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HMB200 2014 Lecture 2.pdf

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Human Biology
John Yeomans

  th Lecture  2:  20  Century  Neuroscience     -­‐ stimulation  of  nerves  and  muscles  by  Galvani  and  Volta  shows  that  these  were  excitable  cells  à  electricity  is   important   à  Helmholtz  and  Dubois:  this  was  not  only  necessary,  but  this  also  lead  to  the  axon  action  potential  cond uction   velocity  in  the  whole  nerve   à  stimulated  whole  nerves  and  produced  twitches  in  muscles   à  spinal  cord  and  brain  also  have  electrically  excitable  tissue   à  brain  was  thought  of  as  an  electrical  organ   involving  stimulation  of  nerves  and  cerebrum,  cerebe llum,  etc.   à  in  each  of  these  systems,  you  can  measure  the  time  it  takes  to  get  a  response  (latency   –  how  Helmholtz   measured  the  conduction  velocity   à  stimulated  nerves  in  2  different  places  and  showed  that  there  was  a   difference  à  calculated  velocity  from  different  response  times/latencies)     20  Century  Neuroscience:  Synapses  and  Neurons   -­‐ People  began  stimulating  circuits   à  what  is  inside  the  CNS  and  whole  nerves  that  produce  these  responses   -­‐ Sherrington,  Cajal  and  Pavlov:  From  Reflexes  to  Synapses,  from  Ci rcuits  to  Learning  (1880-­‐1920)   -­‐ From  Electrical  to  molecular  models  (ions,  transmitters,  proteins)   -­‐ Genes  and  Cognition     Sherrington  (1870-­‐1930)   -­‐ concept  of  “synapse”  as  functional  connection  between    spinal  neurons   • First,  Sherrington  proposed  that  there  is   something  else  happening  inside  the  spinal  cord   à  stimulated  the  nerves  and  showed  that  they  had  different  latencies   à  delays  of  different  times   occurring  inside  the  CNS  (in  the  grey  matter  of  spinal  cord)   à  always  a  delay  of  at  least  ½  millisecond  =   synaptic  delay   1) there  were  synaptic  delay  inside  the  CNS   2) and  inhibitory  effects  -­‐  stimulating  some  nerves  leads  to  excitation,  stimulating  others  lead  to  inhibition   à  there  are  excitatory  and  inhibitory  processes  inside  the  spinal  cord   à  proposed  there  must  be  a   functional  change  due  to  the  connections   happening  between  spinal  inputs  from  dorsal   root,  and  spinal  outputs  from  the  ventral  root   -­‐ mapped  spinal  reflexes,  monosynaptic,  disynaptic,  and   multisynaptic   Ø mapped  these  spinal  reflexes   à  showed  some  of   them  are  fast  and  reliable  (monosynaptic,  single   synapse),  others  have  a  longer  delay  and  involve  2   transformations  (disynaptic  or  multisynaptic)   -­‐ synapses  are  excitatory  or  inhibitory,  and  have  a  delay  of   ~1ms   -­‐ integrative  actions  of  spinal  cord  near  synapses     Ø Spinal  cord  integrates  all  of  these  inputs   à   integrate  actions  occurs  inside  connections  in  the   spinal  cord     Ramon  y  Cajal  (1880-­‐1930)   -­‐ improved  Golgi’s  method  to  see  neurons   -­‐ Golgi’s  method:  used  silver,  and  by  putting  silver  into  the   tissue,  some  of  it  was  concentrated  inside  single  neurons   à  got  pictures  of  clumps  that  look  like  real  neurons   à  hard  to  see  and  separate  à  neurons  are  all  overlapping   à  only  1-­‐2%  of  neurons  take  up  the  silver  (can  see   separate  neurons  using  Golgi’s  silver  method)   -­‐ Cajal  worked  on  this  method  and  improved  it   à  could  distinguish  neurons  anywhere  in  the  brain,  and   show  not  only  neurons  that  are  activated,  and  also  the   synaptic  boutons  that  made  contact  with  these     à  proposed  he  could  follow  axons  and  where  they   terminate,  and  how  those  boutons  made  contact  with  the  cell       -­‐ identification  of  synaptic  structures  at  “boutons”,  i.e.  axon  terminals   • boutons:  enlargement  where  the  vesicles  are   -­‐  output  cells  of  the   -­‐ proposed  “neuron  doctrine”,  that  all  brain  information  is  carried   cerebellar  cortex   in  separate  cells   • All  brain  information  is  carried  in  neurons  by  way  of   -­‐  axons  going  down  to   separate  cells  that   the  deep  cerebellar   make  connections  through  synapses   nuclei   -­‐ Cajal  drew  complete  circuit  diagra ms  of  neuronal  machinery  on   -­‐  boutons:  clusters  of   the  cerebellum  à   proposed  functional  circuit  diagrams  in  many  brain  areas,  e.g.   axon  terminals   retina,  cerebellum,   spinal  cord,  hippocampus,  and  cortex   –  based  on  anatomy  alone   -­‐ Axon  terminals  are  made  on  the  cell  bodies  by   basket  cells  –  forming  a  basket  around  the  purkinjie  cell  bodies   -­‐ Also  noticed  the  same  axonal  connections  made  in  spinal  cord  are  also  made  in  all  brain  areas   à  proposed  that  Sherrington’s  concept  of  a  functional  connection  (synapse  in  spinal  cord)  was  an  anatomical   structure  that  can  be  visualized  using  Golgi’s  method   à  using  Sherrington’s  concept  of  synaptic  connections,  he  drew   wiring  diagrams,  synaptic  circuitry  in  all  brain  area     à  using  this  idea,  Cajal  proposed  that  in  all  brain  areas,   you  could  find  the  axonal  connections  coming  in,  the  context   made  with  cells,  and  all  the  internal  and  output  circuitry  o f  every   brain  structure   § In  the  Olfactory  Bulb  and  Retina  circuits,  Cajal  pla ced  arrows  à   you  can  follow  the  direction  going  from  the  cell  body  to  the  axon   to  the  axon  terminals   à  by  looking  at  the  tissues,  he  would  decide  where  things  were   going  and  where  they  ended  and  made  synaptic  connections   § Cajal  also  looked  at  the  Cerebral  C ortex:  arrows  going  in  and   arrows  going  out  from  parietal  cells  from  the  deep  layer  of  the   cerebral  cortex   § Cajal  suggested  that  anatomy  can  tell  the  circuits  of  the  brain   1) Cajal  improved  on  Golgi’s  method   2) Identified  the  synaptic  structures  at  the  axon   terminals,  which  he  called  “boutons”  –  because  there’s  an   enlargement  where  the  vesicles  are   3) Proposed  that  all  conduction  of  information  in  the  brain  and  the  integration  of  information  in  the  brain  occurs  by   the  way  of  neurons,  not  glia  à  proposed  all  brain  information  is  carried  in  the  neurons  by  way  of  separate  cells   that  make  connects  via  synapses  à  called  the  Neuron  Doctrine     4) Proposed  you  can  make  functional  circuit  diagrams  in  each  of  these  brain  areas   à  allows  him  to  say  Sherrington’s   synapses  in  the  spinal  cord  could  be  visualized  and  this  principle  synaptic  connection  could  be  found  in  all  brain   area   Ø Did  all  of  this  with  just  a  microscope       Pavlov  (1880-­‐1930)   -­‐ studied  visceral  secretions  and  reflexes   • Sherrington  studied  somatic  muscles  and  nerves   • Pavlov  studies  visceral  reflexes   -­‐ shows  that  reflexes  can  become  conditioned  to  neutral  stimuli   • Showed  that  gastric  secretions  and  salivary   secretions  were  produced  by  particular  nerves  and  pathways  in   brain  stem  and  spinal  cord   • These  reflexes  can  be  conditione d  by  neutral  stimuli   Bell  before  giving  food  to  dog   Bell  can  produce  the  secretion  –  even  when  he  walked  in,  secretion  would  occur  as  well  as  the  dog   was  anticipating  the  food   Pairing  of  stimuli  produces  better  conditioning   Removal  of  stimuli  lead  to  extin ction   -­‐ Studied  laws  of  psychological  and  classical   conditioning,  e.g.  pairing,  extinction,  recovery,  discrimination   à   Pavolovian  Conditioning   -­‐ proposed  that  all  higher  learning  could  be  explained  by  changing  neural  circuits  in  cerebral  cortex   • All  higher  learning  can  be  explained  by  circuits  between  visceral  pathways  and   (ex.  auditory  pathways  that   bring  in  the  bell)   • Higher  learning  was  the  result  of  changing  neural  circuits  (perhaps  synapses  inside  the  cerebral  cortex)   à   probably  isn’t  completely  true       • Cajals  circuits  can  explain  higher  human  thoughts   -­‐ conclusion:  neuroscience  results  from  union  of  Anatomy,  Physiology  (by  stimulation),  Neurology,  and  Brain  Injury   (to  see  how  higher  human  disorders  can  result  from  different   brain  areas)  à  led  to  the  idea  that  brain  science   should  be  an  integrated  science  between  all  these  subdisciplines       From  Nerves  to  Neurons   -­‐ wasn’t  sufficient  to  stimulate  the  whole  brain  nor  the  whole  nerve   • Every  nerve  had  hundreds  of  axons  within  that  nerve   • Based  on  neuron  doctrine,  was  action  potentials  made   up  of  many  action  potentials ?   -­‐ Compound  Action  Potential  in  Nerve  ( Lucas,   Erlanger/Gasser  1920)  –  Many  peaks  resolved  with   oscilloscope   à  in  the  1920s,  the  oscilloscope  was  first  applied  to  nervous   system  by  Erlanger/Gasser,  using  Lucas’  method,  they  were   about  to  show  that  the  action  potential  that  was   recorded/stimulated  within  the  whole  nerve,  was  actually   made  up  of  100s  of  action  potentials   à  low  resolution  oscilloscopes  can  only  see  one  big   response   à  if  recorded  with  a  high  resolution  oscilloscope,  you  can   see  that  there  are  subresponses  (little  peaks)   è  compound   action  potential     § Several  subpeaks  (alpha,  beta ,  delta  b  and  c)   § Myelinated  axons:  alpha,  beta,  gamma,  delta   § Unmyelinated  axons:  C  fibers  (most  numerous)   § Oscilloscopes  showed  action  potentials  were  made  of  several  action  potentials  joined  together   à  to  proved  this,  Kato  and  Young  began  to  isolate  single  axons   -­‐ Single  axon  action  potential  ( Kato,  Young  1920s,  1930s)   § Young  -­‐  giant  squid  axons   § Kato  –  cutting  out  subaxons  until  he  isolated  down  to  one  axon  in  the  entire  nerve   § Showed  properties  of  a  single  axon  was  different   à  had  a  simple  form  (squid  action  potential)   à  compound   action  potentials  loses  this  detail   § Only  in  a  single  axon   action  potential  can  you  see  how  the  neuron  works  at  the  single  cell  level   -­‐ Ionic  mechanisms  (Hodgkin/Huxley  1950s)  Na+  and  K+  currents.  “Channels”?   § Showed  action  potential  was  due  to  the  flow  of  2  ions  (Na+  for  positive  part  of  the  potential,  and  K+  for   negative  part)   § Na+  and  K+  ion  currents  could  explain  the  entire  complicated  form  of  the  single  axon  action  potential     § This  study  required  the  Neuron  doctrine,  the  single  axon,  and  then  squid  giant  axon  to  be  able  to  study  how   single  ions  control  flow  of  action  potential   § The  way  these  Na+  and  K+  ions  flow,  is  by  some  special  pore   à  a  channel   à  must  be  a  hole  in  the  membrane  that  allows  ions  to  be  moving   è  channels  that  are  voltage  gated  (ex.   Voltage  gated  Na+  channels  must  be  a  special  mechanism  that  allows  io ns  to  move  è  later  discovered  to  be   a  single  protein)   -­‐ Synapses  and  Ca2+  (Katz  1950s)   § Calcium  is  key  ion  that  controls  release  of  transmitter  and  twitch  of  muscle   à  calcium  is  important  for  synapses  and  muscle  action   § Sodium  and  K  is  important  for  action  pot ential   -­‐ Single  Neurons  in  Brain  (sensory  cortex)   –  (Mountcastle,  Hubel/Wiesel )  1950-­‐90   § Katz’s  discovery  led  to  idea  that  neurons  that  look  similar  inside  the  brain  could  also  work  by  similar   principles   § Tried  to  isolate  single  neurons  in  the  brain,  first  by   recording  them  in  the  sensory  cortex   § Showed  that  single  neurons  have  different  properties  than  the  entire  visual  cortex   à  showed  the  special   properties  that  each  neuron  has  in  putting  visual  and  somatosensory  information     Chemical  Synapses   -­‐ the  study  of  single  chemical  synapses  led  to  discovery  that  there  are  transmitter  chemicals   -­‐ PNS:  Loewi  (ACh  in  the  heart)  Dale  (NE  and  ACh  in  many  organs)  –  1920-­‐1940       • First  transmitter  isolated  were  in  PNS     • Loewi  showed  that  ACh  was  the  molecule  released  by  the  vagus  nerve  that  inhibits  the  heart   • Dale  showed  that  Noepinephrine  and  ACh  are  transmitters  in  many  peripheral  organs   à  also  showered  there  are  different  receptors:  muscarinic  nicotinic  receptors  for  ACh,  a nd  different  types  of   epinephrine  and  norepinephrine  in  the  heart   -­‐ CNS:  Eccles  (ACh  in  spinal  cord)  –  1940-­‐1960   • 1940s:  Eccles  showed  that  ACh  is  also  a  transmitter  in  the  CNS  spinal  cord  à  led  to  discovery  of  where  these   transmitters  are  found  throughout  the  brain   -­‐ Brain  amines  (Hillarp/Carlsson  –  1960-­‐1980)  à  NE,  dopamine,  and  serotonin   • 1960s:  a  whole  family  of  transmitters  (catecholamine’s,  dopamine,  serotonin,  etc)  discovered  by  Hillarp  and   Carlsson   • discovered  that  epinephrine  and  norepinephrine  are  transm itters  in  the  brain   • dopamine  and  serotonin  are   Endolamines  that  work  as  brain  transmitters   à  behavioural  affects  (ex.  Loss  of   dopamine  neurons  in  Parkinson’s  disease,  importance  of  dopamine  receptors  for  schizophrenia  and  drug   abuse)   -­‐ Peptides  (1980s).  Endogenous  opiates   • Peptides  can  be  transmitters  (1980s)   à  endogenous  opiates
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