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Author(s): Peter Hitchcock, PH.D., 2009

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Introductory Lecture

                M1 – CNS Sequence
                Peter Hitchcock, Ph.D.


Winter, 2009
Introduction to today s lecture:

I.     Introduction to the faculty and the Normal CNS, Special Senses,
        Head & Neck Sequence
II.    Anatomical planes and major axes of the central nervous system
III.  Principal cell types in the CNS
IV.  Specialized stains and what they reveal
V.     Schematic representation of the functional organization of the CNS
VI.  Regional anatomy of the central nervous system
VII.  Functional subdivisions, pathways and relevant concepts
VIII.  Topographic organization
IX.  Blood supply to the CNS
X.     The cerebrospinal fluid
Why is learning neuroanatomy such a challenge?


You will simultaneously learn:

1) regional anatomy (spinal cord,
brainstem, etc.)
2. surface (gross) anatomy
3. internal anatomy
4. names and locations of nuclei
and tracts and the pathways they
form
5. functions of the various
pathways in the CNS
6. blood supplyS

 neuronal cell biology
 nerve development and
 regeneration
 neurotransmitters
 chemical neuroanatomy

Gross Anatomy
Histology
Pharmacokinetics

                                                          Source Undetermined




                                    Source Undetermined
There are three principal planes of section
that are used for viewing the brain:
horizontal, frontal (or coronal) and
sagittal.




                                              U.S. Federal Government




     Source Undetermined


frontal section through the cerebral hemispheres
•  There are three principal axes along which
   the internal anatomy of the nervous system
   is organized:
   –  rostral-caudal axis
   –  dorsal ventral axis
   –  medial-lateral axis
•  During its embryonic development the
   human brain bends (known as a flexure). As
   a result, the dorsal-ventral plane changes as
   one moves along the neuraxis, from rostral
   telencephalon to the caudal spinal cord.
•  Several terms are used to indicate the
   relative positions of structures or tracts in the
   brain:
     –  Dorsal - above or superior
     –  Ventral -below or inferior
     –  Rostral -toward the front
     –  Caudal - toward the back
     –  Medial - toward the midline
                                                       Source Undetermined
     –  Lateral - away from the midline
     –  Ipsilateral - on the same side
     –  Contralateral - on the opposite side
•  There are two fundamental cell types in the
   CNS: neurons (10X109) and glia (10-50X
   more numerous than neurons).
•  Neurons communicate to each other via
   specialized junctions known as synapses.
•  Neurons are polarized cells that are
   specialized to receive synapses on
   dendrites and relay electrical impulses to
   other neurons via their axons (also called     Images of glia
   fibers) and their synapses.                     and neurons
•  A collection of neuronal cell bodies outside
   the CNS is called a ganglion.                     removed
•  A collection of neuronal cell bodies within
   the CNS is called a nucleus.
•  A discrete bundle of axons outside the
   CNS is known as a nerve.
•  A discrete bundle of axons within the CNS
   is known as a tract (lemniscus,
   fasciculus).
   (read the handout for more details on
   tracts)
•  Nuclei and tracts that are linked by
   synapses serve a common function are
   generally referred to as a pathway.
Axons that form a tract:
         have cell bodies in a common nucleus
         synapse onto a common target (or set of targets)
         perform a common function, e.g., somatic sensation, voluntary movement

Tracts are often named based on the site of origin and termination of their axons:
         spinothalamic tract – from the spinal cord to the thalamus
         corticospinal tract – from the cerebral cortex to the spinal cord

The names of tracts often identify their relative location within the CNS white matter:
       lateral spinothalamic tract – lateral in the spinal cord
       medial lemniscus – near the midline

Tracts can carry information either up or down the neuraxis
         ascending tract (spinothalamic tract) - sensory function
         descending tract (corticospinal tract) - motor function

Tracts that carry sensory or motor information are generally organized in parallel:
         pain and temperature vs. fine discrimination
The locations and spatial relationships of nuclei and tracts define the
internal anatomy of the CNS. The functions subserved by the various
nuclei and tracts define the functional anatomy of the CNS.
Regions of the brain that contain cell bodies are given the general descriptive term,
gray matter.
                                                         Source Undetermined
      Source Undetermined




                  Spinal cord                        cerebral hemispheres

white matter                gray matter      gray matter                       white matter


  Regions of the brain that contain axons are given the general descriptive term,
  white matter.
Golgi-stained neurons (cortex)

                                 Visualizing neurons and axons in
                                 the central nervous system

                                   nucleic acid stain
                                   (lateral geniculate nucleus [dorsal thalamus])


      Source Undetermined


    myelin-stain (brainstem)




                                        Source Undetermined




      Source Undetermined
A schematic representation of the nervous system organization and function


•  The nervous system of all animals
   performs 3 fundamental biological
   functions:
    –  Monitor and regulate the
       internal environment
    –  Monitor the external
       environment
    –  Initiate behaviors based on
       infor-mation from both the
       internal and external
       environments
•  You are generally unaware of the
   majority of the functions performed
   by your nervous system.                              glands


  sensory systems: transduction, transmission, perception
  motor systems: mentation, transmission, behavior
      P. Hitchcock
Forebrai
                                                                                                               n




REGIONAL ANATOMY OF THE CNS
•  The CNS can be divided into 6 parts:
     1) spinal cord
     2) medulla (meyelencephalon)
     3) pons (metencephalon)
                                                Diencephalon
     4) midbrain (mesencephalon)
     5) thalamus (diencephalon)                       Midbrain
     6) cerebral hemispheres                                     Pons
                                                                                                               Hindbrain

         (telencephalon)                  Brainstem

•  These terms may be used                                                                             Cerebellum

   interchangeably.                                       Medulla




                                                                 Spinal cord: cervical
                                                                              thoracic
                                                                              lumbar
                                                                              sacral
                                                                 Patrick J. Lynch, wikimedia commons
These two diagrams model representative pathways
of the somaticsensory and motor systems,
respectively.




   J.H. Martin. Neuroanatomy: Text and Atlas.McGraw-Hill, 2003. 3rd Edition.

      afferent axons - carry information into the CNS
      efferent axons - carry information out of a structure
      decussation - site where axons cross the midline
Sensory information from the
periphery enters the brain in a very
systematic manner. This creates a      Sensory dermatomes
spatial order, which is preserved
throughout the sensory pathways.




                                       Haines. Fundamental Neuroscience.
                                       Churchill Livingstone, 2002. 2nd ed.


           Source Undetermined
Primary
ALL Sensory and Motor                                             sensory cortex
pathways are
topographically organized.

    Sensory: There is a
    point-to point
    relationship between a
    peripheral sensory
                             Modified from Tristram, wikispaces
    structure and its
    pathway in the CNS.                                            Primary motor
                                                                   cortex
    Motor: Pathways in the
    CNS are organized
    according to somatic
    muscle groups in the
    periphery.

homunculus=little man        Modified from Tristram, wikispaces
Sensory from
information from the
neck and below enters
the CNS via spinal
nerves, whose axons
ascend in white matter
tracts.




Depending on the
nature of the sensation,
axons may or may not
synapse in the spinal
cord.


                           J.H. Martin. Neuroanatomy: Text and Atlas.McGraw-Hill, 2003. 3rd Edition.
Sensory axons may (or may
not) synapse on nuclei in the
brainstem. If they do, the
name of the tract changes.

All axons carrying sensory
information synapse in
discrete nuclei within the
dorsal thalamus.




                                Gray s Anatomy
Cerebral cortex is highly specialized.

Somatic sensory information carried by axons from the dorsal
thalamus synapse on neurons in the postcentral gyrus (primary
somatic sensory cortex) in the parietal lobe.



            Expressive
                                                    Receptive




                 Source Undetermined
The brainstem controls
numerous bodily functions.
Injuries to the brainstem can
be life threatening.

The brainstem also receives
sensory information from the
head and contains the motor
neurons that innervate
muscles of the neck, head
and face.
                                U.S. Federal Government
The internal anatomy of the
brainstem is complex.




    J.H. Martin. Neuroanatomy: Text and Atlas.
     McGraw-Hill, 2003. 3rd Edition.

                                                 Gray s Anatomy
Syringomyelia                                             Brown-Séquard syndrome




      J.H. Martin. Neuroanatomy: Text and Atlas. McGraw-Hill, 2003. 3rd Edition.

Injures to the brainstem and spinal cord give
rise to specific sensory and motor deficits.                                                J.H. Martin. Neuroanatomy:
                                                                                            Text and Atlas. McGraw-Hill,
Injuries to the spinal cord produce sensory                                                 2003. 3rd Edition.

deficits that respect myotomal boundaries.

Place a lesion = what are the symptoms?

Describe the symptoms = can you place the
lesion?
Axons that carry motor commands for voluntary movements
originate in the precentral gyrus (primary motor cortex) of the
frontal lobe, descend into the brainstem and spinal cord and
synapse on motor neurons that innervate skeletal muscles.




             Expressive
                                                        Receptive




                  Source Undetermined
An example of a motor
pathway.

The corticospinal tract extends
from the precentral gyrus to
the spinal cord and subserves
the voluntary control of
skeletal muscles.

Although clinically important,
the corticospinal system is
numerically a minor
component in the control of
skeletal muscles.

                                  Haines. Fundamental Neuroscience. Churchill Livingstone, 2002. 2nd ed.
The cerebellum is a component of the motor system that
is not involved in unconscious control of skeletal
muscle.




           Source Undetermined


Diseases of the cerebellum are known as ataxias.
Special senses:
Vision
Hearing
Balance




                  The Regents of the University of Michigan
The CNS is highly vascularized and interruption in the blood
supply is a common form of nervous system injury




   Source Undetermined
The CNS is filled with and surrounded
by
cerebrospinal fluid (csf).

Internally:
          -lateral ventricles
          -3rd ventricle
          -4th ventricle

Externally:
         -subarachnoid space

CSF is a secretory product that
circulates through the ventricles and
returns to the venous side of the brain
vasculature




                                          Source Undetermined
Additional Source Information
                           for more information see: http://open.umich.edu/wiki/CitationPolicy

Slide 5: Sources Undetermined
Slide 6: Source Undetermined; U.S. Federal Government, http://en.wikipedia.org/wiki/File:BodyPlanes.jpg
Slide 7: Source Undetermined
Slide 11: Sources Undetermined
Slide 12: Sources Undetermined
Slide 13: Peter Hitchcock
Slide 14: Patrick J. Lynch, Wikimedia Commons, http://commons.wikimedia.org/wiki/File:Brain_human_sagittal_section.svg, CC:BY
    http://creativecommons.org/licenses/by/2.5/
Slide 15: Source: J.H. Martin. Neuroanatomy: Text and Atlas.McGraw-Hill, 2003. 3rd Edition.
Slide 16: Source Undetermined; Haines. Fundamental Neuroscience. Churchill Livingstone, 2002. 2nd ed.
Slide 17: Original sources, tristram, Wikispaces, http://tristram.wikispaces.com/file/view/homunculus.gif, CC:BY:SA
    http://creativecommons.org/licenses/by/3.0/
Slide 18: J.H. Martin. Neuroanatomy: Text and Atlas.McGraw-Hill, 2003. 3rd Edition.
Slide 19: Gray s Anatomy, http://www.bartleby.com/107/
Slide 20: Source Undetermined
Slide 21: U.S. Federal Government
Slide 22: J.H. Martin. Neuroanatomy: Text and Atlas. McGraw-Hill, 2003. 3rd Edition.; Gray s Anatomy
Slide 23: J.H. Martin. Neuroanatomy: Text and Atlas. McGraw-Hill, 2003. 3rd Edition.; J.H. Martin. Neuroanatomy: Text and Atlas. McGraw-Hill, 2003. 3rd
    Edition.
Slide 24: Source Undetermined
Slide 25: Haines. Fundamental Neuroscience. Churchill Livingstone, 2002. 2nd ed.
Slide 26: Source Undetermined
Slide 27: The Regents of the University of Michigan
Slide 28: Source Undetermined
Slide 29: Source Undetermined

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03.09.09(a): Introduction

  • 1. Author(s): Peter Hitchcock, PH.D., 2009 License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution–Non-commercial–Share Alike 3.0 License: http://creativecommons.org/licenses/by-nc-sa/3.0/ We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share, and adapt it. The citation key on the following slide provides information about how you may share and adapt this material. Copyright holders of content included in this material should contact open.michigan@umich.edu with any questions, corrections, or clarification regarding the use of content. For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use. Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions about your medical condition. Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
  • 2. Citation Key for more information see: http://open.umich.edu/wiki/CitationPolicy Use + Share + Adapt { Content the copyright holder, author, or law permits you to use, share and adapt. } Public Domain – Government: Works that are produced by the U.S. Government. (USC 17 § 105) Public Domain – Expired: Works that are no longer protected due to an expired copyright term. Public Domain – Self Dedicated: Works that a copyright holder has dedicated to the public domain. Creative Commons – Zero Waiver Creative Commons – Attribution License Creative Commons – Attribution Share Alike License Creative Commons – Attribution Noncommercial License Creative Commons – Attribution Noncommercial Share Alike License GNU – Free Documentation License Make Your Own Assessment { Content Open.Michigan believes can be used, shared, and adapted because it is ineligible for copyright. } Public Domain – Ineligible: Works that are ineligible for copyright protection in the U.S. (USC 17 § 102(b)) *laws in your jurisdiction may differ { Content Open.Michigan has used under a Fair Use determination. } Fair Use: Use of works that is determined to be Fair consistent with the U.S. Copyright Act. (USC 17 § 107) *laws in your jurisdiction may differ Our determination DOES NOT mean that all uses of this 3rd-party content are Fair Uses and we DO NOT guarantee that your use of the content is Fair. To use this content you should do your own independent analysis to determine whether or not your use will be Fair.
  • 3. Introductory Lecture M1 – CNS Sequence Peter Hitchcock, Ph.D. Winter, 2009
  • 4. Introduction to today s lecture: I.  Introduction to the faculty and the Normal CNS, Special Senses, Head & Neck Sequence II.  Anatomical planes and major axes of the central nervous system III.  Principal cell types in the CNS IV.  Specialized stains and what they reveal V.  Schematic representation of the functional organization of the CNS VI.  Regional anatomy of the central nervous system VII.  Functional subdivisions, pathways and relevant concepts VIII.  Topographic organization IX.  Blood supply to the CNS X.  The cerebrospinal fluid
  • 5. Why is learning neuroanatomy such a challenge? You will simultaneously learn: 1) regional anatomy (spinal cord, brainstem, etc.) 2. surface (gross) anatomy 3. internal anatomy 4. names and locations of nuclei and tracts and the pathways they form 5. functions of the various pathways in the CNS 6. blood supplyS neuronal cell biology nerve development and regeneration neurotransmitters chemical neuroanatomy Gross Anatomy Histology Pharmacokinetics Source Undetermined Source Undetermined
  • 6. There are three principal planes of section that are used for viewing the brain: horizontal, frontal (or coronal) and sagittal. U.S. Federal Government Source Undetermined frontal section through the cerebral hemispheres
  • 7. •  There are three principal axes along which the internal anatomy of the nervous system is organized: –  rostral-caudal axis –  dorsal ventral axis –  medial-lateral axis •  During its embryonic development the human brain bends (known as a flexure). As a result, the dorsal-ventral plane changes as one moves along the neuraxis, from rostral telencephalon to the caudal spinal cord. •  Several terms are used to indicate the relative positions of structures or tracts in the brain: –  Dorsal - above or superior –  Ventral -below or inferior –  Rostral -toward the front –  Caudal - toward the back –  Medial - toward the midline Source Undetermined –  Lateral - away from the midline –  Ipsilateral - on the same side –  Contralateral - on the opposite side
  • 8. •  There are two fundamental cell types in the CNS: neurons (10X109) and glia (10-50X more numerous than neurons). •  Neurons communicate to each other via specialized junctions known as synapses. •  Neurons are polarized cells that are specialized to receive synapses on dendrites and relay electrical impulses to other neurons via their axons (also called Images of glia fibers) and their synapses. and neurons •  A collection of neuronal cell bodies outside the CNS is called a ganglion. removed •  A collection of neuronal cell bodies within the CNS is called a nucleus. •  A discrete bundle of axons outside the CNS is known as a nerve. •  A discrete bundle of axons within the CNS is known as a tract (lemniscus, fasciculus). (read the handout for more details on tracts) •  Nuclei and tracts that are linked by synapses serve a common function are generally referred to as a pathway.
  • 9. Axons that form a tract: have cell bodies in a common nucleus synapse onto a common target (or set of targets) perform a common function, e.g., somatic sensation, voluntary movement Tracts are often named based on the site of origin and termination of their axons: spinothalamic tract – from the spinal cord to the thalamus corticospinal tract – from the cerebral cortex to the spinal cord The names of tracts often identify their relative location within the CNS white matter: lateral spinothalamic tract – lateral in the spinal cord medial lemniscus – near the midline Tracts can carry information either up or down the neuraxis ascending tract (spinothalamic tract) - sensory function descending tract (corticospinal tract) - motor function Tracts that carry sensory or motor information are generally organized in parallel: pain and temperature vs. fine discrimination
  • 10. The locations and spatial relationships of nuclei and tracts define the internal anatomy of the CNS. The functions subserved by the various nuclei and tracts define the functional anatomy of the CNS.
  • 11. Regions of the brain that contain cell bodies are given the general descriptive term, gray matter. Source Undetermined Source Undetermined Spinal cord cerebral hemispheres white matter gray matter gray matter white matter Regions of the brain that contain axons are given the general descriptive term, white matter.
  • 12. Golgi-stained neurons (cortex) Visualizing neurons and axons in the central nervous system nucleic acid stain (lateral geniculate nucleus [dorsal thalamus]) Source Undetermined myelin-stain (brainstem) Source Undetermined Source Undetermined
  • 13. A schematic representation of the nervous system organization and function •  The nervous system of all animals performs 3 fundamental biological functions: –  Monitor and regulate the internal environment –  Monitor the external environment –  Initiate behaviors based on infor-mation from both the internal and external environments •  You are generally unaware of the majority of the functions performed by your nervous system. glands sensory systems: transduction, transmission, perception motor systems: mentation, transmission, behavior P. Hitchcock
  • 14. Forebrai n REGIONAL ANATOMY OF THE CNS •  The CNS can be divided into 6 parts: 1) spinal cord 2) medulla (meyelencephalon) 3) pons (metencephalon) Diencephalon 4) midbrain (mesencephalon) 5) thalamus (diencephalon) Midbrain 6) cerebral hemispheres Pons Hindbrain (telencephalon) Brainstem •  These terms may be used Cerebellum interchangeably. Medulla Spinal cord: cervical thoracic lumbar sacral Patrick J. Lynch, wikimedia commons
  • 15. These two diagrams model representative pathways of the somaticsensory and motor systems, respectively. J.H. Martin. Neuroanatomy: Text and Atlas.McGraw-Hill, 2003. 3rd Edition. afferent axons - carry information into the CNS efferent axons - carry information out of a structure decussation - site where axons cross the midline
  • 16. Sensory information from the periphery enters the brain in a very systematic manner. This creates a Sensory dermatomes spatial order, which is preserved throughout the sensory pathways. Haines. Fundamental Neuroscience. Churchill Livingstone, 2002. 2nd ed. Source Undetermined
  • 17. Primary ALL Sensory and Motor sensory cortex pathways are topographically organized. Sensory: There is a point-to point relationship between a peripheral sensory Modified from Tristram, wikispaces structure and its pathway in the CNS. Primary motor cortex Motor: Pathways in the CNS are organized according to somatic muscle groups in the periphery. homunculus=little man Modified from Tristram, wikispaces
  • 18. Sensory from information from the neck and below enters the CNS via spinal nerves, whose axons ascend in white matter tracts. Depending on the nature of the sensation, axons may or may not synapse in the spinal cord. J.H. Martin. Neuroanatomy: Text and Atlas.McGraw-Hill, 2003. 3rd Edition.
  • 19. Sensory axons may (or may not) synapse on nuclei in the brainstem. If they do, the name of the tract changes. All axons carrying sensory information synapse in discrete nuclei within the dorsal thalamus. Gray s Anatomy
  • 20. Cerebral cortex is highly specialized. Somatic sensory information carried by axons from the dorsal thalamus synapse on neurons in the postcentral gyrus (primary somatic sensory cortex) in the parietal lobe. Expressive Receptive Source Undetermined
  • 21. The brainstem controls numerous bodily functions. Injuries to the brainstem can be life threatening. The brainstem also receives sensory information from the head and contains the motor neurons that innervate muscles of the neck, head and face. U.S. Federal Government
  • 22. The internal anatomy of the brainstem is complex. J.H. Martin. Neuroanatomy: Text and Atlas. McGraw-Hill, 2003. 3rd Edition. Gray s Anatomy
  • 23. Syringomyelia Brown-Séquard syndrome J.H. Martin. Neuroanatomy: Text and Atlas. McGraw-Hill, 2003. 3rd Edition. Injures to the brainstem and spinal cord give rise to specific sensory and motor deficits. J.H. Martin. Neuroanatomy: Text and Atlas. McGraw-Hill, Injuries to the spinal cord produce sensory 2003. 3rd Edition. deficits that respect myotomal boundaries. Place a lesion = what are the symptoms? Describe the symptoms = can you place the lesion?
  • 24. Axons that carry motor commands for voluntary movements originate in the precentral gyrus (primary motor cortex) of the frontal lobe, descend into the brainstem and spinal cord and synapse on motor neurons that innervate skeletal muscles. Expressive Receptive Source Undetermined
  • 25. An example of a motor pathway. The corticospinal tract extends from the precentral gyrus to the spinal cord and subserves the voluntary control of skeletal muscles. Although clinically important, the corticospinal system is numerically a minor component in the control of skeletal muscles. Haines. Fundamental Neuroscience. Churchill Livingstone, 2002. 2nd ed.
  • 26. The cerebellum is a component of the motor system that is not involved in unconscious control of skeletal muscle. Source Undetermined Diseases of the cerebellum are known as ataxias.
  • 27. Special senses: Vision Hearing Balance The Regents of the University of Michigan
  • 28. The CNS is highly vascularized and interruption in the blood supply is a common form of nervous system injury Source Undetermined
  • 29. The CNS is filled with and surrounded by cerebrospinal fluid (csf). Internally: -lateral ventricles -3rd ventricle -4th ventricle Externally: -subarachnoid space CSF is a secretory product that circulates through the ventricles and returns to the venous side of the brain vasculature Source Undetermined
  • 30. Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicy Slide 5: Sources Undetermined Slide 6: Source Undetermined; U.S. Federal Government, http://en.wikipedia.org/wiki/File:BodyPlanes.jpg Slide 7: Source Undetermined Slide 11: Sources Undetermined Slide 12: Sources Undetermined Slide 13: Peter Hitchcock Slide 14: Patrick J. Lynch, Wikimedia Commons, http://commons.wikimedia.org/wiki/File:Brain_human_sagittal_section.svg, CC:BY http://creativecommons.org/licenses/by/2.5/ Slide 15: Source: J.H. Martin. Neuroanatomy: Text and Atlas.McGraw-Hill, 2003. 3rd Edition. Slide 16: Source Undetermined; Haines. Fundamental Neuroscience. Churchill Livingstone, 2002. 2nd ed. Slide 17: Original sources, tristram, Wikispaces, http://tristram.wikispaces.com/file/view/homunculus.gif, CC:BY:SA http://creativecommons.org/licenses/by/3.0/ Slide 18: J.H. Martin. Neuroanatomy: Text and Atlas.McGraw-Hill, 2003. 3rd Edition. Slide 19: Gray s Anatomy, http://www.bartleby.com/107/ Slide 20: Source Undetermined Slide 21: U.S. Federal Government Slide 22: J.H. Martin. Neuroanatomy: Text and Atlas. McGraw-Hill, 2003. 3rd Edition.; Gray s Anatomy Slide 23: J.H. Martin. Neuroanatomy: Text and Atlas. McGraw-Hill, 2003. 3rd Edition.; J.H. Martin. Neuroanatomy: Text and Atlas. McGraw-Hill, 2003. 3rd Edition. Slide 24: Source Undetermined Slide 25: Haines. Fundamental Neuroscience. Churchill Livingstone, 2002. 2nd ed. Slide 26: Source Undetermined Slide 27: The Regents of the University of Michigan Slide 28: Source Undetermined Slide 29: Source Undetermined