Chapter 3 PDF - Cells of the Nervous System

Research Focus: A Genetic Diagnosis Fraternal twins Alexis and Noah Beery seemingly acquired brainstem damage perinatally, initially diagnosed with cerebral palsy. Unlike typical cerebral palsy cases, the twins’ condition worsened over time, with poor muscle tone and diffi- culties i...

Research Focus: A Genetic Diagnosis Fraternal twins Alexis and Noah Beery seemingly acquired brainstem damage perinatally, initially diagnosed with cerebral palsy. Unlike typical cerebral palsy cases, the twins’ condition worsened over time, with poor muscle tone and diffi- culties in walking, sitting, and swallowing. Retta Beery, their mother, discovered a news report on dopa-responsive dystonia (abnormal muscle tone caused by dopamine deficiency) and suspected the twins had the same condition. A daily dose of l-dopa, a chemical converted into dopamine by brain cells, led to remarkable improvements in the twins’ condition. In 2005, Alexis developed new symptoms of breathing difficulties, prompting further genetic analysis. Joe Beery, the twins’ father, worked with Life Technologies to sequence the twins’ genome at the Baylor College of Medicine. The genome sequencing revealed an abnormality in a gene affecting the production of both dopamine and serotonin. Adding 5-hydroxytryptophan (a precursor to serotonin) to the l-dopa treatment led to further improvements in the twins’ motor abilities. Alexis competed in junior high school track, and Noah participated in volleyball at the Junior Olympics after the treatment. The Beery twins’ case is the first known instance where genome sequencing led to a successful treatment, contributing to the emerging field of precision medicine. Precision medicine uses genetic diagnoses to create individualized therapies, as demonstrated in the twins’ case. Cells of the Nervous System Neurons: The basis of Information Processing The theory that neurons are the building blocks of the nervous system and behavior emerged from a debate between Camillo Golgi and Santiago Ramón y Cajal. Both Golgi and Cajal were awarded the Nobel Prize in 1906 for their work on nervous system cells. Golgi’s staining technique used silver nitrate to visualize nervous tissue, leading him to conclude that the nervous system is an interconnected network of fibers (the nerve net). Santiago Ramón y Cajal used Golgi’s stain on chick embryos and concluded that the nervous system is composed of discrete cells called neurons. Cajal proposed the neuron theory, which states that neurons are the functional units of the nervous system, and that more neurons lead to more complex behavior. The neuron theory also supports the idea that the number of neurons, rather than brain size, is a better measure of brain function. Since Golgi’s and Cajal’s work, new staining methods and techniques, such as microendoscopes, have been developed to visualize neurons and their activity. Research has confirmed the presence of a structure resembling Golgi’s nerve net, called the perineuronal net, which forms around neurons and stabilizes them as they mature. 1  The perineuronal net is associated with brain development, memory preservation, and conditions like addiction and memory loss. Neurons have three main parts: the cell body (soma), branching extensions (dendrites) that collect information, and the single axon that transmits messages. Neurons outnumber glial cells by a ratio of about 1:1, with 86 billion neurons and 85 billion glial cells in the human nervous system. All neurons share a common structure, and understanding one neuron offers insights into the function of others. Structure and Function of the Neuron Figure 3-3 details the external and internal features common to neurons, with an increased surface area due to extensions into dendrites and an axon. Dendrites are further extended by small protrusions called dendritic spines, which increase contact points with other neurons. A neuron may have up to 20 dendrites, each branching into smaller structures, with thousands of spines, enhancing its information-processing capacity. In mammals, dendrites collect information, and the number of spines corresponds to the neuron’s capacity for processing information. Each neuron has a single axon, starting at the axon hillock, which may branch into hundreds of axon collaterals to send messages to many other neurons. Axon collaterals divide into smaller branches called telodendria, ending in terminal buttons (end feet) that sit near, but usually do not touch, other neurons. The near-connection between neurons is called a synapse, involving the terminal button, the neighboring dendritic spine, and the space between them. Synapses are the main sites of information transfer between neurons. Neurons function like a river system: dendrites collect information from thousands of inputs and channel it to the axon, which sends a single message across collaterals and telodendria. Neurons integrate information into a meaningful signal that is passed to other neurons via the synapse. Neuromorphic computing, which models neuron structure and function, aims to emulate the brain’s abstraction processes for large-scale computing. Three Functions of Neurons Neurons have varying shapes and sizes, structured to perform three specialized functions: Sensory neurons (Figure 3-5A): Conduct information from sensory receptors in or on the body into the spinal cord and brain. Interneurons (Figure 3-5B): Associate sensory and motor activity within the central nervous system (CNS). Motor neurons (Figure 3-5C): Carry information from the brain and spinal cord to the body’s muscles. 2 Sensory Neurons Sensory neurons are the structurally simplest type of neuron. Bipolar neurons: – Found in the retina of the eye. – Have a single short dendrite on one side and a single short axon on the other side. – Transmit afferent (incoming) sensory information from the retina’s light receptors to neurons in the brain’s visual centers. Somatosensory neurons: – Bring sensory information from the body into the spinal cord over long distances. – The dendrite connects directly to the axon, with the cell body positioned to one side of the long pathway. Interneurons Interneurons, also known as association cells, link sensory and motor neurons and extensively branch to collect information from various sources. Stellate cells: – A specific type of interneuron that is small with many dendrites extending around the cell body. – The axon is difficult to see within the maze of dendrites. Brain sizes vary between species largely due to the number of interneurons: – Larger brains contain significantly more interneurons than smaller brains. – The number of interneurons is correlated with behavioral complexity. Pyramidal cells: – Characterized by a long axon and a pyramid-shaped cell body. – Possess two sets of dendrites: ∗ Apical set projects from the apex of the cell body. ∗ Basal set projects from the base of the cell body. – Pyramidal interneurons carry information from the cortex to the rest of the brain and spinal cord. Purkinje cells: – Distinctive interneurons with extremely branched dendrites forming a fan shape. – Carry information from the cerebellum to the rest of the brain and spinal cord. Motor Neurons Motor neurons have extensive dendritic networks to collect information from multiple sources. They feature: – Large cell bodies – Long axons that connect to muscles Motor neurons are located in the lower brainstem and spinal cord. All efferent (outgoing) neural information must pass through motor neurons to reach the muscles. 3 Neuronal Networks Sensory neurons collect afferent (incoming) information from the body and connect to interneurons for pro- cessing. Interneurons pass information to motor neurons, which have efferent connections that move muscles and produce behavior. All networks discussed in this text share three organizational aspects of function: – Input – Association – Output Principle 2: Sensory and motor divisions permeate the nervous system. Neurons that project long distances (e.g., somatosensory neurons, pyramidal neurons, motor neurons) are relatively large: – Neurons with large cell bodies typically have long extensions. – Neurons with small cell bodies (e.g., stellate interneurons) have short extensions. Long extensions carry information to distant parts of the nervous system; short extensions are engaged in local processing. Example: – Dendrite tips of some somatosensory neurons are in the big toe, while their axons can reach targets at the base of the brain. – Sensory neurons can send information over distances up to 2 meters (or more in large animals). – Axons of some pyramidal neurons extend from the cortex to the lower spinal cord, covering distances of up to 1 meter. The size of the pyramidal cell body is related to its need to provide nutrients and cellular supplies for its axons and dendrites. The Language of Neurons: Excitation and Inhibition Neurons communicate by exciting (turning on) or inhibiting (turning off) other neurons. Communication is similar to digital computers, sending yes (excitatory) or no (inhibitory) signals. Neurons can receive thousands of signals per second, allowing them to produce variable signals akin to a radio or speaker. Principle 7: The nervous system works by juxtaposing excitation and inhibition. A neuron sums its inputs: – If excitatory inputs exceed inhibitory inputs, the neuron sends messages to other neurons. – If inhibitory inputs exceed excitatory inputs, the neuron does not communicate. By exciting or inhibiting each other, neurons can detect sensory information and determine appropriate motor responses. Scientists create robotic models to confirm understanding of neural networks producing behavior: – Robots engage in goal-oriented actions similar to animals. – Robotic computers must sense the world, coordinate responses, and mimic nervous system functions. 4  This two-way modeling process is central to: – Neuromorphic computing – Machine learning – Robotic intelligence (AI) based on nervous system principles Example: Barbara Webb’s cricket robot mimics a female cricket’s behavior by locating a male’s chirping song (Webb, 2020). Ongoing AI research aims to develop robots that process and respond to uncertainty and ambiguity in natural environments. Experiment 3-1 presents an example of how excitation and inhibition influence a cricket robot’s behavior. Classes of Glial Cells Glial cells (from Greek for ”glue”) are support cells in the nervous system. Types of glial cells: – Although many exist, five types will be described in this section. Functions of glial cells: – Support and bind neurons together (some act as glue). – Provide nutrients and protection. – Assist neurons in transmitting information. Differences between glial cells and neurons: – Most types of glial cells are produced throughout an organism’s life. – Errors in glial cell replication can lead to abnormal growths (brain tumors). Clinical Focus 3-2: Discusses results of uncontrolled glial cell growth (brain tumors). Ependymal Cells Ependymal cells are located on the walls of the ventricles (fluid-filled cavities in the brain). Function of ependymal cells: – Produce and secrete cerebrospinal fluid (CSF) that fills the ventricles. Characteristics of CSF: – Constantly produced and flows through the ventricles to the base of the brain. – Absorbed into blood vessels. – Functions: ∗ Acts as a shock absorber for the brain. ∗ Carries away waste products. ∗ Helps maintain a constant brain temperature. ∗ Provides nutrients to adjacent brain regions. Narrow passages are present, especially from the cerebral aqueduct to the fourth ventricle (runs through the brainstem). Blockage of these passages can restrict fluid flow: 5  – Continuous CSF production leads to pressure buildup. – Expansion of ventricles pushes on surrounding brain. Consequences of blockage in newborns: – Causes head swelling due to pressure conveyed to the skull. – Condition known as hydrocephalus (literally, ”water brain”). – Can lead to severe intellectual impairment and death. Treatment involves inserting a shunt: – One end into the blocked ventricle and the other into a vein. – Allows excess CSF to drain into the bloodstream. Astroglia Astrocytes (star-shaped glia) are also known as astroglia. Functions of astrocytes: – Provide structural support to the central nervous system (CNS). – Extensions attach to blood vessels and the brain’s lining, forming a scaffolding for neurons. – Serve as pathways for nutrients to move between blood vessels and neurons. – Secrete chemicals that maintain neuron health and assist in healing injuries. Satellite cells in the peripheral nervous system (PNS) have a similar supportive function. Astrocytes contribute to the blood–brain barrier (BBB): – Their ends attach to blood vessel cells, creating tight junctions. – These tight junctions prevent toxins from entering the brain. – Many useful drugs (e.g., antibiotics) cannot pass through the BBB, complicating brain infection treatment. Delivery of drugs can be bypassed by inserting small tubes into the brain. Astrocytes enhance brain activity: – Neuronal activity requires increased oxygen and glucose. – Blood vessels expand in response to neuronal signals, allowing greater blood flow. Astrocytes aid in healing damaged brain tissue: – Form scar tissue to seal off injured areas. – Scar tissue may hinder regrowth of damaged neurons. – Research is ongoing to promote neuron growth around glial scars. Growth factors stimulate and support brain cell growth, survival, and plasticity. New research area: tripartite synaptsomics: – Involves the interaction between two neurons and an astrocyte. – Studies astrocyte roles in neuron-to-neuron communication. – Evidence suggests astrocytes are involved in synaptic functions, information flow, learning, and memory. 6 Microglia Microglia are unique glial cells originating from the blood as part of the immune system, making up about 20% of all glial cells. Unlike other glial cells, microglia migrate throughout the nervous system. The blood–brain barrier restricts most immune cells from entering the brain, but microglia can cross it. Functions of microglia: – Monitor and maintain brain tissue health. – Identify and attack foreign tissue. – Provide growth factors for repair in damaged areas. – Exist in various forms, adapting their shape based on their role. – Engulf foreign tissue and dead brain cells through phagocytosis. Damaged microglia can be identified as small dark bodies in and near damaged brain regions. Microglia are crucial for protecting the nervous system and removing waste. Research focuses on microglia’s involvement in neuroprotection and disease prevention: – In Alzheimer’s disease, microglia typically remove plaque deposits but may fail to do so. – Interact with astrocytes to promote brain healing. Microglia can sometimes have harmful effects by consuming inflamed tissue. Despite their small size, microglia play a vital role in maintaining brain health and may contribute to the production of new neurons. Oligodendroglia and Schwann Cells Myelin acts like plastic insulation on electrical wires, preventing adjacent neurons from short-circuiting. Myelinated neurons transmit information faster than unmyelinated neurons, enhancing communication. Neurons that send messages quickly over long distances, such as sensory and motor neurons, are heavily myelinated. Two types of glial cells responsible for axonal myelination: – Oligodendroglia: ∗ Myelinate axons in the brain and spinal cord. ∗ Extend large, flat branches to enclose and separate adjacent axons. – Schwann cells: ∗ Myelinate axons in the peripheral nervous system (PNS). ∗ Wrap around a part of an axon, resembling beads on a string. Both Schwann cells and oligodendroglia assist in neuron nutrition and functioning: – Absorb chemicals released by neurons. – Release chemicals absorbed by neurons. 7 Glial Cells, Disease, and Neuron Repair The relationships between neurons and glia offer insights into nervous system diseases, brain injury, and recov- ery. Damage to oligodendroglia and Schwann cells can severely impact function, similar to damage to neurons. Multiple Sclerosis (MS): – A degenerative nervous system disorder, commonly an autoimmune disease. – Associated with damage to oligodendroglia, resulting in scar tissue (sclerosis) instead of myelin. – Impairs information flow along affected nerves, leading to movement and cognitive function issues. Glia can aid in nervous system repair: – Severe cuts can sever axons connecting the spinal cord to muscles and sensory receptors. – Severed motor neurons lead to inability to move (paralysis), while severed sensory fibers cause loss of sensation. – Recovery may occur weeks to months after axon severance. Repair Mechanisms: – Microglia and Schwann cells participate in repairing damage in the peripheral nervous system (PNS). – When a PNS axon is cut: ∗ The axon degenerates back to the cell body; microglia clear debris. ∗ Schwann cells shrink and divide to form pathways for new axon growth. ∗ The cell body sends out axon sprouts, with one reaching the target and becoming the new axon. ∗ Schwann cells then envelop the new axon, restoring function. Challenges in CNS Repair: – Damage to the central nervous system (CNS), such as a spinal cord cut, does not lead to regrowth or repair. – CNS recovery is puzzling despite short distances for regrowth. – Mature neuronal circuits develop strategies that inhibit new cell proliferation or existing cell regrowth. – Oligodendrocytes in the CNS inhibit regrowth, contrasting with Schwann cells in the PNS. – Research aims to understand regrowth inhibition to enhance CNS repair. Experiment Question: Can the principles of neural excitation and inhibition control the activity of a simple robot that behaves like a cricket? Procedure A: – A female cricket avoids open, well-lit places to escape predators. – She often chooses between competing males, preferring those with longer chirps. – In a hypothetical robot cricket, sensory neurons are inserted between microphones for sound detection and motors for movement. – Rules: ∗ Rule 1: When a microphone detects a male cricket’s song, an excitatory message is sent to the wheel motors, activating them to move toward the sound. ∗ Rule 2: If the chirp is louder on one side, that microphone activates, making one wheel turn faster to direct the robot toward the sound. 8  Procedure B: – Two additional sensory neurons from photoreceptors are added, which inhibit the motor neurons for the wheels, preventing movement toward a chirping male cricket. – The female robot cricket will only move in dark conditions, mimicking natural behavior. Result: – This setup mimics sensory and motor neuron functions and the principle of summating excitatory and inhibitory signals with only six neurons. Conclusion: – Anthropomimetic robots are designed to model complex behaviors, mimicking human body parts and functioning as replacements for lost or impaired limbs. – Entire robots are constructed to replicate various aspects of human behavior (Webb, 2020). Clinical Focus: Brain Tumors Case Study: R. J. – 19-year-old college sophomore collapsed in class, displaying seizure symptoms. – Experienced repeated severe headaches. – CT scan revealed a tumor over the left frontal lobe. – Tumor was surgically removed; R. J. had an uneventful recovery and no recurrence of symptoms. Tumor Overview: – Tumor: uncontrolled growth of new tissue independent of surrounding structures. – Over 120 types of brain tumors exist; common in children. – Incidence in the U.S.: about 20 per 100,000 (Ostrom et al., 2020). – In adults, tumors grow from glia/supporting cells, while in infants, they may arise from developing neurons. – Growth rate varies by cell type affected. Tumor Types: – Benign Tumors: ∗ Less likely to recur after removal (e.g., R. J.’s tumor). – Malignant Tumors: ∗ Likely to progress, invade surrounding tissue, and recur after removal. – Symptoms: ∗ Caused by increased pressure on brain structures (e.g., headaches, vomiting, seizures). ∗ Symptoms depend on tumor location. Major Types of Brain Tumors: – Gliomas: ∗ Arise from glial cells; most common type. ∗ Slow-growing, rarely malignant; easier to treat if from astrocytes. ∗ Gliomas from precursor cells are often malignant and recur. – Meningiomas: ∗ Attach to meninges, growing outside the brain. ∗ Usually encapsulated; good recovery chances if accessible for surgery. 9  – Metastatic Tumors: ∗ Arise when cells migrate from one region to another. ∗ Typically present in multiple locations; treatment is difficult. Treatment Options: – Surgical removal is primary treatment and diagnostic tool. – Chemotherapy is less effective due to the blood–brain barrier. – Radiation therapy is more effective but may have negative effects, particularly on the developing brain. – Alternative treatments being investigated include genomic tumor identification for targeted destruction. Internal Structure of a Cell Neuronal Structure and Function: – Neurons possess a unique structure that enables them to receive, process, store, and transmit vast amounts of information. – Electron microscopy reveals a neuron contains hundreds of interrelated components that perform essential functions. Role of Proteins: – Proteins largely determine a cell’s characteristics and functions. – Each neuron can manufacture thousands of proteins that contribute to: ∗ Building the cell. ∗ Facilitating communication with other cells. ∗ Involvement in memory formation. ∗ Addressing malfunctions or errors in the neuron. ∗ Restoring function after brain injury. Cellular Composition: – Water, salts, and ions are crucial to cell functions. – Understanding the structure of water and the nature of salts and ions is important for grasping neuronal functions. The Cell as a Factory Cell as a Miniature Factory: – Cells can be compared to factories, containing work centers that collaborate to produce and distribute proteins. – The internal structure of cells is organized into various components called organelles. Cell Membrane: – The cell membrane (or plasmalemma) serves as a double-layered outer wall, separating the cell from its environment. – Regulates the entry and exit of substances, acting as a semipermeable membrane. – Proteins embedded in the cell membrane facilitate the transport of substances, functioning as gates. Intracellular and Extracellular Fluid: 10  – Neurons and glia are separated by extracellular fluid, primarily composed of water, dissolved salts, and chemicals. – Intracellular fluid exists inside the cell, with the cell membrane’s semipermeability maintaining concen- tration gradients. Organelles: – Organelles are surrounded by membranes that are relatively impermeable, concentrating necessary chem- icals. – The nuclear membrane surrounds the nucleus, where genetic blueprints for proteins are stored and copied. – The endoplasmic reticulum (ER) extends from the nuclear membrane and is the site for protein assembly based on nuclear instructions. – Golgi bodies act as ”mailrooms,” where proteins are packaged, addressed, and shipped. Cytoskeletal Components: – Three types of tubules: microtubules, neurofilaments, and microfilaments. – Microfilaments and neurofilaments reinforce the cell’s structure and shape, allowing for flexibility. – Microtubules create a transportation network for proteins, similar to roads in a factory. Cell Membrane: Barrier and Gatekeeper Cell Membrane Function: – Separates intracellular fluid from extracellular fluid. – Allows the cell to function as an independent unit. – Regulates movement of substances, including water. Water Regulation: – Prevents cell from bursting (if too much water enters). – Prevents cell from shriveling (if too much water leaves). – Regulates concentrations of salts and chemicals inside and outside the cell. Phospholipid Structure: – Composed of a head (containing phosphorus) and two tails (fat molecules). – Head has a polar charge; tails consist of hydrogen and carbon (nonpolar). Hydrophilic and Hydrophobic Properties: – Heads are hydrophilic (attracted to water). – Tails are hydrophobic (repel water). Bilayer Formation: – Heads align outward towards water; tails point inward. – Forms a flexible bilayer that acts as a barrier to many substances. Selective Permeability: – Impermeable to polar water molecules and charged ions. – Only small nonpolar molecules (e.g., oxygen, carbon dioxide, glucose) can pass through. 11 The Nucleus and Protein Synthesis Nucleus Function: – Acts as the cell’s executive office. – Stores, copies, and sends blueprints for protein and RNA synthesis. – Blueprints are called genes, segments of DNA that encode specific proteins. Chromosomes: – Chromosomes are double-helix structures that contain an organism’s DNA library. – They are likened to books of blueprints, with each chromosome containing thousands of genes. – A human somatic cell has 46 chromosomes (23 pairs), while reproductive cells have 23 unpaired chromo- somes. DNA Structure: – DNA consists of two strands that coil around each other. – Each strand has a sequence of four nucleotide bases: adenine (A), thymine (T), guanine (G), and cytosine (C). – Base pairing: A pairs with T, and G pairs with C. Genes and Genetic Code: – A gene is a segment of DNA with a specific sequence of nucleotide bases. – The order of bases determines the sequence of amino acids for protein synthesis. – The average gene contains about 30,000 base pairs; the entire human genome has approximately 3 billion base pairs. Transcription Process: – To make a protein, the appropriate gene unwinds to expose its bases. – The exposed DNA sequence attracts free-floating nucleotides, forming a complementary strand of RNA. – The RNA strand detaches and leaves the nucleus, carrying the code for protein synthesis. The Endoplasmic Reticulum and Protein Manufacture RNA Transcription: – RNA forms a single strand of bases, with uracil (U) replacing thymine (T). – The transcribed RNA strand is called messenger RNA (mRNA) as it carries the protein code from the nucleus to the endoplasmic reticulum (ER). Endoplasmic Reticulum (ER): – The ER consists of membranous sheets folded into channels and may be studded with ribosomes. – Ribosomes facilitate protein synthesis by reading the genetic code in mRNA during translation. Translation Process: – mRNA codons (three consecutive nucleotide bases) are translated into amino acids. – Example codons: ∗ UGG encodes tryptophan (Trp). ∗ UUU encodes phenylalanine (Phe). – The sequence of codons determines the amino acid chain’s sequence. 12  Amino Acids: – The human body uses 20 different amino acids, each consisting of a central carbon atom, an amino group, a carboxyl group, and a variable side chain (R). – Amino acids are linked by peptide bonds, forming polypeptide chains. – Polypeptides can be formed into dipeptides (two amino acids) and tripeptides (three amino acids). Protein Production Summary: – Protein production involves: ∗ Transcription of a gene into mRNA. ∗ Translation of mRNA into a polypeptide chain by ribosomes. – The overall process is represented as: DNA → mRNA → protein. Proteins and RNA: The Cell’s Products Polypeptide Chains vs. Proteins: – Polypeptide chains and proteins are related but not identical. – Analogy: length of ribbon vs. bow made from the ribbon. – Polypeptide chains tend to twist into helices or form pleated sheets, folding into complex shapes. – A protein is a folded polypeptide chain; its shape is crucial for its function. – Cells have mechanisms for proper protein folding and for removing misfolded proteins. – Misfolded proteins can cause over 100 nervous system diseases. Prions: – Prions are infectious, misfolded proteins that induce other proteins to misfold. – Implicated in degenerative brain diseases, such as Creutzfeldt-Jakob disease, and some forms of Alzheimer’s and Parkinson’s diseases. Gene and RNA Production in Neurons: – Neurons contain about 20,000 genes for producing RNAs that translate into proteins. – Also have 25,000 genes for producing noncoding RNAs (ncRNA), which have other functions. – The number of proteins produced by a neuron exceeds the number of genes due to: ∗ Cleavage of proteins into multiple pieces. ∗ Combination with other proteins to form new proteins. Protein Function: – A protein’s shape, ability to change shape, and interactions with other proteins are vital for its function. – Proteins can act as enzymes, enhancing chemical reactions. – Membrane proteins can regulate the flow of substances across the membrane. – Proteins can be exported between cells, functioning as messenger molecules. 13 Golgi Bodies and Microtubules: Protein Packaging and Shipment Protein Destination and Transport: – Cellular components package, label, and ship proteins, akin to a postal or shipping service. – Synthesized proteins are wrapped in membranes and marked with addresses in the Golgi bodies. – Packaged proteins are loaded onto motor molecules that transport them along microtubules in the cell. Protein Delivery: – If a protein is to remain in the cell, it is unloaded into the intracellular fluid. – If destined for the cell membrane, it is carried there and inserts itself. – For proteins to be exported from the cell, they undergo exocytosis: ∗ The vesicle containing the protein fuses with the cell membrane. ∗ The protein is excreted into the extracellular fluid. Crossing the Cell Membrane: Channels, Gates, and Pumps Functions of Membrane Proteins: – Embedded proteins in the cell membrane transport small molecules (salts, sugars, chemicals). – Three types of membrane proteins are involved in transport: ∗ Channels: Allow specific substances to pass through. ∗ Gates: Change shape in response to triggers to regulate passage. ∗ Pumps: Actively transport substances across the membrane. Protein Shape and Function: – A protein’s shape is determined by its amino acid sequence. – Shape changes can occur due to binding with chemicals, temperature changes, or electrical charge varia- tions. – Analogous to a lock and key, the shape change allows the protein to serve new functions. Importance in Neurotransmission: – Membrane proteins are critical for neurotransmission processes (discussed in Chapters 4 and 5). – The ability of proteins to change shape is essential for allowing substances to enter and leave the cell, which is crucial for neuronal communication. Chemistry Review Basic Concepts: – The smallest unit of a protein or chemical substance is the molecule. – Molecules and atoms are the raw materials of the cellular factory. Elements, Atoms, and Ions: – Elements are represented by symbols (e.g., O for oxygen, C for carbon). – The smallest quantity of an element is an atom, which is usually electrically neutral. – Chemically reactive elements can lose or gain electrons, forming ions. – Ions can be positively charged (when losing electrons) or negatively charged (when gaining electrons), enabling interaction. 14  Molecules: Salts and Water: – Salt crystals form through electrical attraction between ions (e.g., NaCl, KCl). – A water molecule (H2 O) consists of two hydrogen atoms and one oxygen atom. – Water molecules share electrons unequally, resulting in a polar structure with slight positive and negative charges. Water’s Properties: – Polar water molecules are attracted to other charged substances and to each other, forming hydrogen bonds. – Hydrogen bonding allows water to dissolve salts into their component ions, leading to the formation of salty water. Role of Salty Water in the Brain: – Salty water bathes brain cells, supports their activities, and constitutes the brain’s cerebrospinal fluid (CSF). – Dissolved salts like sodium chloride (N aCl), potassium chloride (KCl), and calcium chloride (CaCl2 ) are components of the brain’s salty water. Genes, Cells, and Behaviour Genotype and Phenotype: – Your genotype (genetic makeup) influences your physical and behavioral traits, which form your phe- notype (individual characteristics). Human Genome Project: – The Human Genome Project cataloged the human genome, comprising approximately 30,000 genes. – Individual genomes are now routinely sequenced, with Craig Venter being the first person to have his genome sequenced (Check, 2007). Genomes of Extinct Ancestors: – Researchers have sequenced genomes of extinct ancestors, including the Neanderthal genome. – Genome sequencing can reveal information about genetic relationships, including possible connections to Neanderthals, especially for individuals of European ancestry. – The cost of genome sequencing is approximately $100. – Consider potential information sharing implications with employers and insurers before sequencing. Mendelian Genetics and Epigenetics: – Mendelian genetics studies how genes influence traits, named after Gregor Mendel. – Epigenetics studies how the environment influences gene expression. – This section discusses how both genetic and environmental factors influence phenotypes. 15 Mendelian Genetics and the Genetic Code Chromosome Composition: – Each human somatic cell contains 23 pairs of chromosomes (46 total). – One chromosome from each pair is inherited from the mother and the other from the father. – Chromosome pairs are numbered 1 to 23 based on size, with chromosome 1 being the largest. Types of Chromosomes: – Chromosome pairs 1-22 are called autosomes, which contain genes that influence physical appearance and behavior. – The 23rd pair consists of sex chromosomes (X and Y) that influence sexual characteristics. – Female mammals typically have two X chromosomes, while males have one X and one Y. – The Y chromosome carries the SRY (sex-determining region Y) gene, which triggers male phenotype development. Gene Copies and Alleles: – Each cell contains two copies of every gene (alleles) from both parents. – Homozygous alleles are identical, while heterozygous alleles are different. Allele Types: – The most common nucleotide sequence in a population is the wild-type allele. – Less frequently occurring sequences are termed mutations, which can be beneficial, neutral, or harmful. Dominant and Recessive Alleles Allelic Expression: – Homozygous alleles encode the same protein. – Heterozygous alleles can encode different proteins. Outcomes of Heterozygous Condition: – (1) Expression of only the maternal allele. – (2) Expression of only the paternal allele. – (3) Simultaneous expression of both alleles. Allele Types: – Dominant Allele: Routinely expressed as a trait. – Recessive Allele: Not expressed when paired with a dominant allele. Types of Dominance: – Complete Dominance: Only the dominant allele’s trait is expressed. – Incomplete Dominance: The dominant allele’s trait is expressed partially. – Codominance: Both alleles’ traits are expressed completely. Gene Contribution: – Each gene contributes independently to inheritance, regardless of visible expression in phenotype. – Recessive alleles can be passed on to future generations despite not being expressed. Examples: – Variations in hair color in humans and coat colors in horses demonstrate the influence of various allelic combinations. 16 Genetic Mutations Mutation Overview: – Errors can occur in nucleotide sequences during gene reproduction, leading to mutations. – A mutation can be a change in a single nucleotide base, known as a single nucleotide polymorphism (SNP). Effects of Mutations: – SNPs can change codons and result in changes in amino acids in proteins, potentially altering their function. – The BRCA1 gene on chromosome 17, a caretaker gene for breast cancer prevention, has over 1000 known mutations, indicating numerous predispositions to cancer. Types of Mutations: – Mutations can be beneficial, disruptive, or both. – Example: A SNP in the HBB gene causes sickle-cell anemia, which gives some malaria protection but impairs oxygen transport. – Sickle-cell anemia affects millions, including about 80,000 individuals in the U.S. Genetic Abnormalities and Behavior: – Neuroscientists have identified approximately 2000 genetic abnormalities affecting the nervous system, leading to severe behavioral consequences. – Errors in genes can produce malfunctioning proteins, such as ion channels or pumps that do not function correctly. Acquired Genetic Mutations Acquired Genetic Mutations: – Individuals can acquire a significant number of genetic mutations during their lifetime, which are not inheritable. – Sources of acquired mutations include: ∗ Mitotic errors during cell division. ∗ Errors during routine DNA activity in protein production. ∗ Aging-related mutations. Distribution of Mutations: – Mutations can occur in different body parts, brain regions, or even individual brain cells. – The human brain contains approximately 86 billion neurons and 85 billion glial cells, all arising from a single cell. – Neurons, which remain metabolically active throughout life, can accumulate mutations. Mutation Accumulation: – At age 1, a neuron may have 300 to 900 mutations; by age 80, it may have up to 2000 mutations. – This translates to a substantial number of mutations across 173 billion brain cells over a lifetime (Miller et al., 2021). Genosenium: – The study of DNA changes in the aging brain is referred to as genosenium. – One theory posits that aging results from the accumulation of genetic mutations. – The genome undergoes significant modifications as we develop and age, in addition to inherited traits from parents. 17 Applying Mendel’s Principles Mendelian Genetics: – Introduced by Gregor Mendel in the 19th century, focusing on dominant and recessive alleles. – Many brain disorders are associated with Mendelian inheritance. Allele Disorders Affecting the Brain: – Tay-Sachs Disease: ∗ Caused by dysfunction in the HEXA gene, which produces the HexA enzyme, responsible for lipid breakdown in brain cells. ∗ Symptoms appear a few months after birth, including seizures, deteriorating eyesight, and loss of motor and mental abilities, usually resulting in death within a few years. ∗ High frequency of mutations among certain ethnic groups, such as Ashkenazi Jews and French Cana- dians. ∗ Caused by two recessive alleles of the HEXA gene (chromosome 15); both parents must pass on the recessive allele for the disease to manifest. ∗ Inheritance probabilities: 25 ∗ Carriers have higher-than-normal lipid accumulation but do not exhibit symptoms due to the presence of a normal allele. ∗ Blood tests can detect carriers, enabling informed reproductive decisions. – Huntington Disease: ∗ Caused by a dominant abnormal HTT (huntingtin) allele; only one defective allele is needed for the disorder to manifest. ∗ Buildup of abnormal huntingtin protein leads to cell death in the basal ganglia and cortex. ∗ Symptoms include abnormal involuntary movements, memory loss, behavioral deterioration, and even- tual death. ∗ Inheritance patterns: 50 ∗ The abnormal allele may not manifest until midlife, allowing it to be unknowingly passed to offspring. ∗ Genetic tests can identify carriers, allowing individuals to choose not to have children to reduce the incidence of the allele in the gene pool. Chromosome Abnormalities Genetic Disorders Beyond Single Defective Alleles: – Nervous system disorders can also result from copy number variations (CNVs), which are abnormalities in parts of chromosomes or entire chromosomes. – CNVs have been associated with various disorders, including: ∗ Autism ∗ Schizophrenia ∗ Learning disabilities – Some CNVs may have little consequence or can even be beneficial. – Example: Humans typically have about 6 copies of the AMY1 (amylase) gene, but can have up to 15 copies, aiding in the digestion of starchy foods (Yang & Ye, 2021). Down Syndrome: – A genetic condition resulting from an extra copy of chromosome 21, affecting approximately 1 in 700 children. 18  – Usually caused by one parent (commonly the mother) passing on two copies of chromosome 21, leading to a total of three copies (trisomy). – Phenotypic effects include: ∗ Characteristic facial features ∗ Short stature ∗ Increased susceptibility to heart defects, respiratory infections, and intellectual impairment ∗ Higher risk of developing leukemia and Alzheimer’s disease – Life expectancy: People with Down syndrome generally have shorter life spans but some live to middle age or beyond. – Improved educational opportunities can significantly enhance the quality of life for children with Down syndrome. Genetic Engineering Genetic Engineering: – Definition: The science of manipulating genes to influence traits. – Methods include: ∗ Selective breeding ∗ Cloning ∗ Transgenic techniques Selective Breeding: – The oldest method to influence genetic traits, starting with domestication over 30,000 years ago. – Example: Selective breeding of dogs has resulted in diverse breeds with specific traits. – Affects brain size and neuron count; dogs have smaller brains than wolves but more cortical neurons (Jardim-Messeder et al., 2017). – Spontaneous mutations can be maintained, leading to various mouse strains with different traits. – Laboratory mice can be engineered to express fluorescent proteins for studying neural and genetic behavior (Rynes et al., 2021). Cloning: – Method: Producing genetically identical offspring through nuclear transfer. – Example: Dolly, the first cloned mammal, was born in 1996. – Applications include preserving traits, studying heredity, and producing tissues for transplants. – Cloning has commercialized, producing better strains and preserving rare species. – Ethical considerations surround cloning of humans and its economic advantages compared to selective breeding. Transgenic Techniques: – Methods to introduce or remove genes in embryos. – Knock-in technology: Adding genes from one species to another (e.g., human HTT gene in animal models for Huntington disease) (Stricker-Shaver et al., 2018). – Knockout technology: Inactivating a gene to study its functions and potential therapies (e.g., producing mouse models for ADHD) (Meng et al., 2021). Gene Modification: – CRISPR/Cas9 technology: A method for altering gene sequences. 19  – Discovered as part of bacterial immune systems; enables targeted gene editing. – Applications include: ∗ Making organisms resistant to infections ∗ Identifying and destroying cancer cells ∗ Creating animal models to study behavior ∗ Facilitating gene drives to manage pest populations. – First successful application in human disease aimed at editing the gene for sickle-cell anemia. The Epigenetic Code Epigenetics Overview: Epigenetic mechanisms shape development by allowing the same genome to produce different phenotypes based on environmental influences, without altering the DNA sequence. Phenotypic Variability: Genetically identical organisms, such as cloned mice, can still show differences in traits (e.g., brain structure) due to epigenetic factors. Twin Studies: Identical twins, despite sharing the same genome, exhibit discordant rates of diseases, high- lighting the role of epigenetics. Mechanisms of Epigenetics: – Histone modification: Affects whether DNA is wrapped tightly or loosely, impacting transcription. – Gene methylation: Methyl groups can block transcription. – mRNA modification: Non-coding RNA can prevent translation. Environmental Influence: Experiences such as stress or pollution can lead to epigenetic changes that affect gene expression and contribute to diseases, which can sometimes be reversed. Transgenerational Epigenetics: Certain epigenetic changes, particularly involving sex chromosomes, can be inherited across generations, influenced by critical periods like prepuberty. Research Findings: Studies on Swedish populations exposed to famine or abundance indicated epigenetic inheritance affecting health and longevity across generations. Open Questions: Further research is needed to understand how epigenetic information is passed down, which chromosomes are affected, and the broader implications for inheritance. Clinical Focus: Huntington Disease Woody Guthrie’s Legacy: Woody Guthrie, known for his protest songs like ”This Land Is Your Land,” is celebrated as a founder of American folk music. His life also reflects the history of Huntington disease, a condition he struggled with until his death in 1967. Huntington Disease Overview: Huntington disease is characterized by memory impairment, abnormal movements (choreas), and personality changes, leading to a loss of behavioral, emotional, and intellectual functioning. The disease is linked to degeneration in the basal ganglia and cortex. Genetics of Huntington Disease: The disease is caused by a mutation in the HTT gene on chromosome 4. This mutation leads to an abnormal huntingtin protein due to an excess number of CAG repeats. The more repeats present, the earlier and faster the disease progresses. Inheritance Patterns: Huntington disease is more common in individuals of European descent, and the number of CAG repeats can increase when inherited from the father. Symptoms typically begin in midlife but can appear at any age. Research and Treatment: Transgenic animal models (mice, rats, and monkeys) with the HTT gene are used to study the disease and develop treatments. Gene-editing technologies, such as CRISPR, offer potential cures for Huntington disease. 20