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Lecture

HMB200 2014 Lecture 26.pdf
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Department
Human Biology
Course
HMB200H1
Professor
John Yeomans
Semester
Winter

Description
  Lecture  26:  Genes  and  Long-­‐Term  Memory   HPC  Pathways   - Hippocampus  important  for:  human  memories,  animal  memory  (spatial),  trace  conditioning,  temporal  and  spatial   relationships  (time  and  space  put  together  in  hippocampus  memories)   - Plastic:  neurons  in  hippocampus  change  greatly     - Lots  of  NMDA  receptors  –  important  for  letting  calcium  get  in   - Glutamate  inputs  through  NMDA  receptors   –  lead  to  calcium  kinases,  short  term  forms  of  plasticity  (early   LTP),  long  term  plasticity  (memories  that  last  days  to  weeks)     - sensory:  entorhinal  cortex  receives  olfactory,  spatial  an d  temporal  inputs   - Entorhinal  cortex  goes  to  all  areas  in  the  hippocampus  (especially  medial  and  lateral  entorhinal  cortex)   - Motivational:  5HT,  ACh,  DA,  NE   - Serotonin  inputs  (from  entire  cortex),  cholinergic  (from  septum,  hippo),  dopamine,  norepinephrine   - Influence  the  state  of  hippo–  are  you  ready?   - Specific  information  about  time,  space,  smell   - And  general  info.   - Internal  sorting  by  GABA  neurons  of  10  types:  parvalbumin,  CCK,  somatostatin,  calbindin…also  in  cortex   - Glutamate  is  the  main  output   - Glutamate  output  is  from  big  pyramidal  cells  of  CA1   - Pattern  separation  in  HPC   - Outputs:  subiculum,  amygdala,  frontal  cortex…   - Amygdala  is  closely  connection  system  for  emotional  memories  rather  than  ideation  or  cognitive   memories   - Frontal  cortex  important  for  executive  planning  and  depression  (where  depression  signals  communicate)   - Long  term  plans  link  to  episodic  memories  in  frontal  cortex     Sensory  Input  From  Visual  Cortex   - Sensory  input  from  visual  cortex  is  relayed  by  several  steps:  V1   à  V2  à  infrotemporal  à  entorhinal  cortex   - Visual  information  provides  great  deal  of  info  from  outside  world   - Gets  segregated  into  color  information,  spatial   information  à  into  movement,  objects,  etc.   - All  these  segregations  occur  in  the  visual  cortex   - Sorting  of  information  occurs  in  the  entorhinal  c ortex  (visual,   auditory,  olfactory  information)   à  come  together  to  influence   the  hippocampus   - These  inputs  are  multimodal   à  very  complex   - Most  come  from  entorhinal  cortex   - Create  all  the  spatial  and  temporal  relationships   - Discovery  of  grid  cells à  from  entorhinal  cortex   • Orientation  of  space  occurs  before  the  hippocampus   in  the   entorhinal  cortex  grid  cell  regions  of  the  medial  entorhinal  cortex   - Also  temporal  inputs  from  many  spatial  areas  (Ex.  Hearing,  touching)   - Motivational  input :  influence  entire  hippocampus  (as  opposed  to  a  single  slice)   –  they  are  motivational   monoamine  influence   à  influence  the  state  of  the  hippocampus  (not  information  nor  memories   à  motivational   influences  that  affect  the  whole  tone  of  the  entire  hippocampus)   - Serotonin  inputs  (go  to  entire   cortex)   - Cholinergic  inputs  (from  septum  and  basal  forebrain)   - Dopamine,  norepinephrine   - Excitatory  glutamate  output  is  coming  from  the  big  pyramidal  cells  of  CA1   - GABA  neurons  (10  types)  are  also  expressed  in  cortex   - All  the  different  types  of  GABA  neurons  are  separately  expressed  in  different  areas   - what  is  the  cortical  code  that  allows  sorting  of  circuits?   - Neatly  organized  in  hippocampus   - Badly  organized  in  neocortex   - Within  this  area,  there  are  3  steps  (3  glutamate  neurons)   - Trisynaptic  glutamate  excitatory  path way   - Lots  of  neurons  in  the  dentate  gyrus  (increasing  and  decrease  by  neurogenesis)   - Suggests  some  sort  of  separation       - When  you  do  a  lot  of  detail  separation,  dentate  gyrus  takes  over     Outputs   - Most  of  the  outputs  (CA1)  go  out  by  way  of  the  subiculum   - All  parts  of  the  hippocampus  has  subiculum  outputs  –  going  everywhere  –  no  clear  reason  how  subiculum   is  mapped   - Some  areas  of  the  entorhinal  cortex  and  hippocampus  that  go  to  amygdala   à  areas  that  are  important  in  fear   conditioning   - Rapid  emotional  learning   - Amygdala  is  a  closely  connected  system  for  emotional  memories   - Frontal  cortex  outputs  are  important  for  executive  planning  (where  depression  signals  communicate  with   hippocampus)   - Where  long  term  plans  are  linked  to  episodic  memories  in  the  fronta   cortex - Important  for  cognitive  evaluation  of  memories     Gene  Control   • Genetic  molecules  help  us  find  single  molecules  that  control  higher  memory  behaviour   • Knockdown  of  RNA:  Antisense  oligos  (DNA),  siRNAs  to  inhibit  mRNA  in  vivo.   – Completely  remove  a  gene  from  embryonic  stem   cells   – Change  the  gene,  put  it  back  in,  make  a  knock  out  mouse   – Can  add  genes  and  make  a  transgenic  mouse  (extra  copies  of  the  gene)   • Slow  down  molecule  by  binding  messenger  RNA   – Slows  down  production  of  protein   – Antisense  (a  complementary  DNA)  oligos  –  stops  the  message  à  a  complementary  DNA  added  can  stop   the  message   – Silencing  RNA  -­‐  controls  gene  production  =  slow  down  gene  production  and  slows  down  behavior  (go  to   anywhere  in  the  brain)   • Knockout  of  Gene:  Remove  gene  permanently  from  genome.  (e .g.  remove  CaMKII  to  block  memory  –  reduce  early   LTP)   – Can  be  used  to  study  memory   – Add  CaMKII  to  improve  memory   – Removal  of  CaMKII  blocks  memory   • Transgenic:  Add  extra  copies  of  gene  permanently.  Memory  improvement  with  stimulants,  or  added  AMPA  or   NMDA  receptors  (Doogie).   – Improve  memories  by  adding  AMPA  receptors     – Increase  NMDA  receptors  =  improve  memories   – Improve  memories  with  caffeine  and  amphetamine   – Allows  glutamate  activation  to  occur  more  widely   – Description  of  NMDA  transgenic  mouse:  more  NMDA  receptors   –  remembers  things  better   • Inducible:  Add  promoter  so  that  you  can  turn  the  gene  on  or  off  at  will  (tetracycline —Tet).   – Tetracycline:  antibiotic   • Can  turn  on  a  promoter  (tetON)  -­‐  turns  specific  genes  on   – Drink  antibiotic  –  gets  into  brain  –  acts  on  gene  –  acts  on  promoter  -­‐  turns  gene  on   – Tet-­‐on  =  more  active   • Gene  Transfection:  Add  or  subtract  gene  (by  virus,  or  electroporation).   – Control  of  specific  neurons  or  neuron  type   – Take  a  virus  (gene  carrier   –  infects  cells  and  injects  its  own  DNA)   – Modify  their  genes   à  Inject  a  new  gene  to  block  or  add  a  gene  (by  adding  new  DNA)  –  can  turn  local   neurons  on   – All  neurons  infected  will  then  add  the  gene  that  you  want  to  add)   • Optogenetics  or  DREDDs:  use  that  gene  to  turn  neurons  on  or   off  (with  light  or  CNO)   – Basically  a  virus  injecting  light  sensitive  molecule   (opsin)  into  neuron  à  when  virus  injects  these   opsin,  you  can  then  turn  on  the  cell  by  flashing  light   on  it   – Millisecond  control   – Optogenetics:  putting  gene  in   – get  it  into  a  single  type  of  neuron:  Cre -­‐line       • mice  that  express  the  gene  only  in  particular  types  of  neuron  (Genetically  defined  neuron)   – Controlling  a  neuron  at  specific  sites  and  specific  time  control  (light  flash)     NMDA  Transgenic  Mouse  Shows  Better  object  Recognition  Memory   - Memory  uses  some  of  the  same  pathw ays  and  signals  important  in  hippocampus  and  LTP   - Internal  plasticity  mechanisms  are  important  for  rodent  behavior   - Genetic  tools  help  us  find  single  molecules  that  control  higher  behavior     Long-­‐term  Memories  and  CREB  (CREB:  signal  that  turns  on  genome  –  turns  on  gene  transcription)   • Block  of  LTM  and  late-­‐phase  LTP  by  CREB  inhibition.  STM  and  early -­‐phase  LTP  unaffected.   – CREB:  critical  for  memories   – Can
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