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Chapter 9

Nervous Tissue
or ... understand the biological wiring deep down

"The sum of all nervous tissues of the human body comprise the nervous system, which - among the other 11 body systems and together with the endocrine system - plays the most important role in maintaining the homeostasis of the human body..."

Objectives:

  •   Know the major functions of the nervous system of the human body:
    -  the
    major functions of the nervous system are:
            1. Adjusting body processes by means of nerve impulses (action potentials)
            2. Enables our perceptions, such as visual, oral, olfactory, and auditory
            3. Is responsible for our behaviors, self-awareness, emotions and memory
            4. It enables and initiates all voluntary movements of our body
            5. Regulation of heat conservation, appetite & temperature production
                (Thermoregulation)

  •   Be able to describe the general organization of the nervous system and to list
    the basic structures as well as basic functions of it
        - know that the nervous system is divided into two main subsystems which are:
           
    1. Central nervous system (CNS)
                - consists of
    brain and spinal cord
                - brain is enclosed by skull and contains about 100 billion neurons
                - spinal cord is connected with the superior located brain; 100 million nerves;
                  is enclosed by vertebral column
            
    2. Peripheral nervous system (PNS)
                - includes all
    nervous tissues outside the CNS, which are:
                    - 12 pairs of cranial nerves
                    - 31 pairs of spinal nerves
                    - small masses of nerve tissues called ganglia, sensory skin receptors,
                      enteric plexus of GI tract
        -  know the
    major functions of the nervous system which are:
                1. Sensory functions
                    - sensory receptors and sensory (= afferent) neurons
                2. Integrative functions
                    - participates in integrative functions with the help of inter-connected nerve
                      cells, so-called
    interneurons
                3. Motor functions
                    - relays on responsive and receiving nerve cells, the so-called motor- or
                      efferent neurons, which make contact with their
                      unique target tissues, the so-called effectors, e.g. a skeletal muscle
     
        - have an understanding of the
    organization of the nervous system and that the
          CNS/PNS is further sub-divided into 3 functional sectors;
          the
    subdivisions are:
               
    1. Somatic nervous system (SNS)
                    - conveys information from somatic and sensory receptors in the body to
                      the brain
                    - voluntary branch of the PNS
               
    2. Autonomic nervous system (ANS)
                    - conveys information from autonomic sensory receptors located in visceral
                      organs to to the CNS
                    - motor neurons that conduct nerve impulses from the CNS to smooth
                      muscles, the cardiac muscle and to glands
                        - the motor part of the ANS consists of two divisions:
                            1. the sympathetic division
                            2. the parasympathetic division
                                    - both with usually opposing actions
                    - involuntary branch of the PNS
               
    3. Enteric nervous system (ENS)
                    - the
    "brain of the gut"
                    - involuntary branch of the PNS
                    - extends the entire length of the GI tract

  •   Be able to contrast the histological characteristics and the biological functions
      of neurons and neuroglia
    - know that the
    nervous tissue consists of two types of cells:
            
    1. Neurons
                - information-processing cells
                - conduct action potentials; enable thinking, sensing, neuro-control of
                  muscles and glands
           
    2. Neuroglia
                - support, nourish, and protect the neurons
                - important neuroglial cell types are:
                       
    1. Astrocytes
                            - establish and maintain proper chemical environment around neurons
                            - nourish the neurons and assist in neuronal migration
                            - essential part of the
    "blood-brain barrier"

       
    "Recently, scientists linked a (currently unknown) substance secreted by astrocytes
          as the culprit in the death of motor neurons in some cases of amyotrophic lateral
          sclerosis (
    ALS or Lou-Gehrig's disease); ALS is a (currently) untreatable disease that
          progressively kills off motor neurons ..."
            [Science  316 (5823): 353 (2007)]

                     
      2. Microglia
                            - phagocytotic "immune cell of the CNS"; help to fend off CNS from
                              invaded microbes;
                            - are able to take up and digest bacteria via a process called
                              phagocytosis
                       
    3. Oligodendrocytes
                            - important for formation of supporting network around CNS
                       
    4. Ependymal cells
                            - cell type which lines the ventricles of the brain; form cerebrospinal
                              fluid and assist in its circulation;

    "In the recent years neurobiologists discovered some unique cells in neuronal tissues, such as the olfactory ensheathing glia (OEG) cells; while nervous tissue - once destroyed - cannot renew itself, OEG cells have been reported to be the only nerve cells of the central nervous system (CNS), capable of constant regeneration;
    OEG cells have been recently successfully been used to partially recover the locomoter activity in dogs paralyzed due to traumatic spinal cord injury!"


    - know that
    neurons are made up from three parts:
           
    1. Cell body & Dendrites
                - contains nucleus and organelles; active synthesis of proteins and
                   neurotransmitter there
                - dendrites are receiving nerve signal inputs from other neurons
           
    2. Axon
                - long, elongated cell process which conducts the nerve impulses (= action
                  potentials) to another neuron
           
    3. Synapse
                - site where two neurons or a neuron and its effector cell contact and
                  communicate

  •   Know that neuroglia are smaller than neurons and make up about half of the volume
      of the CNS
    - know the difference between
    myelinated and unmyelinated neurons
        - axons surrounded by a
    myelin sheath are referred to as myelinated;
            - myelin sheaths are basically phospholipid bilayer membranes rich in
              unique lipids called
    sphingolipids;

    "In certain human diseases, such as Multiple Sclerosis (MS) and Tay-Sachs disease,
      one observes a destruction of the myelin sheaths ... "


        - in the PNS, it is the Schwann cells which produce the myelin sheath;
        - in the CNS, the myelin sheath is produced by the oligodendrocytes;
    - know the process and function of myelination of nerve cells; rehearse the role
       of
    Schwann cells in this process
    - understand the function of the
    Node of Ranvier to the propagation of the nerve
       signal along the axon

    "Myelination of axons of neurons confers insulation to the nerve fiber
      and increases the speed of conduction of the action potential running
      along the axons towards the synapses..."


    - know the difference between gray and white matter in the brain and spinal cord
           
    1. White matter
                - nervous tissue consisting of myelinated and unmyelinated axons of many
                  neurons
                - much of the white matter of the CNS consists of tract = bundles of axons
                  running up and down the spinal cord
            
    2. Grey matter
                - nervous tissue containing neuronal cell bodies, dendrites, unmyelinated
                  axons and neuroglia

  •   Be able to describe how a nerve impulse = action potential is generated and conducted
    - know that the generation of a nerve impulse or
    action potential in nerve cells
      (as well as muscle fibers) depends on 2 basic features of the plasma membrane
      of the neuron (or muscle fiber), which are:
           
    1. Existence of a resting membrane potential (Vm)
                - established due to a dys-balance of ions, most importantly Na+, K+,
                  PO42- (phosphate ion), and Cl- , across the plasma membrane
                  which confer charge differences between in- and outside the neuron
                - know that in a resting neuron the outside surface of the plasma membrane
                   has a
    positive (+) charge due to a high concentration of sodium ions in the
                   interstitial fluid
                -  know that the inside of a neuron has a
    negative (-) charge due to the high
                   concentration of negatively charged ions, such as phosphate (e.g. in ATP
                   molecules) and negative charges of proteins
                - know that there is a higher concentration of potassium ions (K+) than sodium
                  (Na+) within a resting neuron, and a higher sodium than potassium ion
                   concentration outside the resting neuron



                - know that
    the resting membrane potential in neurons is about - 70mV
                - know that the membrane permeability is lower for sodium than for potassium
                  and that neurons possess sodium/potassium pumps to maintain the resting
                  membrane potential despite ion leakage
     
           
    2. The presence of ion-specific channels in the plasma membrane
                - know that
    ion channels are very selective regarding their ions they permit to
                  cross the cell membrane
                - know that they - upon opening - allow rapid diffusion of specific ions across
                  the cell membrane following a concentration gradient and cell polarity
                        - i.e. positively charged ions will move towards a negatively charged area
                          within the cell
                - know that there are two types of ion-specific channels:
                        1. Gated or receptor-associated channels
                            - open and allow ion flux after activation by a ligand-activated cell
                              surface receptor
                        2. Voltage-gated channels
                            - open and allow ion flux after changes of the resting membrane potential
                            - are the ones activated and involved in the propagation of an action
                              potential

        - know that an action potential (AP) or impulse is a sequence of rapidly occuring
          events that decrease and reverse the resting membrane potential of a nerve cell for
          the purpose of signal transportation
        - know the individual events that lead to and contribute to the formation of an action
          potential (see
    Figure below);
          the
    action potential-generating events at a neuron are:
                        1. Arriving of an excitatory signal or stimulus at the synapsis of the neuron
                            begins to change the resting membrane potential which is around
    - 70 mV
                                → muscle fibers and neuron show electrical excitability
                        2.  Rapid influx of about 20,000 sodium (Na+) ions into the cell via
                             voltage-gated sodium channels causes 
    "Threshold depolarization"
                        3. Change of the resting membrane potential above the threshold potential
                            which is
    - 55 mV
                        4. Build up of the depolarization phase (cell interior becomes more and
                            more positively charged)
                        5. Delayed opening of voltage-gated potassium (K+) channels in the cell
                            membrane leads to efflux of potassium ions out of the cell
                        6. Membrane potential reaches
    + 30 mV = maximum membrane
                            depolarization
                        7.  Sodium channels are closing and the continuously outflowing potassium
                             ions generate the repolarization phase of the AP
                        8. excess outflow may be large enough to cause the typical hyperpolarization
                            phase
    of the AP; the cell membrane potential becomes more negative
                            than the resting membrane potential
                        9. ATP-activated sodium/potassium exchange pumps located in the cell
                            membrane bring the membrane potential back to the resting level;
                            they pump sodium ions out of the cell and in the same time potassium
                            ions back into the cell
                        10. The neurons remains in the so-called refractory period during which
                              no new AP can be elicited  

     The different phases and events of a typical action potential in a nerve cell


     

    - know how a typical nerve impulse (or action potential) is conducted (or propagated)
      along a nerve axon; the
    nerve impulse-propagating events include:
                1. rise of an action potential (AP) at the axon hillock of a neuron
                2. conduction or propagation of the AP along the axon towards the axon terminal
                        - be able to differentiate between continuous conduction in unmyelinated axons
                          and saltatory (leaping) nerve impulse conduction in neurons with myelinated
                          axons
                        - understand the importance of the
    Nodes of Ranvier in saltatory AP
                           propagation
                        - know that myelinated axons conduct AP faster than unmyelinated axons
                3. release of neurotransmitter-filled vesicles at the axon terminal into the
                    synaptic cleft



    "Neurons communicate with one another by means of generated action
      potentials, also called nerve impulses..."


     

  •   Be able to explain the events of synaptic transmission and know the different
      types of neurotransmitter involved in nerve signal propagation between
     different neurons
    - know that synaptic transmission refers to the neuronal communication and
       events at the synapsis
    - be able to describe the
    major events at the synapsis after arrival of an action
      potential (AP) (see
    Figure below; the synaptic events are:
            1. an action potential (AP) arrives at the synaptic end bulb of a neuron
            2. depolarizing phase of the AP triggers the opening of voltage-gated
                calcium (Ca2+) channels
            3. influx of calcium ions into the synaptic end bulb triggers the release
                (via exocytosis) of the neurotransmitter content of synaptic vesicles into
                the synaptic cleft
            4. the neurotransmitter - after diffusing across the synaptic cleft - binds to its
                corresponding neurotransmitter receptor which is located on the post-
                synaptic neuron's plasma membrane; as a consequence a receptor-activated
                ion channel opens and allows the influx (Na+) or efflux (K+) of ions
            5. depending on which ion flux the activated channel allows, the membrane
                potential of the second neuron will become either depolarized (sodium) or
                hyperpolarized (potassium)
    - know that this mechanisms assures a "one-way direction of information transfer"
       in the nervous system
    - know that post-synaptic depolarization is observed in excitatory neurons
      (positive signal)
    - know that post-synaptic hyperpolarization is observed in inhibitory neuron
      (suppressive signal)
    - know that a neurotransmitter affects the postsynaptic neuron only as long as it is
       bound to its receptor

Figure: Major events of synaptic transmission of a nerve signal


        - understand that the timely removal of a neurotransmitter from the synaptic cleft is
          crucial to assure dynamics, flexible responsiveness and adaptability of the nervous
          system; know that
neurotransmitter removal can happen in 3 ways:

                1. diffusion away from the receptor due to decreasing concentration
                2. degradation by enzymes, e.g.
cholinesterase, located in the synaptic cleft
                3. active re-uptake back into the neuron that released them or uptake by
                    neighboring neuroglial cells

          - known that many modern prescription drugs used to treat neurological
            disorders work as reuptake inhibitors, e.g. fluoxetine ("Prozac"), which acts
            as a
selective serotonin reuptake inhibitor (SSRI)

"A typical neuron in the central nervous system (CNS) receives input from
 1,000 to 10,000 synapses, some inhibitory, some excitatory ..."

  •   Know the names and mode of action of important neurotransmitter (...the signaling
      molecules of the nervous system)
    - biochemists and neurobiologists identified about 100 substances that are either
      known or suspected 
    neurotransmitters of the human body;
      many neurotransmitters are amino acids or derivatives thereof
    - neurotransmitters are synthesized (= produced) by neurons and packed into
      synaptic vesicles by them;
      they are usually released after arrival of a AP at the synaptic end bulb
    - some neurotransmitter are activating by
    depolarizing the post synaptic cell;
      they are
    excitatory
    - some neurotransmitter are inhibiting by
    hyperpolarizing the post synaptic cell;
      they are
    inhibitory
    - the
    Table below lists the names of prominent neurotransmitters, their mode of
      action at the post synaptic cell and names of important drugs interfering with
      their biological function in the CNS

Important neurotransmitters of the human body

Neurotransmitter Mode of action Interfering drugs / effects / disorders
Acetylcholine (ACh) excitatory/inhibitory
- via either muscarinic (m) or nicotinic (n) receptors
Inhibitors
Curare (- AChR) --> at NMJ,
Botox & local anesthetics (-) --> ACh release
Atropin (- AChR) --> parasympaticus
Parasympatomimetics
Muscarin (+ AChR) --> parasympaticus
Nicotine (+ AChR) --> vegetative ganglia &
           NMJ
Carbachol (+) --> ACh mimetic
Pilocarpin (+) --> ACh mimetic
Norepinephrine (Nor)
Adrenaline (Adr)
excitatory
-stimulate the α1, α2, β1 and β2 adrenoceptors;
Isoprotenerol (+)
Propranolol (-) --> beta-receptors (heart)
Phentolamine (-) --> alpha-receptors (blood
vessels)
Glutamate excitatory
(NMDA-Receptor)
 
Aspartate excitatory  
gamma amino butyric acid (GABA) inhibitory Diazepam ("Valium") (+)
Glycine inhibitory  
Dopamin (DA) excitatory Cocaine (+) - inhib. of reuptake
Zyprexa (-) - inhib. of DA receptor binding
Schizophrenia (excess DA)
Chlorpromazine (-)
Endorphins, Enkephalins excitatory Acupuncture (+) - stim. of analgesia
Euphoria - "Runner's high" effect
Serotonin excitatory

Imipramine  (+)
Fluoxetine (+)  
- selective serotonin re-      
                               uptake inhibitors (SSRIs)
Sertraline (+)                        

Nitric oxide (NO) excitatory
(local neurotransmitter)
 


   Medicine & Pathology:   

  •  Make yourself familiar with the meaning of the following conditions, diseases and disorders connected to the function of the nervous system:

                                                                Meaning/Explanation

    Neurology                                         = branch of medical sciences that deals with the
                                                                    normal functioning and disorders of the
                                                                    nervous system                 

    Neural regeneration                        Repair and (limited) re-growth of damaged or
                                                                 injured neurons with the help of mitotic
                                                                 Schwann cells

    Polyneuritis                                      Inflammatory neurodegenerative disorder characterized
                                                                 by the degeneration of myelin sheaths due to a
                                                                chronic lack of vitamin B1 (thiamin);
                                                                affected patients show impaired reflexes


    NGF
                                                        nerve cell growth factor; important hormone of the
                                                                 CNS which is able to trigger cell division & mitosis of neurons


    Local anesthetics
                                  Usually very lipophilic drugs, e.g. Lidocaine and
                                                                 Procaine, that block the opening of voltage- gated
                                                                 sodium channels of neurons; widely used to
                                                                 locally suppress pain, e.g. during dental work or
                                                                 during suturing of a gash 


    SSRI
                                                        = selective serotonin re-uptake inhibitors;
                                                                 molecules, such as fluoxetine (Prozac) or sertaline
                                                                 that selectively block the re-uptake of the excitatory
                                                                 neurotransmitter serotonin from the synaptic gap
    ;
                                                                
    they block the binding of serotonin to the serotonin
                                                                 transporter;
                                                                 commonly administered to patients for treatment of
                                                                 depression and other mood disorders


    Prozac (fluoxetine)                   
           The most commonly used anti-depressant in
                                                                 the U.S.
    ;
                                                                
    a class of SSRIs which targets the transporter protein
                                                                 (5-HTT) of the neurotransmitter serotonin in the brain;
                                                                 in the presence of Prozac, the excitatory neurotransmitter
                                                                 serotonin remains longer in the synaptic gap

Based on recent findings in newborn mice, where Prozac treatment leads to behavioral
disorders and anxiety, the FDA (in October 2004) released a warning whereas serotonin-
and SSRI-based anti-depressants may raise the risk of suicidal behavior in children...

[Science 306(5697): 792 ff (2004)]
 

        Multiple sclerosis (MS)                       A progressive, inflammatory disease of the CNS,
                                                                         which is caused by the entering of white  blood
                                                                         cells into the brain and their subsequent
                                                                         destruction of the axon-surrounding myelin
                                                                         sheaths;
                                                                         more prevalent in females than in males;
                                                                         affects about 2 million people worldwide;
                                                                         the cause is unknown, but there seems to be a
                                                                         connection to previous viral infection of the
                                                                         CNS, e.g. by the herpes virus;  


        Glaucoma
                                               Neurodegenerative disease which is characterized
                                                                          by the damage of the optic nerve and retina;
                                                                          leads to vision loss and eventual blindness of
                                                                          affected human individuals;


        Guillain-Barre Syndrome (GBS)
        A demyelinating disorder of the PNS characterized
                                                                          by the destruction of axonal myelin sheath by
                                                                          macrophages often after previous microbial
                                                                          infection ;
                                                                          leads to sudden paralysis;


        Wallerian axon degeneration
            a neurodegenerative disorder ("Axonopathy"),
                                                                          which is characterized by progressive self-
                                                                          destruction of the axonal protrusions of nerve
                                                                          cells (due to apoptosis);
                                                                          there seems to be a connection with the dysfunctional
                                                                           biosynthesis of the important cell molecule
                                                                           nicotinamide adenine dinucleotide (NAD+);


        DEET
                                                       Popular synthetic insect repellent, which is used by an estimated
                                                                           200 million people worldwide. According to a recent study it is
                                                                           suspected to cause CNS damage the same way as some insecticides and
                                                                           nerve gases, e.g. sarin, do.
Acetylcholinesterase enzyme inhibitor.

DEET & Toxicology
In 2009, scientists of the Institute for Development Research in Montpellier, France discovered that DEET interferes with the normal breakdown of acetylcholine (ACh), the most common neurotransmitter of the CNS.
DEET blocks the ACh degrading enzyme acetylcholinesterase (AChE),  resulting in the toxic build-up of ACh which prevents the transmission of signals across the neuron synapse.

       
        NMDA ("Ecstasy")   
                              Transient euphoria-triggering, illegal "fashion drug", which
                                                                           strongly affects the serotonin system of the CNS;
                                                                           leads to serotonin increase in the synaptic gaps due to interfering
                                                                           with the serotonin transporter/ 5-HTT uptake system;

       
Ecstasy & Toxicology
        Animal studies strongly suggest that NMDA inflicts lasting damage to the brain's serotonin system.
        According to an UK long-term effect study, people who took ecstasy performed worse on mental
        performance tests, e.g. memory, attention, planning, showed deficiencies in verbal and working
        memory tests
, showed signs of depression and a weakened immune system.

        Gliomas
                                                    Aggressive brain tumors derived from dys-
                                                                           regulated and uncontrolled dividing glial cells;


        Tinnitus
                                                    Chronic ear ringing and "phantom noice"
                                                                            perception due to traumatic destruction of
                                                                            nerve cell endings in the auditory system
                                                                            (trochlear damage)

        Trichothecene                                          Neurotoxic molecule produced by the quite
                                                                            common "indoor fungus" (air-cons) Stachybotrys
                                                                            chartarium
;
                                                                            made responsible for cases of memory loss,
                                                                            depression and pulmonary problems reported
                                                                            in some humans after prolonged exposure
                                                                            to the fungus;
                                                                            often measurable in damp and badly aerated homes;

       
Muscarin                                                   toxic compound of the mushroom Amanita muscaria;
                                                                            stimulates the parasympathetic division of the ANS,
                                                                            especially of the Vagus nerve;
                                                                            poisoning symptoms include:
                                                                                - increased saliva secretion
                                                                                - excessive sweating, diarrhea, vomiting,
                                                                                   miosis and cardiovascular collapse;

       
Nicotine                                                    alkaloid of the tobacco plant Nicotiana tabacum;
                                                                            binds to the post-ganglial n-ACh receptors and
                                                                            leads to ACh-like depolarization with subsequent
                                                                            ganglia are either stimulated (short-term) or
                                                                            blocked in their transmission of action potentials;
                                                                            nicotine symptoms include:
                                                                               - bradycardia with blood pressure decrease
                                                                               - later one observes blood pressure increase
                                                                               - increase in intestinal muscle tone
                                                                            nicotine is toxic; the lethal dose for humans is:
                                                                                1 mg / kg body weight
                                                                                - a cigarette (1g) contains about 10 mg of nicotine
                                                                                - a cigar about 90 mg of nicotine;                                       

        Lead poisoning
                                        The chemical element and heavy metal lead (Pb) is a
                                                                             potent and dangerous
neuro-toxin;
                                                                             lead - often irreversibly - affects the brain, kidneys and
                                                                             the nervous system;
                                                                             studies have linked lead poisoning to low IQs, severe
                                                                             learning disabilities, behavioral/criminal problems and even
                                                                             death (especially in children);
                                                                             until banning its use in household paint ("lead paint") and
                                                                             gasoline in the 1960s, very high blood lead concentrations
                                                                             were observed especially in children far into the 1970s when
                                                                              blood lead levels began to drop;
                                                                              the maximum safe level for lead in children is 10ug/dl;
                                                                                - children whose blood tests show lead levels > than
                                                                                   10ug/dl are considered at risk for lead poisoning;
                                                                                - in 2003, one in four U.S. children had blood lead
                                                                                  levels 5ug/dl or higher;
                                                                                             Percentage of children with elevated
                                                                                             lead levels (numbers for 2005)
                                                                                                - San Diego            0.2%
                                                                                                - Los Angeles        8.13%
                                                                                                - New York            8.50%
                                                                                                - Phoenix                0.98%
                                                                                                - Detroit                  6.00%
                                                                                Treatment/Therapy:
                                                                                - oral chelation therapy
                                                                                    - chemical binds the lead in the blood;

   
"Even though lead has been removed and banned from U.S. products, e.g. gasoline and paint,
      since the 1980s, and fewer children are suffering from lead poisoning, lead still harms
      an estimated 300,000 children in the U.S. alone. In 2006, officials found 1,414 cases of too
      high lead levels in humans living in Milwaukee; most of the still existing cases of exceedingly
      high lead levels are found in humans living in lead paint-containing homes (window paint)
      build before 1950; in 2007, several cases of excessively high amounts of lead found in toys for
      children which were imported into the U.S. from China, stirred up a new debate about the
      safety of consumer products from lead/heavy metal contamination ..."