Week 1- Intro to the course, Review of neurotransmitters, neural circuits and neurogenesis in the CNS. Role of genetics in neurological disorders.pptx

Week 1 Introduction to the Course: Inherited Neurological Disorders (HMG 44110A ) Review of neurotransmitters, neurand neurogenesis in the CNS. Role of genetics in neurological disorders Dr. Merin Thomas merin.t-adjunct@a...

Week 1 Introduction to the Course: Inherited Neurological Disorders (HMG 44110A ) Review of neurotransmitters, neurand neurogenesis in the CNS. Role of genetics in neurological disorders Dr. Merin Thomas [email protected] Office hours : Monday & Wednesday, 3.00pm to 5.00pm 1  Contact details & Office Hours E-mail - [email protected] Office hours : Monday & Wednesday, 3.00pm to 5.00pm You are welcome to drop by for any clarifications outside office hours BUT it is advised to take prior appointment via Teams messenger Kindly avoid calling via Teams; meet me in person for all clarifications and queries - easier to answer doubts in person rather than via text/call. For instructions/queries related to assignments/exam portions etc. check blackboard before you reach out. 2  Rules for my classroom PUNCTUALITY & DISCIPLINE!  Mode of Conducting Classes FACE TO FACE CLASSES Active participation from all students Each class - 1hour45min on Tuesdays & Thursdays Lecture notes will be uploaded in PDF format prior to lecture Attendance of utmost importance – Attendance is marked from day 1. Assessments will be written and on paper Deadlines  Modes of Assessment ASSIGNMENT QUIZZES 800-word essay on given topic 2 quizzes will be given based Topic, rubrics, guidelines will be on topics covered discussed in week 5 10-15min/Quiz ; 1 before Responses to be submitted week midterm 1 after midterm 9 FINAL PROJECT Group presentation on an Inherited MID TERM & FINAL EXAM neurological disorder of choice (not Midterm Exam - Week 6 covered in lectures) Final Exam - end of semester Rubrics, specific guidelines will be discussed in week 6/7 Presentation in week 12 & 13 Assessment Tool Weight Description Quiz 15% TWO quizzes 10-15 minutes each will be distributed across the semester, i.e. 1 quiz before the Midterm Exam and 1 quiz after the Midterm Exam. 7.5% weightage for each quiz Midterm Exam 20% Midterm exam will examine knowledge and understanding of the concepts and issues discussed in weeks 1-6 Assignment 15% Students will prepare an individual essay on a given course-relevant topic. Specific guidelines to be disseminated and discussed. Final Project 20% Student will submit an abstract and present, as a group, Presentation on an Inherited neurological disorder of choice. Specific guidelines to be disseminated and discussed Final exam 30% Final exam will examine knowledge and understanding of the concepts and issues involved in syllabus covered after midterm exam.  TYPES OF QUESTIONS FORMAT MARKS EXAMPLE True or False 1 mark 1.Symptoms of Alzheimer’s may not become noticeable until after changes in the brain occur a.True. b. False Multiple 1 mark 1. What is often the first symptom of Parkinson disease? Choice A. Headache Questions B. Nausea C. Shaking of a hand or foot D. Turning of the head Mix and 4 1. Match type of neurotransmitter to example Match marks i. Monoamines a. Oxytocin ii. Amino acids b. Acetylcholine iii. Peptides c. Histamine iv. Other. d. GABA Short 2 /3/4 1. Name two motor features and two non-motor answers/ marks features Parkinson’s disease? Case studies Two motor features are tremors and rigidity. Two non-motor features are sleep disorders and urinary problems. TIMELINE OF ASSESSMENTS  REFERENCE BOOKS Beart, P., Robinson, M., Rattray, M., & Maragakis, N. J. (2017). Neurodegenerative diseases: Pathology, Mechanisms, and Potential Therapeutic Targets. Springer. Wu, Z. (2017). Inherited neurological disorders: Diagnosis and Case Study. Springer. Greenstein, B., & Greenstein, A. (2011). Color Atlas of Neuroscience: Neuroanatomy and Neurophysiology. Thieme.  Learning Objectives Neurotransmitters Neural circuits Neuroplasticity and neurogenesis in the CNS. Role of genetics in neurological disorders  What are Neurotransmitters? Neurotransmitters are substances/chemical messengers that allow nerve cells (neurons) to communicate with each other and with their target tissues in the process of synaptic transmission (neurotransmission). A neurotransmitter signal travels from a neuron, across the synapse, to the next neuron/ nerve, muscle or gland cell  Neurotransmitters play a role in nearly every What are Neurotransmitters? function in the body. Neurotransmitters are important in boosting and balancing signals in the brain and for keeping the brain functioning. Without neurotransmitters, the body can’t function. Too high or too low levels of specific neurotransmitters results in specific health problems. Medications work by increasing or decreasing the amount of or the action of  What body functions do neurotransmitters help to control? Neurotransmitters help manage automatic responses such as breathing and heart rate, as well as they have psychological functions such as learning, managing mood, fear, pleasure, and happiness.  What body functions do neurotransmitters help to control? Heartbeat and blood pressure. Breathing. Muscle movements. Thoughts, memory, learning and feelings. Sleep, healing and aging. Stress response. Hormone regulation. Digestion, sense of hunger and thirst. Feel sensations (response to sight, hearing, feel, touch and taste). Respond to all information your body receives from  How do neurotransmitters work (neurotransmission) ? – A look at the neuron  How do neurotransmitters work (neurotransmission) ? – A look at the neuron Cell body. The cell body is vital to producing neurotransmitters and maintaining the function of the nerve cell. Axon. The axon carries the electrical signals along the nerve cell to the axon terminal. Axon terminal. This is where the electrical message is changed to a chemical signal using neurotransmitters to communicate with the next group of nerve cells, muscle cells or organs. A synapse is the functional junction between one neuron and another, or between a neuron and an  ELECTRICAL SIGNALS IN A NEURON Signal transmission at Synapses Presynaptic neuron refers to a nerve cell that carries a nerve impulse toward a synapse. It is the cell that sends a signal. Postsynaptic cell is the cell that receives a signal. A nerve cell called a postsynaptic neuron that carries a nerve impulse away from a synapse OR An effector cell that responds to the impulse at the synapse Fig 12.22 ,Examples of Synapses Principles of Anatomy and Physiology , 16th edition, authored by Gerard J. Tortora, Bryan H. Derrickson ; Wiley publications, Nov 2020  How do neurotransmitters work (neurotransmission) ? Signal transmission at Synapse - Chemical Synapse The plasma membranes of presynaptic and postsynapic neurons in a chemical synapse are close but they do not touch - separated by the synaptic cleft, a space that is filled with interstitial fluid. Nerve impulses cannot conduct across the synaptic cleft, so an alternative, indirect form of communication occurs. In response to a nerve impulse, the presynaptic neuron releases a neurotransmitter that diffuses through the fluid in the synaptic cleft and binds to receptors in the plasma membrane of the postsynaptic neuron. The postsynaptic neuron receives the chemical signal and in turn produces a postsynaptic potential, a type of graded potential.  Neurotransmitters are stored within thin-walled sacs called synaptic vesicles. Each vesicle can contain thousands of neurotransmitter molecules.  What happens to neurotransmitters after they deliver their message? After neurotransmitters deliver their message, the molecules must be cleared from the synaptic cleft. They do this in one of three ways: Diffusion Reuptake (Reabsorbed and reused by the nerve cell that released it) Degradation (broken down by enzymes within the synapse) Releas Bindin Deactivat ed Nerve g e Neurotransmit Neurotransmi impulse tter bind to ter is cleared reaches pre- receptors in from the synaptic post-synaptic synaptic cleft. Ca channels button membrane. Diffusion open Ion channels Increased Ca Reuptake open- inflow ions fusion to pre-synaptic of Na and K Degradati membrane ions. Depolarization on release of & formation neurotransmitt of action ers into potential. synaptic cleft.  How many different types of neurotransmitters are there? Scientists identifies more than 100 neurotransmitters and suspect there are many others that have yet to be discovered. They can be grouped into types based on their chemical nature.  Neurotransmitters Monoamines Amino acids Peptides Other Dopamine Glutamate Endorphins Acetylcholine Noradrenaline Adrenaline GABA Oxytocin Nitric oxide Histamine Purines Serotonin  What action or change do neurotransmitters transmit to the target cell? The neurotransmitters bind to receptor proteins in the cellular membrane of the target tissue. The target tissue gets excited, inhibited, or functionally modified in some other way, depending on the specific neurotransmitter.  What action or change do neurotransmitters transmit to the target cell? Excitatory Inhibitory Modulatory or These These neuromodulators neurotransmitters neurotransmitters These neurotransmitters can have an have an inhibiting affect a large number of excitatory/ the neurons. neurons at the same time, as well as being able to influence stimulating Inhibitory the effects of other effect on the neurotransmitters neurotransmitters. These can neurons. If a block or prevent the activate multiple receptors neurotransmitter chemical message as there is not just one receptor is excitatory, it will from being passed for each type of increase the along any farther. It neurotransmitter. likelihood that the decreases the Its action is dependent on the neuron will fire neuron firing action receptor it binds to on the action potential. potential/stimulation. post-synaptic neuron.  Examples of neurotransmitters Excitatory Inhibitory neurotransmitters Neuromodulators neurotransmitters Glutamate (Glu) gamma-Aminobutyric Dopamine (DA) acid (GABA) Acetylcholine (ACh) Serotonin (5-HT) Serotonin (5-HT) Histamine Acetylcholine (ACh) Dopamine (DA) Dopamine (DA) Norepinephrine (NE) Histamine [noradrenaline (NAd)] Epinephrine (Epi) Norepinephrine (NE) [adrenaline (Ad)]  Examples of neurotransmitters Excitatory Inhibitory neurotransmitters Neuromodulators neurotransmitters Glutamate (Glu) gamma-Aminobutyric acid Dopamine (DA) (GABA) Acetylcholine (ACh) Serotonin (5-HT) Serotonin (5-HT) Histamine Acetylcholine (ACh) Dopamine (DA) Dopamine (DA) Norepinephrine (NE) Histamine [noradrenaline (NAd)] Epinephrine (Epi) Norepinephrine (NE) [adrenaline (Ad)]  Examples of neurotransmitters Inhibitory Excitatory neurotransmitters neurotransmitters Neuromodulators Glutamate (Glu) gamma-Aminobutyric Dopamine (DA) acid (GABA) Acetylcholine (ACh) Serotonin (5-HT) Serotonin (5-HT) Histamine Acetylcholine (ACh) Dopamine (DA) Dopamine (DA) Norepinephrine (NE) Histamine [noradrenaline (NAd)] Epinephrine (Epi) Norepinephrine (NE) [adrenaline (Ad)]  Examples of neurotransmitters Excitatory Inhibitory neurotransmitters neurotransmitters Neuromodulators Glutamate (Glu) gamma-Aminobutyric Dopamine (DA) acid (GABA) Acetylcholine (ACh) Serotonin (5-HT) Serotonin (5-HT) Histamine Acetylcholine (ACh) Dopamine (DA) Dopamine (DA) Norepinephrine (NE) Histamine [noradrenaline (NAd)] Epinephrine (Epi) Norepinephrine (NE) [adrenaline (Ad)]  Examples of neurotransmitters Inhibitory Excitatory neurotransmitters neurotransmitters Neuromodulators Glutamate (Glu) gamma-Aminobutyric Dopamine (DA) acid (GABA) Acetylcholine (ACh) Serotonin (5-HT) Serotonin (5-HT) Histamine Acetylcholine (ACh) Dopamine (DA) Dopamine (DA) Norepinephrine (NE) Histamine [noradrenaline (NAd)] Epinephrine (Epi) Norepinephrine (NE) [adrenaline (Ad)]  Why would a neurotransmitter not work as it should? Too much or not enough of one or more neurotransmitters are produced or released. The receptor on the receiver cell (the nerve, muscle or gland) is defective. The cell receptors are not taking up enough neurotransmitter due to inflammation and damage of the synaptic cleft. Neurotransmitters are reabsorbed too quickly. Enzymes limit the number of neurotransmitters from reaching their target cell.  Diseases associated with neurotransmitters When neurotransmitters do not function well, disease can occur. Acetylcholi Serotoni Dopamin Glutama GAB ne n e te A High - Epilipt Alzhei Autis Schizophre Huntingt ic m nia on seizur mer es Low - Parkinson ism  How do medications affect the action of neurotransmitters? Medications can block the enzyme that breaks down a neurotransmitter so that more of it reaches nerve receptors. Example: Donepezil and galantamine block the enzyme acetylcholinesterase, which breaks down the neurotransmitter acetylcholine. These medications are used to stabilize and improve memory and cognitive function in people with Alzheimer’s disease.  How do medications affect the action of neurotransmitters? Medications can block the neurotransmitter from being received at its receptor site. Example: Selective serotonin reuptake inhibitors are a type of drug class that blocks serotonin from being received and absorbed by a nerve cell. These drugs may be helpful in treating depression, anxiety and other mental health conditions. Medications can block the release of a neurotransmitter from a nerve cell. Example: Lithium blocking norepinephrine release.This drug used in the treatment of bipolar  Modifying the Effects of Neurotransmitters Substances naturally present in the body as well as drugs and toxins can modify the effects of neurotransmitters in several ways: Neurotransmitter synthesis can be stimulated or inhibited. For instance, many patients with Parkinson’s disease receive benefit from the drug L-dopa because it is a precursor of dopamine. For a limited period of time, taking L-dopa boosts dopamine production in affected brain areas. Neurotransmitter release can be enhanced or  Modifying the Effects of Neurotransmitters The neurotransmitter receptors can be activated or blocked. An agent that binds to receptors and enhances or mimics the effect of a natural neurotransmitter is an agonist. Isoproterenol (Isuprel®) is a powerful agonist of epinephrine and norepinephrine. It can be used to dilate the airways during an asthma attack. An agent that binds to and blocks neurotransmitter receptors is an antagonist. Zyprexa®, a drug prescribed for schizophrenia, is  Modifying the Effects of Neurotransmitters Neurotransmitter removal can be stimulated or inhibited. For example, cocaine produces euphoria—intensely pleasurable feelings—by blocking transporters for dopamine reuptake. This action allows dopamine to linger longer in synaptic clefts, producing excessive stimulation of certain brain regions.  NEUROPLASTICITY The ability of the nervous system to change its activity in response to intrinsic or extrinsic stimuli by reorganizing its structure, functions, or connections. A change could be temporal(functional) or spatial(structural). A temporal change is further divided into short-term and long-term change and takes place at individual neurons. A spatial change takes place either at synapses, within neurons or within glial cells. VIDEO on neuroplasticity  NEUROPLASTICITY Neuroplasticity is also a phenomenon that aids brain recovery after the damage produced by events like stroke or traumatic injury. This ability to manipulate specific neuronal pathways and synapses has important implications for physiotherapeutic clinical interventions that will improve health. A better understanding of the mechanisms governing neuroplasticity after brain damage or nerve lesion will help improve the patient's quality of life  NEUROGENESIS Neurogenesis, the birth of new neurons from undifferentiated stem cells—occurs regularly in some animals. Until recently, the dogma in humans and other primates was “no new neurons” in the adult brain. Then, in 1992, researchers published their unexpected finding that the hormone like protein epidermal growth factor (EGF) stimulated cells taken from the brains of adult mice to proliferate into both neurons and astrocytes.  NEUROGENESIS Previously, EGF was known to trigger mitosis in a variety of nonneuronal cells and to promote wound healing and tissue regeneration. In 1998, scientists discovered that significant numbers of new neurons do arise in the adult human hippocampus, an area of the brain that is crucial for learning.  NEUROGENESIS The nearly complete lack of neurogenesis in other regions of the brain and spinal cord seems to result from two factors: 1. Inhibitory influences from neuroglia, particularly oligodendrocytes 2. Absence of growth-stimulating cues that were present during fetal development. Axons in the CNS are myelinated by oligodendrocytes rather than Schwann cells, and this CNS myelin is one of the factors inhibiting regeneration of neurons.  NEUROGENESIS Perhaps this same mechanism stops axonal growth once a target region has been reached during development. Also, after axonal damage, nearby astrocytes proliferate rapidly, forming a type of scar tissue that acts as a physical barrier to regeneration. Thus, injury of the brain or spinal cord usually is permanent.  NEUROGENESIS Ongoing research seeks ways to improve the environment for existing spinal cord axons to bridge the injury gap. Scientists also are trying to find ways to stimulate dormant stem cells to replace neurons lost through damage or disease and to develop tissue-cultured neurons that can be used for transplantation purposes. Genetics and Neurological Disorders: The Connection Neurological disorders consist of a broad array of conditions that impact the brain, spinal cord, and nerves. Ranging from Alzheimer's disease and Parkinson's to epilepsy and multiple sclerosis, the variety is extensive. These conditions can result from a mix of genetic, environmental, and lifestyle elements. Some neurological disorders exhibit a recognized genetic inclination, stemming from gene mutations or a blend of genetic factors that heighten susceptibility.  Primary genetic causes of neurological disorders SINGLE GENE MUTATIONS (MENDELIAN DISORDERS): Some neurological conditions are caused by mutations in a single gene. These disorders often follow Mendelian inheritance patterns, such as autosomal dominant, autosomal recessive, or X-linked. Examples include: Huntington’s disease (autosomal dominant mutation in the HTT gene) Friedreich’s ataxia (autosomal recessive mutation in the FXN gene)  Primary genetic causes of neurological disorders MULTIPLE GENE (POLYGENIC) INVOLVEMENT: Some disorders arise from the combined effects of mutations in multiple genes, often in conjunction with environmental factors. These are termed polygenic or complex disorders. Alzheimer’s disease, for instance, has several genetic risk factors, with the APOE ε4 allele being the most prominent.  Primary genetic causes of neurological disorders COPY NUMBER VARIATIONS (CNVS): CNVs are alterations in the DNA that result in the cell having an abnormal number of copies of one or more sections of the DNA. CNVs can be associated with various neurological disorders, including some forms of epilepsy and autism spectrum disorders  Primary genetic causes of neurological disorders MITOCHONDRIAL DNA MUTATIONS: The mitochondria have their own DNA, separate from the nuclear DNA. Mutations in mitochondrial DNA can lead to neurological disorders since the brain is highly dependent on the energy produced by mitochondria. Examples include Leber’s hereditary optic neuropathy and some forms of mitochondrial myopathy.  Primary genetic causes of neurological disorders REPEAT EXPANSION DISORDERS: Some neurological disorders are caused by the abnormal repetition of short sequences of DNA. Over time, these repeats can expand, leading to disease. Examples include: Huntington’s disease (CAG repeat expansion) Fragile X syndrome (CGG repeat expansion) Spinocerebellar ataxias (various repeat expansions)  Primary genetic causes of neurological disorders EPIGENETIC CHANGES: Epigenetics refers to changes in gene activity that don’t involve alterations to the underlying DNA sequence. These changes can affect gene expression and are implicated in some neurological conditions. Rett syndrome, for instance, involves mutations in the MECP2 gene, which plays a role in epigenetic regulation.  Primary genetic causes of neurological disorders PRION DISEASES: These are caused by misfolded proteins called prions. While most prion diseases are sporadic, some, like familial Creutzfeldt-Jakob disease, have a genetic component.  REFERENCES Tortora, Gerard J. And Bryan H Derrickson. Principles of Anatomy and Physiology. John Wiley & Sons, 2020 Beart, P., Robinson, M., Rattray, M., & Maragakis, N. J. (2017). Neurodegenerative diseases: Pathology, Mechanisms, and Potential Therapeutic Targets. Springer. https://www.physio-pedia.com/Neuroplasticity https://www.physiopedia.com/Neural_Circuit Tau, G. Z., & Peterson, B. S. (2009). Normal development of brain circuits. Neuropsychopharmacology, 35(1), 147–168. https://doi.org/10.1038/npp.2009.115