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Neurobiology II: Development and function of the nervous system W3005y Spring 2002 Lecture 1: Systems 1/21/02 Darcy B. Kelley An Introduction to Nervous Introduction This is a course about the brain: how it develops and how it works. Our study of the brain assumes some knowledge of how individual neurons work. Some examples of background information include: How does a neuron receive information? What determines whether a neuron produces an action potential (and what is an action potential)? How does synaptic transmission work? For the most part, however, we will focus not on the individual neuron but on systems of neurons: groups of synaptically connected neurons that perform specific functions. Most of the examples we will study come from vertebrate nervous systems so we begin this course by examining one such system to see how it is put together. Slide 1 All brains, even those of identical twins, are different. This, for example, is roughly what your brain looks like and is seen from the side. Label: a. Anterior (front), posterior (back) b. dorsal (top), ventral c) Cerebral cortex, cerebellum, medulla. Slide 2 Brains of different species look different in characteristic ways that reflect their way of life. Here is a picture of a human brain, a fish brain and a frog brain (not to scale). Though each looks superficially very different, all are formed from the same basic plan. In humans the cerebral cortex is hypertrophied and growns over the entire midbrain. In some fish (electric fish for example), the cerebellum is massively developed in connection with electrolocation and electrocommunication. In this aquatic frog, the caudal hindbrain is hypertrophied and represents the acoustic and lateral line system (sound and water surface waves).. What system of the CNS might you expect to be hypertrophied in echolocating bats? 1 Slide 3 As for real estate, a key principle of brain functions is: location, location and location. We can pinpoint the location of brain structures or even of individual neurons using a co-ordinate system: anterior (rostral) vs. posterior (caudal); dorsal (top) versus ventral (bottom); medial versus lateral. Because brains are bilaterally symmetrical, we must also specify right or left side (the individual’s right or left). What difference in orientation between dogs and men account for differences in names of brain directions? Slide 4 In man, the neuraxis (the anterior/posterior axis of the nervous system) rotates at the border between the midbrain and the forebrain. We distinguish a special orientation for human brains that reflects this rotation: the coronal plane (roughly parallel to the face). The brain is made up mostly of two kinds of cells: neurons and glia. Slide 5 Neurons come in a large variety of shapes (morphological classification). Specific kinds of neurons have characteristic cell body shapes, dendritic trees and axonal arbors. Identify a Purkinje cell, a pyramidal neuron. Injdicate the cell body, the dendritic tree. What are their identifying features?. Suppose you rotated each cell by 90 degrees, what would each look like? Slide 6 Glia are more numerous than neurons. They serve a variety of functions. Durung development, radial glia guide migrating neurons and their processes (axons and dendrites) to more distant destinations. After injury, reactive astrocytes engulf dead and dying neurons and remove debris. Glia also form the fatty sheath (myelin) that wraps around the axon and speed up the conduction of action potentials: in the brain and spinal cord (central nervous system) these myelinating glia are called oligodendroglia. Outside of the CNS, Schwann cells myleinate axons. EXPERIMENTAL METHODS: How do we know what kinds of cells the CNS contains? Stains of sectioned materials Almost all cells in the vertebrate nervous system are too small to be seen with the naked eye. To examine neurons we have to first cut the CNS into thin slices (this allows sufficient illumination) and look at the slices with a microscope (a small neuronal c 3 2 microscope (shorter wavelengths resolve smaller structures) or specialized microscropic methods such as confocal microscopy or DIC (differential interference contrast). Slide 7 Once the brain is sectioned, we need to keep track of where in the brain each section comes from (so that, for example, we can reassemble a three dimensional structure from two dimensional sections) and also we need to know how the section was cut (plane of section). Slide 8 One popular plane of section is transverse (coronal for the human forebrain). This plane of section is perpendicular to the neuraxis. Slide 9 Transverse sections can come from any anterior posterior position in the neuraxis. To reconstruct a brain structure you need to keep track of the rostro/caudal relations of the sections. Slide 10 The other way to recognize A/P levels from a single section is by landmarks. Slide 11 In the transverse plane of section, what directions are preserved; what directions are lost? Slide 12 Another useful plane of section is horizontal. The horizontal plane is parallel to the neuraxis. Slide 13 What directional information is preserved in the horizontal plane? What is lost? Slide 14 The final plane of section is saggital. Parallel or perpendicular to the neuraxis? Slide 15 A saggital section that is right at the midline (the plane of bilateral symmetry) is called midsagittal. What directional information is preserved in the sagittal plane? What is lost? Slide 16 Identify the planes of section of these bread slices, Nissl stains, myelin stains, Golgi Once you have cut the section and are examining it under the microscope, you will need to distinguish the cells or the fiber tracts. These can sometimes be picked out by differences in refraction (Nomarski or differential interference contrast microscopy), but these may only work at high magnifications (where it may be difficult to tell exactly where in the section you are). A method that works at both low and high magnifications is to stain the section using a dye. Some 3 dyes have strong affinities for components of the cell body such as the Nissl substance or cytoplasmic RNA (Nissl stains include cresyl violet and neutral red). Slide 17 This is a transverse section through a song bird forebrain that has been stained with cresyl violet. Each individual purple dot is a cell. Some groups of cells cluster together and stain similarly. These clusters are called brain nuclei. The appearance of brain nuclei after staining enables anatomists to use cytoarchitectonic criteria to characterize different regions of the brain. Because, most often, form reflects function (and vice versa) these staining characteristics can be used reliably to identify functional brain regions (visual cortex for example, as we will see). Slide 18 What can stained sections tell us? These are sections through this same part of the brain male and female song birds. The brain nucleus illustrated is called area X. A and B illustrate area X in male and female canaries, respectively. C. and D. illustrate area X in male and female zebra finches, respectively. What hypotheses are suggested by these stained brain sections? (Figure from Nottebohm and Arnold, 1976, Science). Slide 19 Stains can also be used to visualize fiber tracts (collections of axons) or individual axons (myleinated or not) in brain sections or in the periphery. This is a section through a frog muscle illustrating a fiber bundle, individual myelinated axons and neuromuscular synapses. Label each component. Slide 21 The dyes described above allow us to visualize cell bodies and axons. Except for the very largest neurons (motor neurons for example) dendrites are not stained at all. In the late 1800’s, a Spanish neurologist, Santiago Ramon y Cajal, began to apply a method of impregnation with mlietal salts developed by Camilio Golgi from Italy, to developing and adult brains from a variety of species. Slide 22 For reasons that are still not very well understood, the Golgi stain picks out just a few cells but stains them in their entirety. This is a transverse section through a frog forebrain in which a few cells and their dendrites (point to these with arrows) have been impregnated with the rapid Golgi method. Slide 23 Golgi stains can reveal an individual neuron in all its glory: dendrites, cell body and axon. This feature relies on only having a few cells stain; if all cells stained the section would be an impenetrable black field. The Golgi stain can also reveal details of cellular morphology such as the presence of dendritic spines (small protruberances). Do any of these cells from the frog auditory midbrain have dendritic spines? We can use the Golgi method to stain glia as well as neurons. For neurons, we can describe cells according to their morphology. Some cell type names come from shapes: basket cells, candelabra cells, pyramidal cells. We can use other methods to characterize cells by their axonal projections. These 4 methods involve the transport of substances from the cell body to the axon terminals (anterograde transport) or from the terminals to the cell body (retrograde transport). One of the molecular motors involved in axonal transport is the topic of the first recitation section Using this approach we find that there are three kinds of neurons: primary sensory neurons, motor neurons and interneurons. The central nervous system (CNS) is almost entirely interneurons. Slide 24 To understand neuronal function we need to know more than just the shape of the neuron. For example: What neurotransmitters or modulators are made? What receptors are expressed? To look at which proteins are expressed in a neuron the most common method is immunocytochemistry. An antibody specific to the protein of interest is generated in an animal of one species (a rabbit for example), applied to the section and recognized by another antibody from a second species generated against all antibodies from the first species (a goat anti-rabbit immunoglobulin, for example). This secondary antibody is tagged with a molecule that can be visualized (HRP or biotin are examples; fluorescent tags can also be used). This slide shows frog vocal motor neurons that express the clacium binding protein calbindin reveled using immunocytochemistry. Slide 25 This is a Golgi impregnation of a cell in the ventral horn of the cat spinal cord . We can identify this cell in a variety of easy: its neurotransmitters, its receptors etc. For understanding neural systems, however, we usually want to know what other neurons it connects with synaptically. Inputs to the cell are called afferents and targets of this cell are called efferents. There are three kinds of neurons with regard to the central nervous system: motor neurons, primary sensory neurons and interneurons. Slide 26 We can identify this cell type as a motor neuron by retrograde transport of the plant enzyme (horseradish peroxidase) from its synaptic terminals in muscle fibers (slide 19). The cell bodies of motor neurons are located INSIDE the central nervous system but their synaptic targets, the muscle fibers, are located OUTIDE the nervous system. Slide 27 This is a Golgi impregnation of an olfactory neuron, an example of a primary sensory neuron. Primary sensory neurons convey information into the central nervous system. Their cell bodies lie OUTSIDE the brain and spinal cord. Olfactory neurons reside in the nose (the olfactory epithelium). Their dendrites extend into the mucosal lining of the nose and their axons travel into the CNS to synapse on neurons in the main olfactory bulb at the front of the brain. Slide 28 Every other cell in the CNS is an interneuron. For interneurons, both the cell body and all processes are inside the CNS. The pyramidal cell is an example of an interneuron as are basket cells, candelabra cells etc. 5 Slide 29 CNS interneurons are organized into systems by virtue of specific patterns of connectivity. Slide 30 Today, some of the most popular tracers are fluorescent dextran amines, many of which travel both in the anterograde and the retrograde direction. This is a frog brain split in half in the midsaggital plane. We can place a small injection of a fluorescent dextran amine into a specific brain region and then maintain the isolated brain for a few days while anterograde and retrograde transport is carried out. Slide 31 In the cleared half brain we can follow individual axons to their terminals. Slide 32 We can also discover the sources of input to the region in question. Here cells in the anterior thalamus are shown after retrograde labeling from the anterior preoptic area. Slide 33 We can use anterograde and retrograde transport to define the anatomical connections of interneurons. For example, here the dye Lucifer yellow has been used to identify vocal motor neurons in the hindbrain of a frog. Slide 34 Here we can see synaptic terminals full of a red fluorescent dye ending on the cell body of a Lucifer-yellow filled motor neuron. Slide 35 The holy grail for defining synaptic networks in the CNS is to find tracers that travel across several synapses. For example, if radioactive amino acids are placed into the eye, they are incorporated into proteins and transported to the terminals of retinal ganglion cells in the lateral geniculate nucleus. There the radioactive proteins are broken down again into radioactive amino acids, these are released and taken up by LGN neurons which transport them to their main target, primary visual cortex. Slide 36 If only one eye is injected we can see alternating bands of synaptic inputs, the ocular dominance columns. Slide 37 Some label can also travel across the synapse in a retrograde direction. Here is an example of transfer of biocytin from the post synaptic motor neuron to its afferent interneuron. After the geniculate to cortex synapse there is not enough tracer left travel and be visualized at the next synapse. Current efforts at tracing circuits involve modified neurotrophic viruses that multiply inside the cell and so are not diluted. For small pieces of tissue we can use stimulation and calcium sensitive dyes to look at local circuits. Of course, we can also stimulate one cell and record from 6 its synaptic target to define connectivity. If we record intracellularly from the post-synaptic neurons we can determine whether the synapse is excitatory or inhibitory. First, however, we have to find the presynaptic inputs and it is in the regard that tracing is most valuable. Slide 38 To organize our thinking about brain connectivity we first have to know what part of the brain is under discussion. A major principle here is location. The location in which a developing cell finds itself determines its identity through a series of complex molecular signaling events that we will discuss. The end result if a very stereotyped set of brain regions. Slide 39 Figuring out where you are in the brain: coordinates and landmarks. Slide 40 The most posterior portion of the CNS is the spinal cord. Slide 41 Organizaton of the spinal cord: sensory information enters dorsally (from the ______ ____ _______), motor neurons are located ventrally; everything else is interneurons and fiber tracts made up of axon bundles). Information enters and exits the spinal cord via the spinal nerves. Slide 42 Motor neurons are located in the ventral horn of the spinal cord. Because humans stand on their hind legs, the ventral (bellywards) portion of the spinal cord faces front so ventral horn cells are called anterior horn cells. Slide 43. The medulla is located immediately in front of the spinal cord. Like the spinal cord, sensory information comes in through dorsal nerves and motor outflow exits through ventral nerves (from the medulla forward these nerves are called cranial nerves). Slide 44 Cranial nerves I VII II VIII III IX IV X V XI VI XII Sensory information is processed serially and in parallel. 7 Parallel processing: Sensory information is distributed to different regions of the CNS when it enters; each region can perform a separate processing operation whose results can then be combined. Parallel processing has the advantage of speed. Serial processing: Sensory information can be processed by a series of brain nuclei to extract specific features of a sensory stimulus. Serial processing has the advantage of feature enhancement or detection. Slide 45 In the hindbrain or rhombencephalon (which includes the medulla) each cranial nerve originates from a spoecific segment called a rhombomere. Rhombomeres are established during development by a cascade of signalling molecules that translate location into cellular identity. Slide 46 The hindbrain: cranial nerves and cerebellum. • the cerebellum, a "little brain" that works together with cortex to produce movement and process sensory information •various fiber (axon bundles) tracts ascending or decending to various levels of the neuraxis • groups of interneurons receiving sensory information and • other groups that generate certain motor programs such as breathing. Slide 47 The midbrain: tectum and tegmentum • The midbrain consists of a roof (tectum) and a floor (tegmentum). • The tectum has two major sensory processing nuclei that look, from the outside, like little hills (colliculi). The superior (anterior) colliculus processes visual; information and the inferior (posterior) colliculus processes auditory information. • The tegmentum consists of various fiber tracts and some interneurons involved in generating motor patterns. Slide 48 The forebrain •The hypothalamus is located in the ventral diencephalon; many of its nuclei control the pituitary (aka "master gland"). • The thalamus is located in the dorsal diencephalon; cells in the thalamus project to cortex and receive projections from cortex; the lateral geniculate nucleus provides visual information to cortex and the medial geniculate nucleus provides auditory information to cortex. 8 • The basal ganglia have reciprocal connections with thalamus and motor cortex and play important roles in motor control (Parkinson’s and Huntington’s). • The cortex is an elaborate, crumpled, thick sheet of cells that has reciprocal connections with thalamus and brain stem. The cortex plays an essential role in preceiving, thinking and the planning and execution of movements. Slide 49 The Cerebral Cortex • In humans and primates, the cerebral flexure bends the neuraxis at the level of the forebrain and we distinguish a new plane of section, perpendicular still to the neuraxis, the coronal plane. • The cortex is divided into a number of functionally and cytoarchitectonically distinct regions. •The main subdivisions are: frontal, parietal, occipital and temporal. • The crumpled surface of the cortex can be viewed as hills (gyri) and valleys (sulci). Several large sulci divide up the main subdivisions. • The spatial representation of information is maintained in the cortex as "maps"; maps representing parts of the body are "somatotopic", visual maps are "visuotopic" etc. Motor maps are also somatotopic. A given region of cortex can contain multiple maps. • In general, the larger a region of cortex devoted to a particular job (body part, region of visual space etc.) the smaller the receptive fields of neurons in that region. Glossary Ganglia - collections of nerve cell bodies. The leech nervous system is a chain of ganglia. Many primary sensory neurons are located in the dorsal root ganglia, collections of nerve cell bodies in a chain that runs parallel to the spinal cord. Central nervous system - the brain and spinal cord. Primary sensory neuron- a neurons whose cell body is located outside the CNS. The neuron itself may transduce the sensory signal (eg. pain) or it may receive signals from a transducing cell (eg. sound via the hair cell). Motor neuron - a neuron whose cell body is located inside the CNS but whose axon leaves to innervate muscle. Interneuron- every other cell in the CNS. 9 Rhombomeres- segments of the hindbrain which can be seen at embryonic stages and encompass characteristic domains of gene expression. Cerebellum- structure at the anterior edge of the hindbrain; in mammals attached via the cerebellar peduncles (fiber tracts), has several complete sensory and motor maps of the brain, is critical for motor memory (riding a bicycle) and is made up of repeated sub-structures, folia, containing characteristic cell types with a stereotyped synaptic connections. Sulcus- the bottom of a cerebral fold; eg. the Sylvian fissure. Gyrus- the top of a cerebral fold. Receptive field- the sensory field which drives changes in activity of the neuron you are recording from. Nuclei- a technical term in the CNS meaning a collection of cell bodies, usually subserving the same or a related function, and distinguishable cytoarchitectonically from nearby regions. Cytoarchitectonics- a hideous term, near and dear to the hearts of anatomists, having to do with the ability to distinguish brain regions by their staining characteritics or the packing density of neurons or fiber tracts. The best example is the stripe of Gennari (sp?), a feature that represents incoming afferents from the thalamus and distinguishes striate or striped cortex (aka primary visual cortex) from adjacent regions. Huntington’s and Parkinson’s diseases- human diseases involving the degeneration of cells projecting to, or found within, the basal ganglia. Huntington’s is an autosomal dominant, late onset disease one of whose most famous victims was Woody Guthrie. Parkinson’s disease is due to the death of dopaminergic neurons of the substantia nigra; treated with L-dopa. Neuraxis- the plane parallel to the neural tube. Study questions; 1) Define and give an example of serial and of parallel processing in a sensory system(s). 2) Each of the planes of section preserves two pieces of coordinate information and is missing one. What is present and what is absent from a transverse, an horizontal and a saggital sction? 3) Define afferent and efferent and illustrate the uses of these terms in a transverse section of the spinal cord. 4) Enumerate the cranial nerves; which are sensory, which are motor and which are mixed? 10 5) Where in the CNS are purkinje cells found? 6) In Latin, tectum means ____ and tegmentum means _____. Which part would you expect to find sensory afferents in; which part would you expect to find motor neurons in? Why? 11