Nervous System (Cellular Biology and Nervous System Disorders) PDF

Nervous System (cellular Biology and nervous system disorders) Part-3 Professor Touqeer Ahmed PhD Atta-ur-Rahman School of Applied Biosciences National University of Sciences and Technology Email: [email protected] 23 Sept...

Nervous System (cellular Biology and nervous system disorders) Part-3 Professor Touqeer Ahmed PhD Atta-ur-Rahman School of Applied Biosciences National University of Sciences and Technology Email: [email protected] 23 September 2024 Basic Structure of Neuron Axons can vary greatly in length; some can extend more than 3 m within the body. Most axons in the central nervous system are very thin (between 0.2 and 20 µm in diameter) compared with the diameter of the cell body (50 µm or more). The action potential, the cell's conducting signal, is initiated either at the axon hillock, the initial segment of the axon, or in some cases slightly farther down the axon at the first node of Ranvier. Types of Neurons Figure 2-4 Unipolar cells have a single process, with different segments serving as receptive surfaces or releasing terminals. Unipolar cells are characteristic of the invertebrate nervous system. Multipolar cells have an axon and many dendrites. They are the most common type of neuron in the mammalian nervous system. Spinal motor neurons (left) innervate skeletal muscle fibers. Pyramidal cells (middle) have a roughly triangular cell body; have apical and basal dendrites. These cells are found in the hippocampus and cerebral cortex. Purkinje cells of the cerebellum. Such a structure permits enormous synaptic input. 3 Cellular Diversity in Neurons the Nervous System (shape and type) Glial cells  Types of neurons Most neurons, regardless of type, have four functional regions in common: an input component, a trigger or integrative component, a conductile component, and an output component. 5  Cortical Layers in Human Brain Cortex The neurons of the cerebral cortex are arranged in distinctive layers. The appearance of the cortex depends on what is used to stain it. The Golgi stain reveals neuronal cell bodies and dendritic trees. The Nissl method shows cell bodies and proximal dendrites. A Weigert stain for myelinated fibers reveals the pattern of axonal distribution Cortical layers differ in thickness in different places in the cortices  Cell Types In The Cerebral Cortex In general, the neurons of the cortex are Interneuron – projection neurons (located mainly in layers III, V, and VI and use the excitatory amino acid glutamate as their primary transmitter) – local interneurons (use inhibitory neurotransmitter (GABA), constitute 20-25% of the neurons in the neocortex, and are located in all layers) Projection Neuron  Learning Objectives To get familiar with the cell types in the nervous system and their anatomical location To understand the functions of various cell types The Nervous System Has Two Classes of Cells nerve cells (neurons) glial cells (glia).  Role of Glial Cells Glia are more numerous than neurons in the brain (different references quote different ratios) – Glial cells support neurons, providing the brain with structure. They also separate and sometimes insulate neuronal groups and synaptic connections from each other. – Two types of glial cells (oligodendrocytes and Schwann cells) produce the myelin used to insulate nerve cell axons. – Some glial cells are scavengers, removing debris after injury or neuronal death. – Some glia also take up chemical transmitters released by neurons during synaptic transmission for the efficient neural transmission. – During the brain's development, certain classes of glial cells (“radial glia”) guide migrating neurons and direct the outgrowth of axons. – Some glial cells (astrocytes) help to form an impermeable lining in the brain's capillaries and venules— the blood-brain barrier—that prevents toxic substances in the blood from entering the brain. – Other glial cells apparently release growth factors and otherwise help nourish nerve cells, although this role has been difficult to demonstrate conclusively.  Types of Glial Cells Glial cells in the vertebrate nervous system are divided into two major classes: 1. Microglia (microglial cells) Microglia are phagocytes that are mobilized after injury, infection, or disease. Derived primarily from hematopoietic precursor cells and share many such properties with macrophages found in other tissues, and are primarily scavenger cells. In addition, microglia, like their macrophage counterparts, secrete signaling molecules that can modulate local inflammation and influence cell survival or death. 2. Macroglia (oligodendrocytes, schwann cells and astrocytes) Oligodendrocytes and astrocytes are restricted to CNS whereas schwann cells are present in the peripheral Nervous system ) ❑Oligodendrocytes: small cells with relatively few processes. In white matter (left) they provide the myelin, and in gray matter (right) perineural oligodendrocytes surround and support the cell bodies of neurons.  Types of Glial Cells ❑ Schwann cells provide myelin sheaths that insulate axons in the peripheral nervous system. The sheath assumes its form as the inner tongue of the Schwann cell turns around the axon several times. ❑ Astrocytes, the most numerous of glial cells in the central nervous system, are characterized by their star-like shape and the broad end-feet on their processes. Because these endfeet put the astrocyte into contact with both capillaries and neurons, astrocytes are thought to have a nutritive function. Astrocytes also play an important role in forming the blood brain barrier.  Glial Cells Produce the Insulating Myelin The signal-conducting axons of both sensory and motor neurons are ensheathed in myelin along most of their length The myelin sheath is arranged in concentric bimolecular layers of lipids and protein. Biochemical analysis shows that myelin has a composition similar to that of plasma membranes, consisting of 70% lipid and 30% protein, with a high concentration of cholesterol and phospholipids. B: An electron micrograph of a transverse section in mouse sciatic nerve Axon (Ax), Myelin sheath (Ml), Inner mesaxon (IM; circled). Surface membrane (SM) of the Schwann cell, which is continuous with the outer mesaxon (OM; circled). The Schwann cell cytoplasm (Sc Cyt) is still present, next to the axon; eventually it is squeezed out and the sheath becomes compact.  Defects in Myelin Proteins Disrupt Conduction of Nerve Signals Defective myelin can result in severe disturbances of motor and sensory function. Myelin in both the central and peripheral nervous systems contains a major class of proteins, myelin basic proteins (MBP), which have an important role in myelin compaction. At least seven related proteins are produced from a single MBP gene by alternative RNA splicing. Myelin basic proteins are capable of eliciting a strong immune response. When injected into animals they cause experimental allergic encephalomyelitis, local inflammation and destruction of the myelin sheaths (demyelination). Electron micrographs show the state of myelination in the optic nerve of a normal mouse, a shiverer mutant, and a mutant transfected with the gene for myelin basic protein. Myelination is incomplete in the shiverer mutant. As a result, the shiverer mutant exhibits poor posture and weakness. Neurological Disorders 15  Neurodegenerative diseases Neurodegenerative diseases of the CNS include Parkinson disease, Alzheimer disease, multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). These devastating illnesses are characterized by the progressive loss of selected neurons in discrete brain areas, resulting in characteristic disorders of movement, cognition, or both. – Alzheimer disease is characterized by the loss of cholinergic neurons in the nucleus basalis of Maynert. It is the most prevalent form of dementia, estimated to have affected some 4 million people in 2000. The number of cases is expected to increase as the proportion of elderly people in the population increases. – Parkinson disease is associated with a loss of dopaminergic neurons in the substantia nigra.  Overview of Parkinson disease Parkinsonism is a progressive neurological disorder of muscle movement, characterized by – tremors – muscular rigidity, – bradykinesia (slowness in initiating and carrying out voluntary movements), – and postural and gait abnormalities. Most cases involve people over the age of 65, among whom the incidence is about 1 in 100 individuals. Dopamine signaling Dopamine signals travel from the substantia nigra to brain regions including the corpus striatum, the globus pallidus, and the thalamus in order to control movement and balance. In Parkinson's disease, most of the dopamine signals from the substantia nigra are lost. Parkinson disease Etiology (cause) The exact cause is unknown for most patients. The disease is correlated with destruction of dopaminergic neurons in the substantia nigra with a consequent reduction of dopamine actions in the corpus striatum, parts of the brain’s basal ganglia system that are involved in motor control. The loss of dopamine neurons in the substantia nigra can be detected by reduced uptake of dopamine precursors in this region using positron-emission tomography and the dopamine analog fluorodopa. Genetic factors do not play a dominant role in the etiology of Parkinson disease. It appears increasingly likely that an as-yet unidentified environmental factor may play a role in the loss of dopaminergic neurons. Flourodopa  Parkinson disease Substantia nigra: The substantia nigra, part of the extrapyramidal system, is the source of dopaminergic neurons (shown as red neurons in Figure) that terminate in the neostriatum/striatum. Each dopaminergic neuron makes thousands of synaptic contacts within the neostriatum and, therefore, modulates the activity of a large number of cells. Treatment of Neurodegenerative Diseases  Alzheimer Disease Pharmacologic intervention for Alzheimer disease is only palliative and provides modest short-term benefit. None of the currently available therapeutic agents have been shown to alter the underlying neurodegenerative process. Dementia of the Alzheimer type has three distinguishing features: – 1) accumulation of senile plaques (β-amyloid accumulations) – 2) formation of numerous neurofibrillary tangles – 3) loss of cortical neurons, particularly cholinergic neurons. Current therapies are aimed at either improving cholinergic transmission within the CNS or preventing excitotoxic actions resulting from overstimulation of NMDA-glutamate receptors in selected brain areas. Alzheimer Disease Frontiers in Bioscience-Landmark 26(10):851 - 865 23 Amyloid Plaques Neurofibrillary Tangles Impaired Cholinergic Neurotransmission  Risk Factors for Alzheimer's Disease Age. 10% of all people over the age of 65 have Alzheimer's disease. Gender. Alzheimer's disease affects women more frequently than men. Family history. – Down syndrome. People with Down syndrome often develop Alzheimer's disease in their 30s and 40s, although the exact reason is not known. Head injury. Some studies have shown a link between Alzheimer's disease and a significant head injury. Environmental toxins. Some researchers suspect that increased exposure to certain substances such as aluminum may make a person more susceptible to Alzheimer's disease. Low education level. Although the reason is not clearly understood, some studies have shown that low education levels can be related to an increased risk for Alzheimer's disease. Other factors. Research also suggests that high cholesterol levels and high blood pressure -- factors linked to heart disease and stroke -- may also increase the risk for developing Alzheimer's. Loneliness Depression Mania  Depression and Mania The symptoms of depression are – intense feelings of sadness, – hopelessness, and despair as well as the inability to experience pleasure in usual activities – changes in sleep patterns and appetite – loss of energy, and suicidal thoughts. On the other hand, Mania is characterized by – enthusiasm – rapid thought and speech patterns, – extreme self-confidence, and impaired judgment Depression and mania are different from schizophrenia There are two distinct types of depressive syndrome – unipolar depression: mood changes are always in the same direction. Usually non-familial, clearly associated with stressful life events – bipolar affective disorder: depression alternates with mania. Usually appears in early adult life and it is less common disorder and results in oscillating depression and mania over a period of a few weeks. Depression vs Mania Clinical Depression & Mood Disorders Dysthymia: persistent mild depression Cyclothymia: a mental state characterized by marked swings of mood between depression and elation; bipolar disorder.  Theories of Depression THE MONOAMINE THEORY: – The main biochemical theory of depression is the monoamine hypothesis, first proposed by Schildkraut in 1965, which states that depression is caused by a functional deficit of the monoamine transmitters, noradrenaline and 5- hydroxytryptamine (5-HT) at certain sites in the brain, while mania results from a functional excess. Rather than thinking of the monoamine deficiency as causing direct changes in the activity of putative 'happy' or 'sad' neurons in the brain, we should think of the monoamines as regulators of longer-term trophic effects, whose time course is paralleled by mood changes.  Cerebral palsy is a group of conditions that Cerebral Palsy affect movement and posture and caused by damage to the developing brain, most often before birth. Symptoms appear during infancy or preschool years and vary from very mild to serious. The arms, legs and trunk may appear floppy. Or they may have stiff muscles, known as spasticity. Symptoms also can include irregular posture, movements that can't be controlled, a walk that's not steady or some combination of these. The cause of cerebral palsy and its effect on function vary from person to person. Some people with cerebral palsy can walk while others need assistance. There is no cure, but treatments can help improve function. The symptoms of cerebral palsy may vary during the child's development, but the condition doesn't get worse. The condition generally stays the same over time. 32 33  The Nature of Epilepsy The term 'epilepsy' is used to define a group of neurological disorders all of which exhibit periodic seizures. It affects 0.5-1% of the population. What is a seizure? An epileptic seizure (a fit) is a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain”. Symptoms preceding the onset of a partial seizure are called auras. Auras commonly include abnormal sensations such as a sense of fear, a rising feeling in the abdomen, or even a specific odor. The site of origin of the abnormal neuronal firing determines the symptoms that are produced. e.g. – Motor cortex involved: symptoms include abnormal movements or a generalized convulsion. – Parietal or occipital lobe: symptoms include visual, auditory, and olfactory hallucinations. The small population of neurons in brain from where discharge occurs, is referred to as the “primary focus.” Types of Epilepsy The clinical classification of epilepsy is done on the basis of characteristics of the seizure There are two major categories, namely – Partial – Generalized seizures, although there is some overlap in many varieties of each (A tonic-clonic seizure consists of an initial strong contraction of the whole musculature, causing a rigid spasm and an involuntary cry. Respiration stops, and defaecation, micturition and salivation often occur. ) Epilepsy can also be labeled into two types base on the etiology Idiopathic: if the etiology is unknown and no trauma or neoplasm could be found as causative Symptomatic: if it is secondary to an identifiable condition (drug use, tumor, head injury, hypoglycemia, meningeal infection, and the rapid withdrawal of alcohol from an alcoholic, can precipitate seizures)  Partial Seizures Partial seizures: Discharge begins locally and often remains localised. The symptoms depend on brain region involved: include involuntary muscle contractions, abnormal sensory experiences or autonomic discharge. The EEG discharge in this type of epilepsy is normally confined to one hemisphere. Partial seizures can often be attributed to local cerebral lesions, and their incidence increases with age. In some individuals, a partial seizure can develop into a generalised seizure  Generalised Seizures Generalised seizures involve the whole brain, including the reticular system, thus producing abnormal electrical activity throughout both hemispheres. Immediate loss of consciousness is characteristic of generalised seizures. Types of Generalized Seizures 1. Tonic-clonic: These seizures result in loss of consciousness, followed by tonic (continuous contraction) and clonic (rapid contraction and relaxation) phases. 2. Absence: These seizures involve a brief, abrupt, and self-limiting loss of consciousness. The onset generally occurs in patients at 3 to 5 years of age and lasts until patient is adult. The patient stares and exhibits rapid eye-blinking, which lasts for 3 to 5 seconds. 3. Myoclonic: These seizures consist of short episodes of muscle contractions that may recur for several minutes. They generally occur after wakening and exhibit as brief jerks of the limbs. 4. Status epilepticus: In status epilepticus, two or more seizures occur without recovery of full consciousness between them. Status epilepticus is life-threatening and requires emergency treatment. Generalised Seizures Example of the tonic-clonic seizures