Introduction to Neurobiology INTRODUCTION TO NEUROBIOLOGY Open Edition AVINASH SINGH University of Oregon Libraries Eugene Introduction to Neurobiology Copyright © 2024 by Avinash Singh is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License, except where otherwise noted. https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ CONTENTS Introduction 1 Adaptation Statement 2 What is Neurobiology? iii Part I. Neuron Structure & Function 1. Cells of the Nervous System: The Neuron 21 2. Cells of the Nervous System: Glia 40 3. Ion Movement 47 4. Membrane Potential 53 5. The Membrane at Rest 66 6. Graded Potentials 75 7. Action Potentials 86 8. Voltage Clamp 105 Part II. Neuronal Communication 9. Steps in Synaptic Signaling 119 10. Synapse Structure 130 11. Neurotransmitter Synthesis and Storage 138 12. Neurotransmitter Release 153 13. Neurotransmitter Action: Ionotropic Receptors 160 14. Neurotransmitter Action: G-Protein-Coupled Receptors 171 15. Neurotransmitter Clearance 185 16. Drug and Toxin Effects 193 Part III. Nervous System Organization 17. Anatomical Terminology 201 18. Nervous System Development 207 19. External Brain Anatomy 222 20. Internal Brain Anatomy 233 21. Brainstem and Spinal Cord 240 22. Peripheral Nervous System 249 Part IV. Sensory Systems 23. General Principles of Sensory Systems 271 24. Vision: The Retina 275 25. Vision: Central Processing 294 26. Somatosensory Systems 312 27. Touch: The Skin 317 28. Touch: Central Processing 326 29. Pain 339 30. Gustatory System 351 31. Olfactory System 365 Part V. Motor System 32. Spinal Motor Control and Proprioception 383 33. Spinal Reflexes 405 34. Central Pattern Generators 411 35. Planning of Movement 416 36. Basal Ganglia 423 37. Execution of Movement 440 38. Neurodegenerative Diseases: Motor 449 Part VI. Behavior 39. Motivated Behavior: Reward Pathway 465 40. Motivated Behavior: Feeding Behavior 472 41. Motivated Behavior: Sexual Behavior 491 42. Sex Steroid Hormones 497 43. Organizational and Activational Effects of Steroid Hormones 505 44. Social Bonding 515 45. Sleep and EEG 524 46. Circadian Rhythms 536 47. Memory Systems 544 48. Molecular Mechanisms of Memory: Aplysia 564 49. Molecular Mechanisms of Memory: Hippocampus 570 Bioelectricity Electricity fundamentals for BI360 583 Genetics 593 Images of Animations 601 Glossary 663 INTRODUCTION Introduction to Neurobiology is aimed at undergraduate students new to the field of neurobiology. The first edition specifically targets students enrolled in BI360 Neurobiology at the University of Oregon and primarily contains topics covered in that course. The textbook is modified from a combination of from two existing open texbtooks: Foundations of Neuroscience by Casey Henley, and Introduction to Neuroscience by Valerie Hedges. An introduction to Bioelectricity has been added. Figures and text have been added, and edited or modified as needed. Citations are being added as appropriate. As established by Casey Henley, original text follows principles of Universal Design for Learning: multiple means of representation will be provided for students to engage with the content. Clear, accessible text will be divided into short, easily digestible chapters that focus on one concept. Numerous images and animations will be paired with the text, and a captioned video version of the text is shared for each chapter. The text is written with the undergraduate student that is new to neuroscience in mind. Neuroscience terminology will be introduced in an easy-to-understand manner, and supporting content will be clear and concise to minimize cognitive load not associated with understanding new material. Each chapter will end with an interactive quiz for student self-evaluation of the content. All quiz answers (i.e. both correct and incorrect) will provide feedback, so students can self-check their understanding at the end of each concept and receive immediate feedback about their learning. Find errors or have suggestions? Email avinash at uoregon dot edu. • Avinash D Singh Bala, PhD • Biology & Neuroscience, University of Oregon INTRODUCTION | 1 https://openbooks.lib.msu.edu/neuroscience/ https://openbooks.lib.msu.edu/introneuroscience1/ https://udlguidelines.cast.org/ https://udlguidelines.cast.org/ ADAPTATION STATEMENT This book is an adaptation of two introductory neuroscience OER. Chapters 3-8, 10-17, 19-29, 35-38 and 44 were adapted from Foundations of Neuroscience by Casey Henley which is licensed CC BY NC SA. Chapters 1, 2, 9, 18, 30-34, 38-43, 45-49 were adapted from Introduction to Neuroscience by Valerie Hedges which is licensed CC BY NC SA. Valerie Hedges’s book is also an adaptation of Casey Henley’s book and another introductory neuroscience OER. Many chapters from both Henley’s and Hedges’ versions were excluded from this book. Avinash Singh, the author of Introduction to Neurobiology, made significant changes to several chapters, added citations as needed, and contributed a new Bioelectricity chapter. He also made significant changes to many of the figures in this book. All the figures that he contributed are licensed under the same license as the text. Figures by Henley and Hedges have license statements included in the caption. 2 | ADAPTATION STATEMENT https://openbooks.lib.msu.edu/neuroscience/ https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ https://openbooks.lib.msu.edu/introneuroscience1/ https://creativecommons.org/licenses/by-nc-sa/4.0/ Resources • Scientist links to learn more • Glossary Terms • Key Takeaways • Test Yourself WHAT IS NEUROBIOLOGY? What is Neurobiology? Neurobiology is the study of the structure and function of the nervous system, the collection of nerve cells that interpret all sorts of information which allows the body to coordinate activity in response to the environment. Neurobiology has taught us that the brain is a complicated organ with several connection routes, both between different bodily organs and within itself. Some of those connections communicate information down towards the body, such as signals that allow us to control the movements of our muscles or to change the activity of our internal organs. Other connections ascend into the brain, conveying all sorts of information from the world around us into a representation of our surroundings. Still, other routes communicate between brain areas, such as when the sudden detection of a threat passes through our visual system and turns into a “get ready” signal that then prepares the rest of our body for conflict. Because of this complex system of communication, the nervous system can be thought of as a series of highways and roads that connect different cities (organs). The nervous system conveys all of these different types of information using a combination of electrical and chemical signals. The main active cellular units of the nervous system, the neurons, are highly sensitive to changes in their environment. A wide variety of chemicals called neurotransmitters are responsible for passing information between neurons. WHAT IS NEUROBIOLOGY? | 3 Figure 1.1. Brain size comparison between different vertebrate mammals. Brain images are shown for a rat, cat, chimpanzee, human, and dolphin. There are similarities in the layout of the structure of the brain across all species. Neurobiology is the biology of the brain, while Neuroscience is an integrative field of study Realistically, our modern understanding of “neuroscience” is a combination of several academic disciplines, all using their strengths to understand some aspect of the nervous system. Because of this integrative nature, it is possible to study neuroscience from many different perspectives, each of them more fitting for answering different types of questions. These “angles” of analysis are described below. Biology At the root of the study is biology. Whenever you are studying living processes, such as learning, visual perception, or consciousness, you dip into the realm of biology. The broad field of biology can be subdivided into smaller, more precise categories. Molecular neurobiologists study proteins and gene regulation, cellular neurobiologists examine how networks of neurons communicate with one another, and cognitive neuroscientists study the underlying causes of behaviors. Understanding neuroscience involves genetics, such as the autosomal dominant neurodegenerative condition Huntington’s disease. Other biological sub-disciplines, such as 4 | WHAT IS NEUROBIOLOGY? ecology and evolution, are also considered in neuroscience as well, such as the parasite Toxoplasma, which changes an animal’s response to fearful stimuli, allowing the organism to reproduce as it moves through different species in the food web. Psychology Psychology provided the earliest explanations about the brain and ideas about the origin of the mind. Some questions in this field branched off from philosophy as people began thinking about the “mind–body problem”, the discussion that centered around the question of whether a function as complex as consciousness could result from the activity of a clump of cells. Psychologists also wondered whether parts of the brain in isolation have different properties than when those parts are working together. This property, called emergence, is the idea that the whole is greater than the sum of its parts. Psychologists examine neuroscience from a top- down view, aiming questions at understanding the whole organism before looking at smaller components of the organism (compare this with biological approaches, often a bottom-up view that starts at the level of cells or molecules). Chemistry Chemistry is a strong influencer of nervous system function—just ask anyone who forgot their morning cup of coffee! We use a variety of endogenous (originating from within the body) chemicals that act as signaling molecules, allowing communication between cells. These chemicals exist in many different structures, which determine their function; some are acidic while others are basic, some are polar, others are fat-soluble, and some are even gases. The nervous system is also highly sensitive to influence by exogenous chemicals (meaning they originate from outside the body), such as caffeine and cocaine. Physics Many principles of physics can be observed through the functioning of neurons. For example, neurons maintain a negative electrical charge, usually measured on the scale of tens of millivolts (a millivolt is a thousandth of a volt.) The main way for neurons to send signals depends on a temporary change in this voltage; this signal is called an action potential. This change in voltage is brought on by the movement of charged ions across the cell membrane, and they closely follow the rules of magnetism: opposite charges attract while like charges repel. WHAT IS NEUROBIOLOGY? | 5 Mathematical Modeling The field of computational neuroscience has grown from the use of mathematical modeling to describe or predict some aspect of the nervous system. If our current estimates are correct, we have around 86 billion neurons in the brain, a number so large that it is difficult to conceptualize. It would be nearly impossible to understand that many components of a system without taking advantage of the sheer mathematical strength of a computer. Healthcare Providers Healthcare providers, like neurologists and psychiatrists, work from a different angle. They coordinate closely with researchers to apply scientific knowledge from the field or laboratory to treat patients, thus using biological principles as therapies. For example, neurologist Dr. Oliver Sacks used his knowledge of the dopamine neurotransmitter system to treat patients with a paralysis-like condition in the 1960s, leading to the development of levadopa treatment for Parkinson’s disease. Other healthcare providers use imaging strategies like a CT scan to assess the extent of a head injury or the location of a brain tumor, while an EEG can be helpful for the diagnosis of epilepsy. Engineers Engineers help develop the tools needed to understand questions in neuroscience, such as the patch clamp rig or electron microscope, highly specialized pieces of lab equipment. They also work closely with healthcare providers to translate science into therapy, such as the deep brain stimulator devices for the treatment of conditions such as Parkinson’s disease. Collectively, all the people who participate in neuroscience in some way are united by their interest in the workings of the body. Because of the overwhelming complexity of the nervous system, there are many questions still unanswered. The continual appearance of new questions in neuroscience keeps us wondering, inspires curiosity, and promises a multitude of fascinating career paths for centuries to come. 6 | WHAT IS NEUROBIOLOGY? Figure 1.2 Neurobiology is one of the areas of study that contribute to our understanding of how our brains work. Many fields contribute to our understanding of modern neuroscience including biology – which we will focus on, and others that we will only cover when they impact biology – psychology, chemistry, mathematical modeling, healthcare providers, and engineers. How do we learn about neurobiology? Experimental design The gold standard in science is the use of experimental design. In an experiment, the scientist uses a stepwise process of developing a research question and hypothesis, then answering that question by performing tests. The main goal of an experiment is to establish a causal relationship between one factor that is being changed, the independent variable, and the factor that is influenced, the dependent variable. A well-designed experiment has variables that are carefully controlled, which minimizes the influence of extraneous variables, often called confounding variables. The influence of confounding variables can be eliminated by comparing the experimental group with a control group, a group that is as similar as possible in every way except for the manipulation of the independent variable. Importantly, subjects or patients are generally assigned to the experimental or control group at random. WHAT IS NEUROBIOLOGY? | 7 Figure 1.3 The Scientific Method. The Scientific Method starts with the development of a research question or observation that will lead to a research topic area and hypothesis. The hypothesis is tested through experimentation and analysis. The results of the experiment are then communicated via a report, which can further support additional observations or questions. Case Studies Another strategy is the case study, a highly detailed description of a single patient and their condition. A case study documents the details regarding a specific deficit or enhancement and is an opportunity to examine individuals with very rare conditions, which are useful for informing about the functions of different brain structures. Like a quasi-experimental study, case studies only show correlation, not causation. It is difficult to generalize the findings from a case study to the population at large. Perhaps the most famous case study in all of neuroscience is the 1848 story of the railroad worker Phineas Gage. Gage was a construction foreman working on the railroad when an unfortunate explosive workplace accident caused a iron rod to be driven through his left frontal lobe, largely destroying it. Remarkably, Gage survived this accident and lived another 12 years. However, Gage’s acquaintances described subsequent changes in his personality, teaching us that one of the functions of this area of the brain is regulating our inhibitions. 8 | WHAT IS NEUROBIOLOGY? https://openbooks.lib.msu.edu/app/uploads/sites/87/2022/04/The_Scientific_Method.svg https://en.wikipedia.org/wiki/Phineas_Gage Figure 1.4 Image of Phineas Gage and his site of injury. The figure on the left is an image of Phineas Gage holding the iron rod that caused his injury. The image on the right shows a Magnetic Resonance Image rendering of the location of the rod in the injury. The rod entered below the left eye and damaged much of the left frontal cortex. Case studies can be helpful for the development of hypotheses that can later be tested experimentally. For example, consider another famous case study of Patient HM, the man who had his left and right hippocampus surgically removed and couldn’t create certain types of memory. A research question based on this case study might be: “Is the hippocampus needed for the creation of navigational memory?” Then, an experimental study could be performed in rodents, where we surgically remove the hippocampus (experimental group) or a different part of the brain (control group) and see how well the rodents perform on a memory task. The Use of Animals in Research Though there are many ways that we can directly study humans through experimentation or case studies, it is often impossible to test every question in humans. Instead of always studying humans, scientists often use nonhuman model organisms, the most common organisms being the worm C. elegans, fruit flies (Drosophila melanogaster), zebrafish (Danio rerio), song birds, mice, rats, and macaque monkeys. WHAT IS NEUROBIOLOGY? | 9 https://en.wikipedia.org/wiki/Henry_Molaison Figure 1.5 Experimental Animal Models. Images of C. elegans (worms), Drosophila melanogaster (fruit flies), mice, rats, and Macaque monkeys. The closer we move towards the human, the more similarities the model organism shares with us. Of the commonly used model organisms, macaque monkeys are the non-humans that are most similar to humans. We share 93% of our genetic material with macaques, but we still have different metabolic and physiological processes, and our behaviors are much different from theirs. Ethical constraints prevent us from performing experiments that may cause physical or psychological harm if performed in humans. We would never conduct a test on humans to assess what concentration of neurotoxin leads to brain damage (these experiments aren’t done very frequently in nonhumans anyway). Invertebrates, such as worms and fruit flies are not as heavily regulated by ethics oversight committees, allowing scientists to conduct a wider set of experiments on these animals. Our moral responsibilities toward animal subjects are that: 1. Animals should only be used in worthwhile experiments. 2. All steps are taken to minimize pain and distress. 3. All possible alternatives to animal research are considered. 10 | WHAT IS NEUROBIOLOGY? Research facilities at colleges and universities are monitored by an Institutional Care and Use Committee (IACUC). The IACUC consists of fulltime veterinarians, scientists, and community members. They must follow federal laws when approving animal research. Experimental Preparations Performing an experiment in an intact, living organism, whether human or nonhuman, is described as an in vivo (Latin meaning “within life”) preparation. The main strength of this strategy is that the data collected here are more predictive of the human condition, which is one of the main goals of biomedical research. However, the in vivo preparation has challenges, because thousands of variables within a living system are uncontrolled or still unknown. There are also very strict ethical limitations on the nature of experiments that can be done in vivo. On the other hand, an in vitro (Latin meaning “within glass”) preparation is an experiment performed on cultured cells or isolated molecules of DNA, RNA, or protein. These preparations have the opposite strengths and weaknesses of in vivo preparations. They allow for extremely good control over variables, but the results are less reliable in translating to a therapy. The regulations on these experiments are much more lax compared to in vivo experiments; most of the regulatory guidelines are to protect the experimenter rather than the patient or the experimental subject. Falling in between these two preparations is an ex vivo experiment. In this kind of experiment, a section of the living organism is taken, such as a slice of brain, a tissue biopsy, or a detached frog leg. The strengths and limitations of these experiments are somewhere in between that of the other two preparations. WHAT IS NEUROBIOLOGY? | 11 https://en.wikipedia.org/wiki/Institutional_Animal_Care_and_Use_Committee https://en.wikipedia.org/wiki/Institutional_Animal_Care_and_Use_Committee Figure 1.6 Experimental Preparations. Details of the in vivo, ex vivo, and in vitro preparations can be found in the text. The in vivo preparation has the least control over variables, but increased ability to predict therapeutic potential and increased strictness of ethical regulations. The ex vivo preparation has more control over variables, and decreasing ability to predict therapeutic potential and strictness of ethical regulations. The in vitro preparation has the most control over variables but the least ability to predict therapeutic potential and the least strict ethical regulations. What the brain is not! As complex as the brain is, naturally misconceptions make their way into popular culture. It’s valuable to address these myths about neuroscience and explain the evidence that refutes these statements . Myth 1: “We only use 10% of our brain.” This wildly inaccurate statistic has been the foundation for several fictional movies, TV shows, and books. The truth is that we use every part of the brain, and most of our brain is active most of the time—just not at the same time. Neurologist V.S. Ramachandran uses a great analogy to describe the fallacy of this myth: does a traffic light only use 33% of its lights? A properly functioning traffic light 12 | WHAT IS NEUROBIOLOGY? https://en.wikipedia.org/wiki/V._S._Ramachandran will use all three lights at very precise times. The activity of the brain is closely regulated by multiple mechanisms which prevent unusual electrical activity. In fact, if too many cells were active at the wrong times, just like a traffic light showing both green and red, chaos ensues—one cause of seizures is excessive neural activity. Myth 2: “Forming memories causes new neurons to be born.” Another misconception is the idea that each new cell in our brain represents a new memory. While we are far from understanding the process of exactly how memories are formed in the brain, we do have a few clues. Most likely, memories are stored at the sites of close contact between neurons, called synapses. Changes in ways neurons connect and communicate with one another is likely the mechanism behind how memories are formed and stored, rather than the creation of new neurons. Even though the process of cell reproduction is halted in the majority of adult neurons, we are still capable of new neuronal growth, a process called neurogenesis. A few brain areas in particular, like the hippocampus (used in learning and memory functions and the olfactory epithelium (used for smelling), do exhibit frequent birth and death of new neurons. Myth 3: “The brain cannot repair itself.” If neurons aren’t being replaced in adulthood, then how do people spontaneously recover from neurological injuries like a stroke? One of the most amazing features of the brain is the phenomenon of plasticity, the ability to change over time. Even if critical brain areas are damaged, it is theorized that the brain learns how to “rewire itself”, essentially figuring out how to carry out these functions without using the damaged connections. Unfortunately, there are some conditions that are neurodegenerative, meaning that their symptoms get progressively worse over time. Many of these disorders, like Parkinson’s disease and Alzheimer’s disease, currently do not have any simple cures or treatments that don’t carry risks and side effects. For people with these conditions, there is not strong evidence that the brain can recover from the destruction caused by these diseases. Myth 4: “If you are analytical, you are left brain WHAT IS NEUROBIOLOGY? | 13 dominant, but if you are creative, you are right brain dominant.” A common misconception is that the two hemispheres of the brain are responsible for wildly different functions. The truth is that nearly every function that the left half of the brain can do, the right half can do just as well, and vice versa. Sensory information, voluntary control of the muscles, memories, and many other behaviors can be performed equally well by both the left and right halves of the brain. A major exception to the “left vs. right” component is the processing and production of language. For some reason unknown to scientists, these functions are heavily lateralized in the left hemisphere for most people. Fascinatingly, we do have one strange quirk about signaling between the brain and the rest of the body: signaling pathways from the left brain crosses over to communicate with the right half of the body, and vice versa. This contralateral organization is an unintended consequence of evolution, and is one of the major distinguishing features of the vertebrate brain. Neurobiology is ever-changing One of the most exciting and satisfying aspects of modern science is the rapidity of new discoveries in the field. New findings are often communicated by publishing academic studies in scientific journals. More neurobiology studies were published between 2015 and 2020 than in the previous seventy years! But the study of the brain hasn’t always advanced so quickly: for hundreds, perhaps thousands of years, neurobiology like all other sciences was a static field of study, with intellectuals looking back to the ancient Greeks for inspiration, rather than nature. This meant that all sorts of superstitious rituals and beliefs flourished unchecked – and some unfortunately survive to this day. Trepanation was a surgical intervention that involved drilling a hole into an individual’s skull. It is believed to be one of the oldest surgical procedures according to archaeological evidence. Interestingly, skulls that show evidence of trepanation have been dated to 6500 BCE and show evidence of healing, indicating that the patient survived the surgery. 14 | WHAT IS NEUROBIOLOGY? Figure 1.7 Trepanated Skull. This image shows an example of trepanation, or drilling holes in the skull of individuals as a form of treatment. The growth of the skull around the site of surgery suggests healing and that this procedure was performed while the individual was still alive. Localizationism For hundreds of years, physicians attempted to correlate behaviors with changes in the brain. In the mid 1800s, the physician Paul Broca contributed to localization theory by concluding that specific areas of the brain were responsible for carrying out specific functions. This idea was supported by ablation studies that demonstrated that when different brain structures were ablated, or lesioned, there were specific associated functional losses. Further, electrically exciting specific brain structures resulted in eliciting specific behaviors. Most likely, some behaviors are more localized than others, but still rely on signals from across many other brain areas. As with most fields of biology, absolutes are rare in neuroscience. WHAT IS NEUROBIOLOGY? | 15 https://en.wikipedia.org/wiki/Paul_Broca Figure 1.8. Image of Paul Broca. Plasticity The real strength of our brain is its flexibility: brains are capable of changing and adapting to a wide variety of circumstances. Blind people use their visual areas of the brain while echolocating, stroke survivors can regain lost motor functions using the unaffected brain circuits, and babies can effortlessly learn two languages simultaneously in a bilingual household. Plasticity is based on the idea that not only is the brain capable change, but that our experiences change the structure and function of our nervous system. 16 | WHAT IS NEUROBIOLOGY? Figure 1.9 Example of Brain Plasticity. Brain images are shown of two different individuals, a blind individual that is an echolocation expert and a control participant. The blind echolocation expert shows an increase in activity within areas of the brain that typically respond to visual information, but no activation in areas of the brain that respond to auditory information. The brain is plastic and has allowed for the blind individual to use areas of the brain that typically process sight to instead process echolocation information. Key Takeaways • Neuroscience is the study of the nervous system and is an integrative field of study that incorporates biology, psychology, chemistry, physics, mathematical modeling, and health care providers. • The study of neuroscience is accomplished through experimental studies, case studies, and the use of experimental animal models. • There are many popular myths concerning neuroscience and it is important to analyze data that refutes these myths. • Though the field of neuroscience is relatively young and ever-changing, humans have been interested in the brain and its function for centuries. WHAT IS NEUROBIOLOGY? | 17 Test Yourself! An interactive H5P element has been excluded from this version of the text. You can view it online here: https://opentext.uoregon.edu/neurobiology/?p=497#h5p-42 Attributions This chapter is adapted from “What is Neuroscience?” in Introduction to Neuroscience by Valerie Hedges which is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. 18 | WHAT IS NEUROBIOLOGY? https://opentext.uoregon.edu/neurobiology/?p=497#h5p-42 https://openbooks.lib.msu.edu/introneuroscience1/chapter/what-is-neuroscience/ https://openbooks.lib.msu.edu/introneuroscience1/chapter/what-is-neuroscience/ https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ PART I NEURON STRUCTURE & FUNCTION NEURON STRUCTURE & FUNCTION | 19 20 | NEURON STRUCTURE & FUNCTION Resources • Scientist Links to Learn More • Glossary Terms • Key Takeaways • Test Yourself 1. CELLS OF THE NERVOUS SYSTEM: THE NEURON There are 2 major cell types within the nervous system: Neurons and Neuroglia. Neurons are cells that transmit electrical information. Neuroglia are supporting cells of the nervous system. Neurons are the cells or basic units of the brain, and were first, and beautifully described by Camillo Golgi who stained nervous system tissue using a new silver staining method, revealing the structure of neurons. This discovery sparked a boom in neuroscience, and Golgi, along with Santiago Ramon-y-Cajal, won both a Nobel Prize for Physiology and Medicine, 1906, and the joint title of fathers of neurobiology. The main function of neurons is to send electrical signals over short and long distances in the body, and they are electrically and chemically excitable. The function of the neuron is dependent on the structure of the neuron. The typical neuron consists of the dendrites, cell body, axon (including the axon hillock), and presynaptic terminal. CELLS OF THE NERVOUS SYSTEM: THE NEURON | 21 https://openbooks.lib.msu.edu/neuroscience/chapter/the-neuron#key https://openbooks.lib.msu.edu/neuroscience/chapter/the-neuron#test https://en.m.wikipedia.org/wiki/Camillo_Golgi https://en.m.wikipedia.org/wiki/Santiago_Ram%C3%B3n_y_Cajal https://www.nobelprize.org/prizes/medicine/1906/summary/ https://www.nobelprize.org/prizes/medicine/1906/summary/ Figure 1.1. A typical neuron. Dendrites branch out from the cell body, where the nucleus is located. The axon hillock is located where the cell body transitions into the axon. The axon begins at the axon hillock and ends at the presynaptic terminal, which can branch into multiple terminals. ‘Neuron’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC-BY-NC-SA) 4.0 International License. Although neurons do have a variety of adaptations that make them unique from other types of cells in the body, they are still cells. Therefore, they contain all of the basic features of a typical mammalian cell. For example, they are made up of an aqueous cytoplasm bounded by a cell membrane. This cell membrane, also called a plasma membrane or lipid membrane, consists of a sheet of several individual molecules called phospholipids, which consist of two hydrophobic (water-fearing) tails and a hydrophilic (water-loving) end. These phospholipids arrange themselves into a bilayer, with the hydrophobic tails touching each other and the hydrophilic sides facing the cytoplasm and the extracellular space, which are both mostly water. Because of the chemical properties of the cell membrane, it is very effective at keeping ions and charged molecules separated, while allowing small molecules like water and oxygen across the cell. Neurons also have all the organelles that you would see in other cell types, like a nucleus and mitochondria. The number of neurons in the adult human brain, according to our current best 22 | CELLS OF THE NERVOUS SYSTEM: THE NEURON https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Neuron.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Neuron.jpg https://openbooks.lib.msu.edu/neuroscience/chapter/the-neuron/ https://creativecommons.org/licenses/by-nc-sa/4.0/ estimate, is close to 86 billion. This number was calculated using a revolutionary technique, the isotropic fractionator or “brain soup”, developed by Brazilian neuroanatomist Suzana Herculano- Houzel. To put this number in context, we have about 37 trillion cells in the whole body, so neurons in the brain make up about 0.2% of all cells in the body. Below are some unique characteristics that neurons have in common. 1. Neurons are electroactive, which means that they are charged cells that can change their charge. 2. Neurons are specialized for rapid communication. Many cells are capable of sending and receiving chemical signals across long distances and time scales, but neurons are able to communicate with a combination of electrical and chemical signals in a matter of milliseconds. Additionally, the shape of neurons and the organization of the neurons on a microscopic level make them effective for sending signals in a very specific direction. 3. Neurons are “forever” cells. We are constantly replacing non-neuronal cells. For example, the cells in our bones replace themselves frequently at a rate of about 10% each year. Our body makes new skin cells to replace the dying skin cells on the surface so that we have a “new” skin every month. The cells along the inside of our stomachs, exposed to very harsh acidic conditions, get replaced about every week. About 100 million new red blood cells are created every minute! On the other hand, the mature nervous system generally does not undergo much neurogenesis: the creation of new neurons. The neurons that we have after development are the ones that we will keep until we die and this permanence of neuronal count makes them different from almost every other cell of the body. However, the idea of adult neurogenesis is a topic of debate among neuroscientists since some areas, like the olfactory system and the hippocampus, display new nerve cell production. 4. …But, neurons can change. Even though new neurons are not created in most areas of the brain, neurons still have the capability to change in their structure and function. Some of these changes, such as physical changes to the structures of the input sites of the neurons, are believed to last for a lifetime. We use the word plasticity to describe the ability for the brain to alter its morphology. This term is derived from the Greek plastikos, meaning “capable of being shaped or molded”—think of plastic surgery, where a person changes their physical appearance. Also, neurons do have the capacity to repair themselves to some extent. Neurons of the Peripheral Nervous System may get injured or completely destroyed as a result of trauma to the CELLS OF THE NERVOUS SYSTEM: THE NEURON | 23 https://en.wikipedia.org/wiki/Suzana_Herculano-Houzel https://en.wikipedia.org/wiki/Suzana_Herculano-Houzel body. Afterwards, those injured neurons can regrow to connect once again with their original partner. This regrowth seems to depend on a few chemical signals that the body produces, such as nerve growth factor and brain derived neurotrophic factor. However, this process is often very slow, and does not always successfully restore the nervous system to the way it was pre-injury. Dendrites The main function of neurons is to use changes in electrical properties in order to communicate with connected cells. This communication usually moves in one direction, and we will use this pathway as an outline for discussing the anatomical structures of the neurons. Dendrites, shown here in green, are processes that branch out in a tree-like fashion from the cell body. They are the main target for incoming signals received from other cells. The number of inputs a neuron receives depends on the complexity of the dendritic branching. Dendrites may also have small protrusions along the branches known as spines. Spines (illustrated in the inset box) are the sites of some synaptic contacts. Spines increase the surface area of the dendritic arbor, which may be an important factor in receiving communication. We believe that spines are one of the most important sites where the nervous system is able to change. For example, neurons change shape after exposure to various environmental conditions, such as stress or exposure to drugs. Tiny changes to the surface of the neuron at the level of dendritic spines is an example of plasticity. Dendritic plasticity is thought to underlie the reason that we can learn new facts or maintain memories about our childhood over long periods of time. Some set of tiny, submicroscopic changes to the morphology of dendritic spines may represent a single complex memory that you form. A neuron does not need spines for receiving information or for plasticity to take place. Many cells lack spines but are still capable of permanently changing. The input site may be anywhere along the dendrite, or even at the cell body—the “center” of the neuron. 24 | CELLS OF THE NERVOUS SYSTEM: THE NEURON Figure 1.2. Dendrites branch out from the soma. Their function is to receive information from other neurons. Some dendrites have small protrusions called spines that are important for communicating with other neurons. ‘Dendrites’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC-BY-NC-SA) 4.0 International License. Cell Body Information that arrives through the many dendrites of a neuron eventually filters into the cell body, or the soma, of the neuron. The cell body (shown below in green) contains the nucleus and cellular organelles, including the endoplasmic reticulum, Golgi apparatus, mitochondria, ribosomes, and secretory vesicles. The nucleus houses the DNA of the cell, which is the template for all proteins synthesized in the cell. The organelles (illustrated in the inset box) in the soma are responsible for cellular mechanisms like protein synthesis, packaging of molecules, and cellular respiration. The cell body is responsible for deciding whether to pass a signal onto the next cell. The cell membrane of the soma performs a complex set of “cellular arithmetic” that weighs all of the incoming signals: excitatory, inhibitory, and modulatory signals. After all of the calculations have been performed, the membrane decides to send a signal, either a “yes” or “no” output, which travels down the axon. CELLS OF THE NERVOUS SYSTEM: THE NEURON | 25 https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Dendrites.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Dendrites.jpg https://openbooks.lib.msu.edu/neuroscience/chapter/the-neuron/ https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ Figure 1.3. The cell body, or soma, of the neuron contains the nucleus and organelles that are commonly found in other cell types and are important for basic cellular functions. These organelles include mitochondria, endoplasmic reticulum, and Golgi apparatus. ‘Soma’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC-BY-NC-SA) 4.0 International License. Axon The axon is the main output extension of the neuron. The axon (highlighted in green) is usually a long, single process that begins at the axon hillock and extends out from the cell body. The axon hillock is located where the cell body transitions into the axon. Axons can branch in order to communicate with more than one target cell. Several axons can bundle and travel together; these are nerves. Axons can be very long; the longest axon in the human body is part of the sciatic nerve that runs from the posterior end of the spinal cord down the leg to control the muscles of the big toe. 26 | CELLS OF THE NERVOUS SYSTEM: THE NEURON https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Soma.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Soma.jpg https://openbooks.lib.msu.edu/neuroscience/chapter/the-neuron/ https://creativecommons.org/licenses/by-nc-sa/4.0/ Figure 1.4. The axon is a long single projection that begins at the axon hillock, the region between the cell body and the axon. The axon terminates at the presynaptic terminal. ‘Axon’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC-BY-NC-SA) 4.0 International License. Action Potential The axon transmits an electrical signal—called an action potential—from the axon hillock to the presynaptic terminal, where the electrical signal will result in a release of chemical neurotransmitters to communicate with the next cell. The action potential is a very brief change in the electrical potential, which is the difference in charge between the inside and outside of the cell. During the action potential, the electrical potential across the membrane moves from a negative value to a positive value and back. One or more interactive elements has been excluded from this version of the text. You can view them online here: https://opentext.uoregon.edu/ neurobiology/?p=510#video-510-1 CELLS OF THE NERVOUS SYSTEM: THE NEURON | 27 https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Axon.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Axon.jpg https://openbooks.lib.msu.edu/neuroscience/chapter/the-neuron/ https://creativecommons.org/licenses/by-nc-sa/4.0/ https://opentext.uoregon.edu/neurobiology/?p=510#video-510-1 https://opentext.uoregon.edu/neurobiology/?p=510#video-510-1 Animation 1.1. The action potential is a brief but significant change in electrical potential across the membrane. The membrane potential will move from a negative, resting membrane potential, shown here as -65 mV, and will rapidly become positive and then rapidly return to rest during an action potential. The action potential moves down the axon beginning at the axon hillock. When it reaches the synaptic terminal, it causes the release of chemical neurotransmitter. ‘Action Potential Propagation’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC-BY-NC-SA) 4.0 International License. View static image of animation. Myelin Many axons are also covered by a myelin sheath, a fatty substance that wraps around portions of the axon and increases action potential speed. There are breaks between the myelin segments called Nodes of Ranvier, and this uncovered region of the membrane regenerates the action potential as it propagates down the axon in a process called saltatory conduction. There is a high concentration of voltage-gated ion channels, which are necessary for the action potential to occur, in the Nodes of Ranvier. 28 | CELLS OF THE NERVOUS SYSTEM: THE NEURON https://openbooks.lib.msu.edu/neuroscience/chapter/the-neuron/ https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ https://openbooks.lib.msu.edu/neuroscience/back-matter/images-of-animations/#C1A1 Figure 1.5. Myelin wraps around and insulates the axon. The spaces between the myelin sheath, where the axon is uncovered, are call the Nodes of Ranvier. ‘Myelin’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC-BY-NC-SA) 4.0 International License. Axon Characteristics Axon Length The length of an axon is variable depending on the location of the neuron and its function. The axon of a sensory neuron in your big toe needs to travel from your foot up to your spinal cord, whereas an interneuron in your spinal cord may only be a few hundred micrometers in length. CELLS OF THE NERVOUS SYSTEM: THE NEURON | 29 https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Myelin.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Myelin.jpg https://openbooks.lib.msu.edu/neuroscience/chapter/the-neuron/ https://creativecommons.org/licenses/by-nc-sa/4.0/ Figure 1.6. Axons vary in length. Spinal interneurons, neurons that fully exist within the spinal cord, can have short axons, whereas sensory or motor neurons, which need to reach from the spinal cord to the appropriate body region, for example the toe, have long axons. ‘Axon Length’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC-BY-NC-SA) 4.0 International License. Axon Diameter Axon diameter is also variable and can be used to differentiate different types of neurons. The diameter affects the speed at which the action potential will propagate. The larger the diameter, the faster the signal can travel. Additionally, larger diameter axons tend to have thicker myelin. 30 | CELLS OF THE NERVOUS SYSTEM: THE NEURON https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/AxonLength.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/AxonLength.jpg https://openbooks.lib.msu.edu/neuroscience/chapter/the-neuron/ https://openbooks.lib.msu.edu/neuroscience/chapter/the-neuron/ https://creativecommons.org/licenses/by-nc-sa/4.0/ Figure 1.7. The diameter of the axon and the amount of myelination varies. Large diameter axons typically have thicker myelin sheath, which results in fast action potential speed. Small diameter axons may have no myelin present, resulting in slow action potential speed. ‘Axon Diameter’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC-BY-NC-SA) 4.0 International License. Axoplasmic Transport Axoplasmic transport refers to the movement of material within the axon. Organelles, vesicles, and proteins can be moved from the cell body to the terminal via anterograde transport or from the terminal to the cell body via retrograde transport. Anterograde transport can be either fast or slow. Microtubules run the length of the axon and provide the cytoskeleton tracks necessary for the transportation of materials. Proteins aid in axoplasmic transport. Kinesin is a motor protein that uses ATP and is used in anterograde transport of materials. Dynein is another motor protein that also uses ATP, but is used in retrograde transport of materials. CELLS OF THE NERVOUS SYSTEM: THE NEURON | 31 https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Axon-Diameter.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Axon-Diameter.jpg https://openbooks.lib.msu.edu/neuroscience/chapter/the-neuron/ https://creativecommons.org/licenses/by-nc-sa/4.0/ Figure 1.8. Cellular components need to be able to move throughout the cell to have proper functioning. Anterograde transport moves components from the cell body toward the terminal. Retrograde transport moves components from the terminal toward the cell body. ’Axonal Transport’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC BY-NC-SA) 4.0 International License. The Synapse The synapse is the physical distance that separates two neurons. Electrical Synapse Electrical synapses physically share cytoplasm. An electrical synapse may be less than 5 nanometers apart. Cells connected by electrical synapses share cytoplasm, but have two separate cell membranes. 32 | CELLS OF THE NERVOUS SYSTEM: THE NEURON Figure 1.9. Since an electrical synapse is a direct, physical connection between the cytoplasm of two neurons, ions are able to flow in either direction across the gap junction. ‘Bidirectional Electrical Synapse’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC BY-NC-SA) 4.0 International License. Chemical Synapse Chemical synapses use neurotransmitters to communicate. Chemical synapses can vary depending on the nature of the synapse. A chemical synapse is a larger distance, about 15–40 nm across. Adjacent neurons connected by chemical synapses do not share cytoplasm. CELLS OF THE NERVOUS SYSTEM: THE NEURON | 33 Figure 1.10. Synapses are found between two adjacent cells. In this image, the axon terminals (presynaptic terminals) are synapsing on the dendrites of another neuron (postsynaptic cell). “Presynaptic Terminal’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC-BY-NC-SA) 4.0 International License. Presynaptic versus Postsynaptic The axon terminates at the presynaptic terminal or terminal bouton. The terminal of the presynaptic cell forms a synapse with another neuron or cell, known as the postsynaptic cell. When the action potential reaches the presynaptic terminal, the neuron releases neurotransmitters into the synapse. The neurotransmitters act on the postsynaptic cell. Therefore, neuronal communication requires both an electrical signal (the action potential) and a chemical signal (the neurotransmitter). Most commonly, presynaptic terminals contact dendrites, but terminals can also communicate with cell bodies or even axons. Neurons can also synapse on non-neuronal cells such as muscle cells or glands. 34 | CELLS OF THE NERVOUS SYSTEM: THE NEURON https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Presynaptic-Terminal.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Presynaptic-Terminal.jpg https://openbooks.lib.msu.edu/neuroscience/chapter/the-neuron/ https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ Figure 1.11. The presynaptic terminal forms synaptic contacts with a postsynaptic cell. ‘Presynaptic Terminal’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC-BY-NC-SA) 4.0 International License. The terms presynaptic and postsynaptic are in reference to which neuron is releasing neurotransmitters and which is receiving them. Presynaptic cells release neurotransmitters into the synapse and those neurotransmitters act on the postsynaptic cell. CELLS OF THE NERVOUS SYSTEM: THE NEURON | 35 https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Presynaptic-Terminal.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Presynaptic-Terminal.jpg https://openbooks.lib.msu.edu/neuroscience/chapter/the-neuron/ https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ Figure 1.12. The presynaptic cell is the neuron that releases neurotransmitters into the synapse to act upon the postsynaptic cell. ‘Postsynaptic Cell’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC-BY-NC-SA) 4.0 International License. Variations in Structure Although these typical structural components can be seen in all neurons, the overall structure can vary drastically depending on the location and function of the neuron. Some neurons, called unipolar, have only one branch from the cell body, and the dendrites and axon terminals project from it. Others, called bipolar, have one axonal branch and one dendritic branch. Multipolar neurons can have many processes branching from the cell body. Additionally, each of the projections can take many forms, with different branching characteristics. The common features of cell body, dendrites, and axon, though, are common among all neurons. 36 | CELLS OF THE NERVOUS SYSTEM: THE NEURON https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Postsynaptic-Cell.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Postsynaptic-Cell.jpg https://openbooks.lib.msu.edu/neuroscience/chapter/the-neuron/ https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ Figure 1.13. Neuron structure is variable, but the main components of cell body (shown in black), dendrites (shown in brown), and axon (shown in blue) are common among all neurons. ‘Neuron Types‘ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC-BY-NC-SA) 4.0 International License. Key Takeaways • Each structural component of the neuron has an important function CELLS OF THE NERVOUS SYSTEM: THE NEURON | 37 https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Neuron-Types.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Neuron-Types.jpg https://openbooks.lib.msu.edu/neuroscience/chapter/the-neuron/ https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ • Overall structure of the cell can vary depending on location and function of the neuron Test Yourself! An interactive H5P element has been excluded from this version of the text. You can view it online here: https://opentext.uoregon.edu/neurobiology/?p=510#h5p-43 Attributions This chapter is adapted from “Cells of the Nervous System: the Neuron” in Introduction to Neuroscience by Valerie Hedges which is licensed under a Creative Commons Attribution- NonCommercial-ShareAlike 4.0 International License. Media Attributions • Comparison of Brain Size Across Species © OpenStax adapted by Valerie Hedges is licensed under a CC BY-SA (Attribution ShareAlike) license • Neuroscience is an integrative field of study © T. Wesley Mills adapted by Valerie Hedges is licensed under a Public Domain license • Scientific method © Efbrazil adapted by Valerie Hedges is licensed under a CC BY-SA (Attribution ShareAlike) license • Phineas Gage and his injury adapted by Valerie Hedges is licensed under a Public Domain license • Commonly used animal models in neuroscience adapted by Valerie Hedges 38 | CELLS OF THE NERVOUS SYSTEM: THE NEURON https://opentext.uoregon.edu/neurobiology/?p=510#h5p-43 https://openbooks.lib.msu.edu/introneuroscience1/chapter/the-neuron/ https://openbooks.lib.msu.edu/introneuroscience1/chapter/what-is-neuroscience/ https://openbooks.lib.msu.edu/introneuroscience1/chapter/what-is-neuroscience/ https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ https://commons.wikimedia.org/wiki/File:Figure_35_03_05_Brain_size_Vertical.png https://creativecommons.org/licenses/by-sa/4.0/ https://commons.wikimedia.org/wiki/File:Brain_Drawing.svg https://en.wikipedia.org/wiki/T._Wesley_Mills https://creativecommons.org/publicdomain/mark/1.0/ https://commons.wikimedia.org/wiki/File:The_Scientific_Method.svg#file https://creativecommons.org/licenses/by-sa/4.0/ https://creativecommons.org/licenses/by-sa/4.0/ https://commons.wikimedia.org/wiki/File:Phineas_Gage_CGI.jpg https://creativecommons.org/publicdomain/mark/1.0/ • Preparations © Valerie Hedges is licensed under a CC BY-SA (Attribution ShareAlike) license • Trepanated skull © Rama adapted by Valerie Hedges is licensed under a CC BY-SA (Attribution ShareAlike) license • Paul Broca © Unknown is licensed under a Public Domain license • Plasticity © Alan Thistle adapted by Valerie Hedges is licensed under a CC BY-SA (Attribution ShareAlike) license CELLS OF THE NERVOUS SYSTEM: THE NEURON | 39 https://commons.wikimedia.org/wiki/File:54986main_mouse_med.jpg%20https://upload.wikimedia.org/wikipedia/commons/c/c7/Galvani-frogs-legs-electricity.jpg%20https://upload.wikimedia.org/wikipedia/commons/0/05/Cell_culture.jpg https://creativecommons.org/licenses/by-sa/4.0/ https://commons.wikimedia.org/wiki/File:Trepanated_skull_of_a_woman-P4140363-white.jpg https://commons.wikimedia.org/wiki/User:Rama https://creativecommons.org/licenses/by-sa/4.0/ https://creativecommons.org/licenses/by-sa/4.0/ https://commons.wikimedia.org/wiki/File:Paul_Broca_2.jpg https://creativecommons.org/publicdomain/mark/1.0/ https://commons.wikimedia.org/wiki/File:Brain_image_of_blind_echolocator.tif https://creativecommons.org/licenses/by-sa/4.0/ https://creativecommons.org/licenses/by-sa/4.0/ Resources • Glossary Terms • Key Takeaways • Test Yourself 2. CELLS OF THE NERVOUS SYSTEM: GLIA Although most of neuroscience is concerned with understanding the functions of neurons, there are other cells in the nervous system that are just as interesting. These cells are grouped together under the umbrella classification of glia. Historically, when these non- neuronal cells were visualized under the microscope, the histologists and anatomists had no idea about their function. They were seen all around the neurons, so the assumption was that these cells were structural elements, a sort of living glue, that held the nervous system together. Today, we know that these glia serve a variety of functions; unfortunately, the misnomer “glia”—derived from the Latin word for “glue”—is still used to describe these non- neuronal components of the nervous system. Astrocytes Astrocytes are named for their characteristic star-shaped morphology. One of the main functions of astrocytes in the brain is to help maintain the blood-brain barrier. At the end of the extensions of the astrocyte are protrusions called “endfeet”. These endfeet are often wrapped around the endothelial cells that surround the blood vessels. The endfeet release important biological compounds that allow the endothelial cells to remain healthy as they function in maintaining the blood-brain barrier. Astrocytes are also very closely associated with synapses. Astrocytes also synthesize and produce a variety of trophic factors, which are helper molecular signals that serve several different functions. For one, trophic factors signal to neurons that the neuron 40 | CELLS OF THE NERVOUS SYSTEM: GLIA should continue to live, or that specific synapses should be maintained. They help guide the neurons as they reach out, forming synapses where appropriate. Figure 2.1 Astrocyte. A green fluorescent marker has been used to stain astrocytes within brain tissue. The astrocytes has star-like projections off the cell body. Oligodendrocytes The main function of the oligodendrocytes is to add a layer of myelin around the axons of nearby neurons in the central nervous system. A single oligodendrocyte is able to myelinate up to 50 segments of axons. As cells that produce myelin, they are responsible for increasing the conduction speed of nearby neurons as they send signals. Oligodendrocytes only exist in the central nervous system. CELLS OF THE NERVOUS SYSTEM: GLIA | 41 Figure 2.2 Image of an oligodendrocyte. A single oligodendrocyte shown in blue covers axons from multiple neuron axons with myelin sheath. Schwann Cells Schwann cells can only be found in the peripheral nervous system. The main action of Schwann cells is to provide a section of myelin sheath for peripheral nervous system neurons, and in this way, they function similarly to the oligodendrocytes. Schwann cells produce only a single section of myelin, compared to oligodendrocytes, which myelinate multiple sections. Schwann cells also function in the regeneration of injured axons. When nerves in the peripheral nervous system are damaged after trauma, Schwann cells rapidly mobilize to the site of injury. 42 | CELLS OF THE NERVOUS SYSTEM: GLIA Figure 2.3 Schwann Cell. The Schwann cell is shown in blue. A single Schwann cell wraps myelin around a neuron axon, shown in yellow. Multiple Schwann cells are needed to myelinate one neuron axon. Microglia Microglia are a bit different from the other glial cell populations. For one, microglia are more immune cells rather than neural. They act as cellular scavengers that travel throughout the brain and spinal cord. It is estimated that microglia make up 10-15% of all cells in the brain. As immune cells, microglia identify and destroy clumps of proteins, dead/dying cells, or foreign pathogens that enter into the brain. After an injury to the central nervous system, like a traumatic blow to the head, microglia rapidly react to the area of the insult. CELLS OF THE NERVOUS SYSTEM: GLIA | 43 Figure 2.4 Photograph of microglia and neurons. In this microscope photograph, microglia are stained with a green fluorescent stain and neurons are stained with a red fluorescent stain. Microglia are much smaller than neurons. Ependymal Cells Along the inside of the ventricles are a lining of glia called ependymal cells. These ependymal cells are columnar with small fingerlike extensions called cilia that extend into the ventricles and into the central canal that runs down the inside of the spinal cord. The cilia have motor properties that allow for them to rhythmically beat to create a current in the surrounding fluid. Figure 2.5 Image of brain ventricles. The brain ventricles (shown in blue) are hollow areas within the brain that are interconnected and filled with cerebrospinal fluid. The ventricles are connected to the central canal of the spinal cord. The ventricles are show in a lateral view (left) and anterior view (right). 44 | CELLS OF THE NERVOUS SYSTEM: GLIA Ependymal cells produce cerebral spinal fluid (CSF). In total, the body can make about half a liter of CSF each day (a little more than two cups.) The ependymal cells are part of a structure called the choroid plexus, the network of blood vessels and cells that form a boundary between the blood and the CSF. Figure 2.6. Ependymal Cells. Ependymal cells are ciliated columnar cells that line the ventricles and other fluid-filled spaces of the central nervous system. The rhythmic beating of the cilia create movement of the surrounding cerebral spinal fluid. ‘Ependymal Cells’ by Valerie Hedges is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC-BY-NC-SA) 4.0 International License. Key Takeaways • There are multiple different types of glia cells that each have their own functions CELLS OF THE NERVOUS SYSTEM: GLIA | 45 Test Yourself! An interactive H5P element has been excluded from this version of the text. You can view it online here: https://opentext.uoregon.edu/neurobiology/?p=517#h5p-44 Attributions This chapter is adapted from “Cells of the Nervous System: Glia” in Introduction to Neuroscience by Valerie Hedges which is licensed under a Creative Commons Attribution-NonCommercial- ShareAlike 4.0 International License. Media Attributions • Astrocyte © Bruno Pascal adapted by Valerie Hedges is licensed under a CC BY-SA (Attribution ShareAlike) license • Oligodendrocyte © Holly Fischer adapted by Valerie Hedges is licensed under a CC BY (Attribution) license • Schwann cell © OpenStax adapted by Valerie Hedges is licensed under a CC BY-SA (Attribution ShareAlike) license • Microglia © Gerry Shaw adapted by Valerie Hedges is licensed under a CC BY-SA (Attribution ShareAlike) license • Brain Ventricles © Bruce Blaus adapted by Valerie Hedges is licensed under a CC BY (Attribution) license • Ependymal Cells © Valerie Hedges is licensed under a CC BY-NC-SA (Attribution NonCommercial ShareAlike) license 46 | CELLS OF THE NERVOUS SYSTEM: GLIA https://opentext.uoregon.edu/neurobiology/?p=517#h5p-44 https://openbooks.lib.msu.edu/introneuroscience1/chapter/cells-of-the-nervous-system-glia/ https://openbooks.lib.msu.edu/introneuroscience1/chapter/what-is-neuroscience/ https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ https://commons.wikimedia.org/wiki/File:Human_astrocyte.png https://creativecommons.org/licenses/by-sa/4.0/ https://creativecommons.org/licenses/by-sa/4.0/ https://commons.wikimedia.org/wiki/File:Oligodendrocyte_illustration.png https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ https://commons.wikimedia.org/wiki/File:CeluladeSchwann.jpg https://creativecommons.org/licenses/by-sa/4.0/ https://creativecommons.org/licenses/by-sa/4.0/ https://commons.wikimedia.org/wiki/File:Microglia_and_neurons.jpg https://creativecommons.org/licenses/by-sa/4.0/ https://creativecommons.org/licenses/by-sa/4.0/ https://upload.wikimedia.org/wikipedia/commons/d/d4/Blausen_0896_Ventricles_Brain.png https://commons.wikimedia.org/wiki/User:BruceBlaus https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ Resources • Key Takeaways • Test Yourself • Video Lecture 3. ION MOVEMENT Ion flow into and out of the neuron is a critical component of neuron function. The control of ion movement affects the cell at rest and while sending and receiving information from other neurons. Phospholipid Bilayer Prevents Ion Movement The neuronal membrane is composed of lipid molecules that form two layers. The hydrophilic heads of the molecules align on the outside of the membrane, interacting with the intra- and extracellular solution of the cell, whereas the hydrophobic tails are arranged in the middle, forming a barrier to water and water-soluble molecules like ions. This barrier is critical to neuron function. Figure 3.1. The neuronal membrane is composed of two layers of phospholipid molecules that form a barrier to water and water-soluble molecule due to the organization of the hydrophilic heads and hydrophobic ends of the molecules. ‘Phospholipid Bilayer’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial (CC-BY-NC) 4.0 International License. ION MOVEMENT | 47 https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Phospholipid-Bilayer.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Phospholipid-Bilayer.jpg https://creativecommons.org/licenses/by-nc/4.0/ Ions move in predictable ways Ion Channels Allow Ion Movement Embedded throughout the neuronal membrane are ion channels. Ion channels are proteins that span the width of the cell membrane and allow charged ions to move across the membrane. Ions cannot pass through the phospholipid bilayer without a channel. Channels can be opened in a number of different ways. Channels that open and close spontaneously are called leak or non-gated channels. Channels that open in response to a change in membrane potential are called voltage-gated. Channels that open in response to a chemical binding are called ligand-gated. Other mechanisms like stretch of the membrane or cellular mechanisms can also lead to the opening of channels. Channels can be specific to one ion or allow the flow of multiple ions. Figure 3.2. The phospholipid bilayer with embedded ion channels. The dotted, blue channels represent sodium channels; the striped, green channels represent potassium channels; the solid yellow channels represent chloride channels. ‘Membrane with Channels’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial (CC-BY-NC) 4.0 International License. Ion channels control ion movement across the cell membrane because the phospholipid bilayer is impermeable to the charged atoms. When the channels are closed, no ions can move into or out of the cell. When ion channels open, however, then ions can move across the cell membrane. One or more interactive elements has been excluded from this version of the text. You can view them online here: https://opentext.uoregon.edu/neurobiology/?p=37#video-37-1 48 | ION MOVEMENT https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Membrane-with-Ion-Channels.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2020/11/Membrane-with-Ion-Channels.jpg https://creativecommons.org/licenses/by-nc/4.0/ https://opentext.uoregon.edu/neurobiology/?p=37#video-37-1 Animation 3.1. When ion channels in the membrane are closed, ions cannot move into or out of the neuron. Ions can only cross the cell membrane when the appropriate channel is open. For example, only sodium can pass through open sodium channels. The dotted, blue channels represent sodium channels; the striped, green channels represent potassium channels; the solid yellow channels represent chloride channels. ‘Ion Movement’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial (CC-BY-NC) 4.0 International License. View static image of animation. Gradients Drive Ion Movement Ions move in predictable ways. Concentration and electrical gradients drive ion movement. Ions will diffuse from regions of high concentration to regions of low concentration. Diffusion is a passive process, meaning it does not require energy. As long as a pathway exists (like through open ion channels), the ions will move down the concentration gradient. In addition to concentration gradients, electrical gradients can also drive ion movement. Ions are attracted to and will move toward regions of opposite charge. Positive ions will move toward regions of negative charge, and vice versa. For discussion of ion movement in this text, the combination of these two gradients will be referred to as the electrochemical gradient. Sometimes the concentration and electrical gradients driving ion movement can be in the same direction; sometimes the direction is opposite. The electrochemical gradient is the summation of the two individual gradients and provides a single direction for ion movement. One or more interactive elements has been excluded from this version of the text. You can view them online here: https://opentext.uoregon.edu/neurobiology/?p=37#video-37-2 Animation 3.2. Concentration and electrical gradients drive ion movement. Ions diffuse down concentration gradients from regions of high concentration to regions of low concentration. Ions also move toward regions of opposite electrical charge. ‘Gradients’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial (CC-BY-NC) 4.0 International License. View ION MOVEMENT | 49 https://creativecommons.org/licenses/by-nc/4.0/ https://creativecommons.org/licenses/by-nc/4.0/ https://opentext.uoregon.edu/neurobiology/?p=37#video-37-2 https://creativecommons.org/licenses/by-nc/4.0/ static image of animation. When Gradients Balance, Equilibrium Occurs When the concentration and electrical gradients for a given ion balance, meaning they are equal in strength but in different directions, that ion will be at equilibrium. Ions still move across the membrane through open channels when at equilibrium, but there is no net movement in either direction meaning there is an equal number of ions moving into the cell as there are moving out of the cell. One or more interactive elements has been excluded from this version of the text. You can view them online here: https://opentext.uoregon.edu/neurobiology/?p=37#video-37-3 Animation 3.3. When an ion is at equilibrium, which occurs when the concentration and electrical gradients acting on the ion balance, there is no net movement of the ion. The ions continue to move across the membrane through open channels, but the ion flow into and out of the cell is equal . In this animation, the membrane starts and ends with seven positive ions on each side even though the ions move through the open channels. ‘Ion Equilibrium’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial (CC-BY-NC) 4.0 International License. View static image of animation. Key Takeaways • The phospholipid bilayer prevents ion movement into or out of the cell • Ion channels allow ion movement across the membrane 50 | ION MOVEMENT https://opentext.uoregon.edu/neurobiology/?p=37#video-37-3 https://creativecommons.org/licenses/by-nc/4.0/ https://creativecommons.org/licenses/by-nc/4.0/ • Electrochemical gradients drive the direction of ion flow • At equilibrium, there is no net ion movement (but ions are still moving) Test Yourself! An interactive H5P element has been excluded from this version of the text. You can view it online here: https://opentext.uoregon.edu/neurobiology/?p=37#h5p-2 1. Explain how chemical and electrical gradients affect ion flow. 2. Explain ion movement at equilibrium. Video Lecture One or more interactive elements has been excluded from this version of the text. You can view them online here: https://opentext.uoregon.edu/neurobiology/?p=37#oembed-1 ION MOVEMENT | 51 https://opentext.uoregon.edu/neurobiology/?p=37#h5p-2 Attributions This chapter was adapted from “Ion Movement” in Foundations of Neuroscience by Casey Henley which is licensed under a Creative Commons Attribution NonCommerical ShareAlike 4.0 International License. 52 | ION MOVEMENT https://openbooks.lib.msu.edu/neuroscience/chapter/ion-movement/ https://openbooks.lib.msu.edu/neuroscience/ https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ Resources • Key Takeaways • Test Yourself • Video Lecture 4. MEMBRANE POTENTIAL The membrane potential is the difference in electrical charge between the inside and the outside of the neuron. This is measured using two electrodes. A reference electrode is placed in the extracellular solution. The recording electrode is inserted into the cell body of the neuron. MEMBRANE POTENTIAL | 53 Figure 4.1. The membrane potential is measured using a reference electrode placed in the extracellular solution and a recording electrode placed in the cell soma. The membrane potential is the difference in voltage between these two regions. ‘Measuring Membrane Potential’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC BY-NC-SA) 4.0 International License. Terminology There is more than one way to describe a change in membrane potential. If the membrane potential moves toward zero, that is a depolarization because the membrane is becoming less polarized, meaning there is a smaller difference between the charge on the inside of the cell compared to the outside. This is also referred to as a decrease in membrane potential. This means that when a neuron’s membrane potential moves from rest, which is typically around -65 mV, toward 0 mV and becomes more positive, this is a decrease in membrane potential. Since the membrane potential is the difference in electrical charge between the inside and outside of the cell, that difference decreases as the cell’s membrane potential moves toward 0 mV. 54 | MEMBRANE POTENTIAL https://openbooks.lib.msu.edu/app/uploads/sites/6/2021/01/MeasuringMembranePotential.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2021/01/MeasuringMembranePotential.jpg https://creativecommons.org/licenses/by-nc-sa/4.0/ If the membrane potential moves away from zero, that is a hyperpolarization because the membrane is becoming more polarized. This is also referred to as an increase in membrane potential. Figure 4.2. A decrease in membrane potential is a change that moves the cell’s membrane potential toward 0 or depolarizes the membrane. An increase in membrane potential is a change that moves the cell’s membrane potential away from 0 or hyperpolarizes the membrane. ‘Membrane Potential Terms’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC BY-NC-SA) 4.0 International License. The solution inside of the neuron is more negatively charged than the solution outside Voltage Distribution At rest, ions are not equally distributed across the membrane1. This distribution of ions and other 1. Hille B. Ionic channels in nerve membranes. Prog Biophys Mol Biol. 1970;21:1-32. doi: 10.1016/0079-6107(70)90022-2. PMID: 4913288. MEMBRANE POTENTIAL | 55 https://openbooks.lib.msu.edu/app/uploads/sites/6/2021/01/MembranePotentialTerms.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2021/01/MembranePotentialTerms.jpg https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ charged molecules leads to the inside of the cell having a more negative charge compared to the outside of the cell. Figure 4.3. The inside of the neuron has a more negative charge than the outside of the neuron. ‘Membrane Potential’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC BY-NC-SA) 4.0 International License. A closer look shows that sodium, calcium, and chloride are concentrated outside of the cell membrane in the extracellular solution, whereas potassium and negatively-charged molecules like amino acids and proteins are concentrated inside in the intracellular solution. 56 | MEMBRANE POTENTIAL https://openbooks.lib.msu.edu/app/uploads/sites/6/2021/01/MembranePotential.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2021/01/MembranePotential.jpg https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ Figure 4.4. For a typical neuron at rest, sodium, chloride, and calcium are concentrated outside the cell, whereas potassium and other anions are concentrated inside. This ion distribution leads to a negative resting membrane potential. The dotted, blue channels represent sodium leak channels; the striped, green channels represent potassium leak channels; the solid yellow channels represent chloride leak channels. ‘Membrane at Rest’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC BY-NC-SA) 4.0 International License. The distribution of the different ions across the membrane creates electrochemical gradients that drive ion movement These concentration differences lead to varying degrees of electrochemical gradients in different directions depending on the ion in question. For example, the electrochemical gradients will drive potassium out of the cell but will drive sodium into the cell. MEMBRANE POTENTIAL | 57 https://openbooks.lib.msu.edu/app/uploads/sites/6/2021/01/IonDistributionAtRest.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2021/01/IonDistributionAtRest.jpg https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ Figure 4.5. The distribution of ions on either side of the membrane lead to electrochemical gradients for sodium and potassium that drive ion flow in different directions. If the membrane is permeable to sodium, ions will flow inward. If the membrane is permeable to potassium, ions will flow outward. The dotted, blue channels represent sodium channels; the striped, green channels represent potassium channels; the solid yellow channels represent chloride channels. ‘Gradients Across Membrane’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC BY-NC-SA) 4.0 International License. Equilibrium Potential The neuron’s membrane potential at which the electrical and concentration gradients for a given ion balance out is called the ion’s equilibrium potential. The ion is at equilibrium at this membrane potential, meaning there is no net movement of the ion in either direction. Let’s look at sodium in more detail: Example: Driving Forces on Sodium Ions 58 | MEMBRANE POTENTIAL https://openbooks.lib.msu.edu/app/uploads/sites/6/2021/01/GradientsAcrossMembrane.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2021/01/GradientsAcrossMembrane.jpg https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ When sodium channels open, the neuron’s membrane becomes permeable to sodium, and sodium will begin to flow across the membrane. The direction is dependent upon the electrochemical gradients. The concentration of sodium in the extracellular solution is about 10 times higher than the intracellular solution, so there is a concentration gradient driving sodium into the cell. Additionally, at rest, the inside of the neuron is more negative than the outside, so there is also an electrical gradient driving sodium into the cell. As sodium moves into the cell, though, these gradients change in driving strength. As the neuron’s membrane potential become positive, the electrical gradient no longer works to drive sodium into the cell. Eventually, the concentration gradient driving sodium into the neuron and the electrical gradient driving sodium out of the neuron balance with equal and opposite strengths, and sodium is at equilibrium. The membrane potential of the neuron at which equilibrium occurs is called the equilibrium potential of an ion, which, for sodium, is approximately +60 mV. One or more interactive elements has been excluded from this version of the text. You can view them online here: https://opentext.uoregon.edu/neurobiology/?p=46#video-46-1 Animation 4.1. At rest, both the concentration and electrical gradients for sodium point into the cell. As a result, sodium flows in. As sodium enters, the membrane potential of the cell decreases and becomes more positive. As the membrane potential changes, the electrical gradient decreases in strength, and after the membrane potential passes 0 mV, the electrical gradient will point outward, since the inside of the cell is more positively charged than the outside. The ions will continue to flow into the cell until equilibrium is reached. An ion will be at equilibrium when its concentration and electrical gradients are equal in strength and opposite in direction. The membrane potential of the neuron at which this occurs is the equilibrium potential for that ion. Sodium’s equilibrium potential is approximately +60 mV. The dotted, blue channels represent sodium channels; the striped, green channels represent potassium channels; the solid yellow channels represent chloride channels. ‘Sodium Gradients’ by Casey Henley is licensed under a Creative Commons MEMBRANE POTENTIAL | 59 https://opentext.uoregon.edu/neurobiology/?p=46#video-46-1 https://creativecommons.org/licenses/by-nc-sa/4.0/ Attribution Non-Commercial Share-Alike (CC BY-NC-SA) 4.0 International License. View static image of animation. Calculate Equilibrium Potential with Nernst Equation The gradients acting on the ion will always drive the ion towards equilibrium. The equilibrium potential of an ion is calculated using the Nernst equation: The Nernst Equation The constant 61 is calculated using values such as the universal gas constant and temperature of mammalian cells Z is the charge of the ion [Ion]inside is the intracellular concentration of the ion [Ion]outside is the extracellular concentration of the ion An Example: Sodium’s Equilibrium Potential For Sodium: z = 1 60 | MEMBRANE POTENTIAL https://creativecommons.org/licenses/by-nc-sa/4.0/ [Ion]inside = 15 mM [Ion]outside = 145 mM It is possible to predict which way an ion will move by comparing the ion’s equilibrium potential to the neuron’s membrane potential Predict Ion Movement by Comparing Membrane Potential to Equilibrium Potential Let’s assume we have a cell with a resting membrane potential of -70 mV. Sodium’s equilibrium potential is +60 mV. Therefore, to reach equilibrium, sodium will need to enter the cell, bringing in positive charge. On the other hand, chloride’s equilibrium potential is -65 mV. Since chloride is a negative ion, it will need to leave the cell in order to make the cell’s membrane potential more positive to move from -70 mV to -65 mV. MEMBRANE POTENTIAL | 61 Figure 4.6. A) If a cell is at rest at -70 mV, sodium ions will flow into the cell to move the cell’s membrane potential toward sodium’s equilibrium potential of +60 mV. B) At the same resting membrane potential, chloride would flow out of the cell, taking away its negative charge, making the inside of the cell more positive and moving toward chloride’s equilibrium potential of -65 mV. The dotted, blue channels represent sodium channels; the striped, green channels represent potassium channels; the solid yellow channels represent chloride channels. ‘Moving Toward Equilibrium’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC BY-NC-SA) 4.0 International License. 62 | MEMBRANE POTENTIAL https://openbooks.lib.msu.edu/app/uploads/sites/6/2021/01/MovingTowardEquilibrium.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2021/01/MovingTowardEquilibrium.jpg https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ Concentration and Equilibrium Potential Values We will use the following ion concentrations and equilibrium potentials: [table id=1 /] Key Takeaways • Moving the membrane potential toward 0 mV is a decrease in potential; moving away from 0 mV is an increase in potential • The distribution of ions inside and outside of the cell at rest vary among the different ions; some are concentrated inside, some are concentrated outside • Equilibrium potentials are calculated using the Nernst equation • To predict ion movement, compare the current membrane potential of the neuron with the ion’s equilibrium potential. Determine which way the ion needs to move to cause that membrane potential change (i.e. does the ion need to move into the cell or out of the cell?) Test Yourself! Try the quiz more than once to get different questions! MEMBRANE POTENTIAL | 63 An interactive H5P element has been excluded from this version of the text. You can view it online here: https://opentext.uoregon.edu/neurobiology/?p=46#h5p-3 An interactive H5P element has been excluded from this version of the text. You can view it online here: https://opentext.uoregon.edu/neurobiology/?p=46#h5p-4 1. Define resting membrane potential (Vm) of a cell. 2. Explain the differences between the resting membrane potential and the equilibrium potential. 3. Using the concentration values from the table below, calculate the equilibrium potential of potassium using the Nernst equation. [table id=4 /] Video Lecture One or more interactive elements has been excluded from this version of the text. You can view them online here: https://opentext.uoregon.edu/neurobiology/?p=46#oembed-1 Attributions This chapter was adapted from “Membrane Potential” in Foundations of Neuroscience by Casey Henley 64 | MEMBRANE POTENTIAL https://opentext.uoregon.edu/neurobiology/?p=46#h5p-3 https://opentext.uoregon.edu/neurobiology/?p=46#h5p-4 https://openbooks.lib.msu.edu/neuroscience/chapter/membrane-potential/ https://openbooks.lib.msu.edu/neuroscience/ which is licensed under a Creative Commons Attribution NonCommerical ShareAlike 4.0 International License. MEMBRANE POTENTIAL | 65 https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ Resources • Key Takeaways • Test Yourself • Video Lecture 5. THE MEMBRANE AT REST As covered in the previous chapter, at rest there is an uneven distribution of ions on either side of the membrane. The inside of the membrane is more negatively charged than the outside, which is expressed as a negative membrane potential. 66 | THE MEMBRANE AT REST Figure 5.1. For a typical neuron at rest, sodium, chloride, and calcium are concentrated outside the cell, whereas potassium and other anions are concentrated inside. This ion distribution leads to a negative resting membrane potential. The dotted, blue channels represent sodium leak channels; the striped, green channels represent potassium leak channels; the solid yellow channels represent chloride leak channels. ‘Membrane at Rest’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC BY-NC-SA) 4.0 International License. The membrane at rest is most permeable to potassium. Permeability for other ions, like chloride and sodium, is significantly lower. Permeability at Rest How the ions are distributed across the membrane plays an important role in the generation of the resting membrane potential. At rest a type of non-gated ion channels, called leak channels are actually THE MEMBRANE AT REST | 67 https://openbooks.lib.msu.edu/app/uploads/sites/6/2021/01/IonDistributionAtRest.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2021/01/IonDistributionAtRest.jpg https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ open. Significantly more potassium channels are open than sodium channels, and this makes the membrane at rest far more permeable to potassium than sodium. Figure 5.2. At rest, the distribution of ions across the membrane varies for different ions. Additionally, at rest, more potassium non-gated ion channels (emphasized by green circles) are open than sodium channels (emphasized by the blue circle). The dotted, blue channels represent sodium leak channels; the striped, green channels represent potassium leak channels; the solid yellow channels represent chloride leak channels. ‘Channels at Rest’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC BY-NC-SA) 4.0 International License. Potassium Can Cross Membrane at Rest Since the membrane is permeable to potassium at rest due to the open non-gated channels, potassium 68 | THE MEMBRANE AT REST https://openbooks.lib.msu.edu/app/uploads/sites/6/2021/01/ChannelsAtRest.jpg https://openbooks.lib.msu.edu/app/uploads/sites/6/2021/01/ChannelsAtRest.jpg https://creativecommons.org/licenses/by-nc-sa/4.0/ ions flow across the membrane. Since permeability to potassium is hundreds of times more than that to sodium, the electrochemical gradients at work will cause potassium to flow out of the cell in order to move the cell’s membrane potential toward potassium’s equilibrium potential of -80 mV. One or more interactive elements has been excluded from this version of the text. You can view them online here: https://opentext.uoregon.edu/neurobiology/?p=52#video-52-1 Animation 5.1. Electrochemical gradients drive potassium out of the cell, removing positive charge, making the cell’s membrane potential more negative, in the direction of potassium’s equilibrium potential. The dotted, blue channels represent sodium leak channels; the striped, green channels represent potassium leak channels; the solid yellow channels represent chloride leak channels. ‘Potassium Flow at Rest’ by Casey Henley is licensed under a Creative Commons Attribution Non- Commercial Share-Alike (CC BY-NC-SA) 4.0 International License. View static image of animation. Resting Membrane Potential Value You might ask, though, if the cell has these open non-gated ion channels, and ions are moving at rest, won’t the cell eventually reach potassium’s equilibrium potential if the membrane is only permeable to potassium? If the only structural element involved in ion flow present in the cell membrane were the open non- gated potassium channels, the membrane potential would eventually reach potassium’s equilibrium potential. However, the membrane has other open non-gated ion channels as well. There are fewer of these channels compared to the potassium channels, though. The permeability of chloride is about half of that of potassium, and the permeability of sodium is about 25 to 40 times less than that of potassium. This leads to enough chloride and sodium ion movement to keep the neuron at a resting membrane potential that is slightly more positive than potassium’s equilibrium potential. THE MEMBRANE AT REST | 69 https://opentext.uoregon.edu/neurobiology/?p=52#video-52-1 https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ One or more interactive elements has been excluded from this version of the text. You can view them online here: https://opentext.uoregon.edu/neurobiology/?p=52#video-52-2 Animation 5.2. The membrane is most permeable to potassium at rest, and this leads to potassium efflux. However, the membrane is also permeable to chloride and sodium, and the flow of these ions keep the resting membrane potential more positive than potassium’s equilibrium potential. The dotted, blue channels represent sodium leak channels; the striped, green channels represent potassium leak channels; the solid yellow channels represent chloride leak channels. ‘Ion Flow at Rest’ by Casey Henley is licensed under a Creative Commons Attribution Non-Commercial Share-Alike (CC BY- NC-SA) 4.0 International License. View static image of animation. The sodium-potassium pumps work to keep the ion concentrations stable even as ions cross the membrane at rest. Maintenance of Gradients As ions move across the membrane both at rest and when the neuron is active, the concentrations of ions inside and outside of the cell will change. This leads to changes in the electrochemical gradients that are driving ion movement. What, then, maintains the concentration and electrical gradients critical for the ion flow that allows the neuron to function properly? The key mechanism for maintaining gradients across the neuronal membrane is the sodium- potassium pump. The pump uses energy in the form of ATP to move three sodium ions out of the cell and two potassium ions in. This moves the ions against their electrochemical gradients, which is why it requires energy. The pump functions to keep the ionic concentrations at proper levels inside and outside the cell. The sodium-potassium pump is so critical to function, that it uses fully 30-40% of the brain’s energy consumption. 70 | THE MEMBRANE AT REST https://opentext.uoregon.edu/neurobiology/?p=52#video-52-2 https://creativecommons.org/licenses/by-nc-sa/4.0/ One or more interactive elements has been excluded from this version of the text. You can view them online here: https://opentext.uoregon.edu/neurobiology/?p=52#video-52-3 Animation 5.3. The sodium-potassium pump is embedded in the cell membrane and uses ATP to move sodium out of the cell and potassium into the cell, maintaining the electrochemical gradients necessary for proper neuron functioning. Three intracellular sodium ions enter the pump. ATP is converted to ADP, which leads to a conformational change of the protein, closing the intracellular side and opening the extracellular side. The sodium ions leave the pump while two extracellular potassium ions enter. The attached phosphate molecule then leaves, causing the pump to again open toward the inside of the neuron. The potassium ions leave, and the cycle begins again. ‘Sodium- Potassium Pump’ by by Casey Henley is licensed under a Creative Commons Attribution Non- Commercial Share-Alike (CC BY-NC-SA) 4.0 International License. View static image of animation. Calculating Membrane Potential with Goldman Equation It is possible to calculate the membrane potential of a cell if the concentrations and relative permeabilities of the ions are known. Recall from the last chapter, the Nernst equation is used to calculate one ion’s equilibrium potential. Knowing the equilibrium potential can help you predict which way one ion will move, and it also calculates the membrane potential value that the cell would reach if the membrane were only permeable to one ion. However, at rest, the membrane is permeable to potassium, chloride, and sodium. To calculate the membrane potential, the Goldman equation is needed. The Goldman Equation THE MEMBRANE AT REST | 71 https://opentext.uoregon.edu/neurobiology/?p=52#video-52-3 https://creativecommons.org/licenses/by-nc-sa/4.0/ https://creativecommons.org/licenses/by-nc-sa/4.0/ Like the Nernst equation, the constant 61 is calculated using values such as the universal gas constant and temperature of mammalian cells Pion is the relative permeability of each ion [Ion]inside is the intracellular concentration of each ion [Ion]outside is the extracellular concentration of each ion Example: The Neuron at Rest [table id=2 /] Key Takeaways • At rest, the membrane is most permeable to potassium because Non-gated (leak) potassium channels are open at resting potential • Other ion channels (chloride and sodium) are also open, but fewer are open than potassium 72 | THE MEMBRANE AT REST • Therefore, the resting membrane potential of a typical neuron is relatively close to the equilibrium potential for potassium (EK) • Electrochemical gradients needed for normal neuronal function are maintained, despite constant flow through leak channels, by the sodium-potassium pump, which expends energy to translocate K+ into the cell, and Na+ out of the cell. Test Yourself! An interactive H5P element has been excluded from this version of the text. You can view it online here: https://opentext.uoregon.edu/neurobiology/?p=52#h5p-5 • From memory, draw a diagram of a neuronal membrane at rest that includes the non-gated ion channels in their correct state (i.e., open, closed, inactivated). • If all other conditions (see purple box above) are unchanged, but PNa is 0.004 instead, how will the resting potential change? Video Lecture THE MEMBRANE AT REST | 73 https://opentext.uoregon.edu/neurobiology/?p=52#h5p-5 One or more interactive elements has been excluded from this version of the text. You can view them online here: https://opentext.uoregon.edu/neurobiology/?p=52#oembed-1 Attributions This chapter was adapted from “The Membrane at Rest” in Foundations of Neuroscience by Casey Henley which is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. 74 | THE MEMBRANE AT REST https://openbooks.lib.msu.edu/neuroscience/chapter/the-membrane-at-rest/ https://openbooks.lib.msu.edu/n