Chapter 17: The Nervous System

1. Chapter 17: The Nervous System

2. The Nervous System • Neurotoxicity is the alteration of normal function of the nervous system as the result of exposure to natural or artificial neurotoxicants. The damage may be specific to a particular cell type, a given region, or a particular function. The nervous system is structurally divided into two major anatomical components: • The central nervous system (CNS), consisting of the brain, cranial nerves, and the spinal cord • The peripheral nervous system (PNS), consisting of sensory (afferent) neurons, which relay impulses from the receptors to the CNS, and motor (efferent) neurons, which relay impulses from the CNS to effectors such as the glands and muscles of the body.

3. The Nervous System The efferent division of the PNS can be divided into: • the voluntary or somatic nervous system, which regulates skeletal muscle activity • the autonomic or involuntary nervous system, which regulates the glands and cardiac and smooth muscles

4. The voluntary (somatic) nervous system • regulates skeletal muscle activity • uses one group of motor neurons to stimulate the effectors, whereas the autonomic nervous system requires both a preganglionic and a postganglionic neuron to stimulate the effector • consists of the skeletal and cranial nerves that send sensory information to the CNS and motor nerve fibers that innervate the skeletal muscles.

5. The autonomic (involuntary) nervous system • regulates the glands and cardiac and smooth muscles • is composed of both sensory and motor neurons that control the internal environment of the body’s internal organs • is further divided into the sympathetic and parasympathetic systems.

7. The Nervous System The sympathetic division of the autonomic nervous system (the “fight or flight” response system) is responsible for: • Increasing cardiac output • Elevating blood pressure • Increasing heart rate • Bronchodilatation • Increasing pupil size • Increasing blood flow from peripheral vessels to skeletal muscle • Mobilization of glycogen in fat

8. The Nervous System The parasympathetic division of the autonomic nervous system is generally antagonistic to the sympathetic system and is responsible for: • Decreasing cardiac output • Decreasing blood pressure • Decreasing heart rate • Decreasing pupil size • Bronchoconstriction • Increasing digestion and absorption of foods • Eliminating wastes

9. The Nervous System – the Brain • The brain can be divided into several regions: • Forebrain, consisting of the cerebrum and the diencephalon (thalamus and the hypothalamus) • Midbrain (mesencephalon), consisting of the tectum and tegmentum • Hindbrain, consisting of the medulla oblongata (myelencephalon) and the metencephalon (pons and cerebellum)

10. The Nervous System – the Brain, cont. • The cerebrum is the largest part of the brain and can be subdivided as follows: • Frontal lobe, which controls such things as creative thought, intellect, problem solving, attention, behavior, abstract thinking, smell, emotions, and coordination of movement • Temporal lobe, which controls such things as language, auditory and visual memory, speech, and hearing • Parietal lobe, which controls such things as tactile perception, responses to internal stimuli, sensory interpretation, and some visual function • Occipital lobe, which processes visual information

11. Cells of the Nervous System • The neuron (single nerve cell) is the functional unit of the nervous system. These are the excitable cells that are capable of generating and propagating an electrical signal, filing and storing information to support basic communication processes and higher functions such as learning, memory, and behavior. • The functional classes of neurons are: • Sensory or afferent neurons that carry information to the CNS • Motor or efferent extrinsic neurons that carry information from the CNS to the tissues and organs

12. Structure of a typical neuron

13. Cells of the Nervous System • Neuroglial or glial cells are supportive to the nervous system and are represented by several types of cells in the CNS: • Oligodendrocytes - responsible for the production of myelin in the CNS and hence are responsible for normal propagation of action potentials • Astrocytes - the most abundant glia • they comprise the largest portion of the blood–brain barrier (BBB) • located within the CNS • critical to the maintenance of the BBB • help to regulate concentrations of potassium (K+) • maintain extracellular pH, glutamate, and water • Ependymal cells -line the ventricles in the CNS and produce and circulate the cerebrospinal fluid through ciliary activity • Microglia - macrophages that differ from other glial cells because they are monocyte derived.

14. The Blood-Brain Barrier (BBB) • The BBB is an anatomical and physiological “barrier” between the brain and circulation, which regulates the entry and leaving of both endogenous and exogenous substances into and out of the brain. • The key factors that determine this are: • Molecular size • Lipid solubility • Molecular charge • Concentration differences • Specialized transport mechanisms

15. The Blood-Brain Barrier (BBB) • The BBB is composed of tight junctions (zonulae occludens) between endothelial cells of brain capillaries and astrocytic cell membrane projections that surround these capillaries. • The barrier is relatively ineffective for lipid-soluble molecules, whereas water-soluble substances such as glucose require special mechanisms for transport. • Compounds that mimic essential chemicals such as certain ions and nutrients can be actively transported across the BBB as occurs when organic mercury combines with the amino acid cysteine and is transported by amino acid uptake systems. • Certain ions such as Pb2+ can be transported by normal ion exchange systems.

16. The Blood-Brain Barrier (BBB) • The BBB is not a continuous barrier in that there are places within the CNS where the barrier is relatively ineffective, such as the median eminence, pineal, neurohypophysis, and the hypothalamus. • The BBB is not fully developed in children, thus making them much more susceptible to the effects of certain chemicals when compared with the adult brain. • Small exposures to lead, for example, are of greater concern in children than in adults due to the more permeable nature of their cerebral capillaries.

17. Neuron Action Potential and Synaptic Function • The unequal distribution of ions across a neuron cell membrane, like other excitable cells, is the basis for the nervous action potential. • This is brought about by electrical and chemical gradients that are created across the cell membrane by active transport mechanisms and selective membrane permeability. • Electrical conduction involves the movement of sodium and potassium ions across the nerve cell membrane through sequential changes in its permeability to sodium (Na+) and potassium (K+) ions. • The membrane potential difference can be measured by ascertaining the difference between the electrical charge inside and outside the cell.

18. Neuron Action Potential and Synaptic Function, cont. • There are two basic kinds of electrical signals in neurons: • graded potentials – • graded potentials travel short distances • action potentials – • action potentials travel over longer distances • They do not lose amplitude as they travel, nor do they vary

19. Neuron Action Potential and Synaptic Function, cont. • At the terminal end of an axon (i.e., the presynaptic terminal) are synaptic vesicles containing chemicals known as neurotransmitters. • Upon arrival of action potentials at the axon terminals, a neurotransmitter is released that diffuses across the synaptic or neuromuscular junction and activates postsynaptic receptors, thereby initiating another action potential or the response of the effector cell.

20. Neuron Action Potential and Synaptic Function, cont. • Examples of neurotransmitters include: • Acetylcholine • Catecholamines (dopamine, norepinephrine, epinephrine) • Serotonin • Glutamate • Gamma-aminobutyric acid (GABA -an inhibitory neurotransmitter) • Peptides

21. Typical Synapse

22. Neurotoxicity • Neuropathic damage can result from exposure to neurotoxicants like carbon monoxide, carbon tetrachloride, mercury, or lead. • Lead is a ubiquitously occurring toxicant found naturally in the environment and therefore can be found in water, food, and air, as well as in many manufactured products. • Despite the efforts for lead reduction by the U.S. Environmental Protection Agency (EPA) and the U.S. Food and Drug Administration (FDA), lead exposures still remain an important public health concern, especially in children, who are both more likely to be exposed to certain sources and more sensitive to the effects of lead.

23. Neurotoxicity, cont. • It is now clear that even relatively low lead exposures during childhood development have neurobehavioral and developmental effects that may persist into adulthood. • The problem is still of greatest concern in urban environments where exposures to lead, especially from lead-based paint and plumbing fixtures in old housing, are commonplace.

24. Neurotoxicity, cont. • Neurotoxicity can be produced in the CNS after exposure to a chemical agent. At the cellular level, injury can occur at: • Motor neurons, producing muscle dysfunction and paralysis • Interneurons, producing decrements in memory and learning coordination • Sensory neurons and sensory receptors, producing dysfunction in vision, hearing, and the senses of temperature, pressure, touch, taste, smell, and pain

25. Neurotoxicity, cont. • Injuries to the structure and physiological perturbations in the nervous system include: • Direct cytotoxicity and death of neurons and glia • Conduction abnormalities and interference with synaptic and neuroeffector transmission • Damage occurs selectively in the tissues of the nervous system, depending on the presence and penetrability of barriers, differences in blood flow, differences in metabolic rates, and differences in metabolic function. • Cells of the cerebellum and visual cortex, for example, are preferentially killed by methylmercury.

26. Neurotoxicity, cont. • Toxic responses to the nervous system have been classified as falling into several categories: • Neuronopathy: damage to neuronal cell body • Axonopathy: damage to axon or axonal transport • Myelinopathy: loss of or abnormal formation of myelin • Conduction/transmission: associated effects where conduction or neurotransmitter functions are altered

27. Examples of Neurotoxic Chemicals

28. Neurotransmission-associated Toxicities Represent a category of toxicities that refer to any chemical that • Affects the function of synaptic vesicles • Blocks or activates synaptic or effector receptors • Blocks the release of neurotransmitter • Blocks the reuptake or degradation of neurotransmitter • Produces uncontrolled release of neurotransmitter • Interferes with action potential conduction

29. Neurotransmission-associated Toxicities Chemicals that can produce neurotransmission-associated toxicities include those that: • Block impulse conduction along axons (e.g., local anesthetic and tetrodotoxin blockade of Na+ channel function) • Block synaptic function by interfering with the normal calcium channel activity, which triggers the release of synaptic vesicles (e.g., metals such as cadmium, lead, nickel, and cobalt; toxins such as curare, alpha-bungarotoxin) • Activate synaptic function (e.g., nicotine)

30. Neurotransmission-associated Toxicities, cont. • Block reuptake or breakdown of neurotransmitter resulting in receptor overstimulation (e.g., organophosphates, carbamates, which competitively bind acetylcholinesterase, thus blocking breakdown of acetylcholinesterase; cocaine, which blocks catecholamine reuptake) • Produce massive release of neurotransmitter (e.g., black widow spider venom increases acetylcholine and amphetamine increases norepinephrine releases) • Block the release of neurotransmitter (e.g., botulinum toxin blockage of acetylcholine release)