized by a slowing of movement, muscle rigidity, the presence of a resting tremor (which usually disappears when the person voluntarily moves), and difficulty in speaking and engaging in skilled motor behaviours like writing (Fallon et al., 2015). This disease affects over six million people worldwide, including over 100,000 people in Canada (GBD 2015 Neurological Disorders Collaborator Group, 2018); actor Michael J. Fox has been diagnosed with this disease. What Is Serotonin? Serotonin is involved in the regulation of sleep and waking activity, mood, attention, and learning. In regulating states of sleep and wakefulness, it teams with acetylcholine and norepinephrine. Serotonin also plays a role in mood regulation, with low levels of serotonin associated with increased depression (Jenkins et al., 2016) and even aggression (Coccaro et al., 1996). Figure 3.9 shows the brain pathways for serotonin. The most commonly prescribed antidepressants work on the serotonin system. For example, a class of antidepressant drugs called SSRIs (selective serotonin reuptake inhibitors) work by blocking the serotonin transporters. These transporters help to “suck up” serotonin released into the synapse and reduce the amount of serotonin available to bind to its receptor. SSRIs block this reuptake and thus increase the amount of serotonin available in the synapse (Little et al., 2006). There is extensive evidence that links deficiency of serotonin with depression. For example, depletion of tryptophan (which is the precursor used to make serotonin in the brain) can trigger a relapse of depression symptoms in people who have recovered from depression (Schopman et al., 2021). Moreover, levels of serotonin in the brain (and in blood) are reduced in patients with depression, and return back to normal following antidepressant treatment (Zhuang et al., 2018). Finally, genetic studies have identified several genes involved with the serotonin system that are associated with an elevated risk for developing depression (Houwing et al., 2017; Lesch, 2011). However, some researchers have criticized the view that serotonin deficiency is actually linked to depression (Healy, 2015; Moncrieff et al., 2022). This is based on the observation that SSRI medications increase synaptic levels of serotonin within hours or days after administration, yet these drugs require several weeks of administration before a therapeutic effect occurs. This delayed action of antidepressant suggests that other mechanisms beside serotonin dysfunction must be involved somehow in the development of depression. Page 87 In addition to neurotransmitters, there are also neuropeptides. Neuropeptides are sequences of amino acids; very long sequences are considered proteins. Unlike the neurotransmitters, neuropeptides are synthesized in the cell body (or soma). Once synthesized, the neuropeptide is enveloped by vesicles (similar to neurotransmitters) and then transported to the axon terminals, where it can be stored in proximity to vesicles containing neurotransmitters. When released, neuropeptides produce much longer effects on their target cells (on the range of seconds to minutes) compared to neurotransmitters (on the range of milliseconds). Approximately 40 percent of the brain’s synapses involve the classic neurotransmitters; the remainder involve neuropeptides. There are hundreds of neuropeptides, but the more familiar neuropeptides are the enkephalins and endorphins (which evoke euphoria and analgesia), corticotropin-releasing hormone (CRH, which controls the release of stress hormones and affects the electrical activity of neurons especially found in emotional processing regions of the brain), vasopressin (contributes to the control of blood pressure, fluid balance, and when disrupted produces diabetes mellitus), and oxytocin (which modulates the ejection of milk during breastfeeding or the Figure 3.9 Serotonin Pathways Each of the neurotransmitters in the brain has specific pathways in which it functions. Shown here are the pathways for serotonin. contraction of the uterus during birth). Let us consider just two of these important neuropeptides. What Are Endorphins? Endorphins are natural opiates—substances that depress nervous system activity and eliminate pain—that mainly inhibit the firing of neurons. As opiates, endorphins shield the body from pain and elevate feelings of pleasure. A long-distance runner, a woman giving birth, and a person in shock after a car wreck all have elevated levels of endorphins (Bali et al., 2015). As early as the fourth century BCE, the Greeks used wild poppies to induce euphoria. More than 2,000 years later, the magical formula behind opium’s addictive action was finally discovered. In the early 1970s, scientists found that opium plugs into a sophisticated system of natural opiates that lie deep within the brain’s pathways (Pert, 1999; Pert & Snyder, 1973). Morphine (the most important narcotic of opium) mimics the action of endorphins by stimulating receptors in the brain involved with pleasure and pain (Navratilova et al., 2015). What Is Oxytocin? Oxytocin is a neuropeptide that plays an important role in the experience of love and social bonding. A powerful surge of oxytocin is released in mothers who have just given birth, and oxytocin is related to the onset of lactation (milk production) and breastfeeding (Vrachnis et al., 2011). Oxytocin, however, is involved in more than a mother’s ability to provide nourishment for her baby. It is also involved in making babies more attractive and rewarding, thus contributing to the experience of some parents who find themselves “in love at first sight” with their newborn (Olazábal, 2018). Oxytocin is released during a sexual orgasm and is thought to play a role in the human tendency to feel pleasure during orgasm and to form emotional bonds with romantic partners (Khajehei & Behroozpour, 2018). Higher levels of oxytocin are present in new lovers and higher levels persist six months later compared to nonattached single young adults (Schneiderman et al., 2012). Higher oxytocin levels are associated with positive affect, affectionate touch, and preoccupation with one’s partner and the relationship. Provocative research also has linked oxytocin to the way that some individuals respond to stress (Neumann & Landgraf, 2012). According to Shelley Taylor (2011b), women under stress do not experience the classic “fight or flight” response— rather, the influx of oxytocin they experience suggests that women may seek bonds with others when under stress. This response has been referred to as “tend and befriend” and it more accurately represents the stress response of women (von Dawans et al., 2019). You would probably not be surprised to hear that oxytocin has fascinated not only scientists but the public as well. It sounds like a natural love potion. Recently, some research on the effects of oxytocin on interpersonal trust has been called into question. To read about that work, see the Critical Controversy. Page 88 CRITICAL CONTROVERSY Does Oxytocin Make People More Trusting? Unsurprisingly, oxytocin has been one of the most studied chemicals in all of the behavioural sciences. Imagine: a neurotransmitter that appears to be a kind of natural love potion. Some have called it “liquid trust”! Even better, oxytocin can be administered to people in a simple nasal spray. Early experiments with oxytocin showed fascinating results. In one study, participants were given a nasal spray containing either oxytocin or placebo and asked to complete a questionnaire containing highly personal questions (Mikolajczak et al., 2010). Participants were then asked to place the questionnaire in an envelope and give it to the experimenter (who assured the participants that they would not look at their responses). Participants were informed that they could seal the envelope and were offered tape for the seal. The key dependent measure was whether (and how) participants sealed the envelope. The results were dramatic: Over 80 percent of those in the placebo group sealed the envelope with tape, compared to fewer than 7 percent in the oxytocin group. In addition, 60 percent of those in the oxytocin group did not seal the envelope at all (Mikolajczak et al., 2010). Maybe oxytocin really is liquid trust! Or is it? Years later, the same team of researchers tried to reproduce their findings, but they couldn’t (Lane et al., 2015). In fact, in two studies they found that oxytocin did not affect how individuals treated the envelope at all: Those who received oxytocin were just as protective of BrianAJackson/iStock/ Getty Images their personal information as those in the placebo group. What could explain the difference? The earlier study and the newer ones differed in one key way: The original study was only “single blind.” This means that, although participants did not know whether they received oxytocin or the placebo in the nasal spray, the experimenter interacting with them did. Mikolajczak and colleagues now consider that the experimenter treated participants in subtly different ways, leading the oxytocin group to behave differently (Lane et al., 2015). Replication is the foundation of good science. It is important for experimenters to verify their own work, and the work of others, under different conditions. This example shows us that even clever research designs require rigorous standards. WHAT DO YOU THINK? If you thought that someone you were interacting with had been given “liquid trust,” how might you behave? Can you think of a different way to test the hypothesis that oxytocin is liquid trust? Quiz Yourself