Design additional experiments to determine its mechanism of action.

Instructions  for  Fundamentals  of  Neuroscience  assignment     This  exam  is  intended  to  determine  how  well  you  have  grasped  the  concepts  presented  in  class   and   supplemented   by   your   readings.   You   can   use   your   notes,   textbooks,   journals,   and   your   handouts  to  help  you  answer  these  questions.  Any  resource  except  each  other!     All  questions  are  in  essay  format,  and  are  intended  to  make  you  think  and  integrate  the  material   presented  to  you.   In  general,  answers  should  be  approximately  2  pages  in  length,  but  remember,  quantity  is  not   necessarily  equivalent  to  quality!    You  are  welcome,  if  appropriate  and  utile,  to  include  figures,   drawings,  diagrams  etc,  but  be  wise!  And  all  material   from  published  sources  should  be  cited   appropriately.         Please  answer  ALL  of  these  questions:       Question  1  –       Question  2  –       Question  3  –       Question  4  –       Question  5  –       Question  6  –       Question  7  –

NAME:                         Question  1       1)  Describe  three  ways  that  the  synthetic  activity  of  tyrosine  hydroxylase  can  be  increased,  and   discuss  differences   in  the  mechanism  and  the  time  frame  over  which  each  of  these  processes   works.       2)  Describe  how  each  of  these  processes  links  changes  in  catecholamine  neurotransmission  to:                                  a)  changes  in  neuronal  activity  of  catecholamine  neurons,  and                                  b)  changes  in  the  internal  (body)  or  external  (world)  environment       3)  Discuss  the  modulatory  effects  of  catecholamines  on  their  target  circuits,  and  how  each  of  the   TH-­‐regulatory  processes  might  produce  different  functional  changes  in  these  modulatory  effects.

NAME:                         Question  2           It   is  well-­‐known   that  a  key  mechanism  by  which  drugs   increase   locomotor  activity   (i.e.   cause   hyperactivity)   is  by   increasing  extracellular  dopamine.     In  preclinical   tests,   investigators   found   that  a  novel  compound  (called  “hyper”)  increased  locomotor  activity  in  mice.    The  investigators   wanted  to  know  the  mechanism  by  which  “hyper”  produced  this  behavioral  effect  and  asked  the   question,  “Is  the  increased  locomotor  activity  induced  by  “hyper”  due  to  an  action  of  the  novel   compound  to  increase  extracellular  dopamine  by  inhibiting  dopamine  uptake  via  the  dopamine   transporter  in  vivo?”    Based  on  material  covered  in  the  “Neurotransmitter  Transporter”  lectures,   and  your  supplemental  readings,  design  experiments  to  answer  their  question.     Hint:    Design  your  answer  as  if  you  were  writing  a  short  research  proposal  (therefore  your  answer   should   be   longer   than   a   few  pages).     Your   research   proposal   should   have   the   following   sub-­‐ sections:   1.  Background  and  rationale  for  the  proposed  experiments   2.  Hypothesis  to  be  tested   3.  Experiments  to  be  carried  out   4.  Expected  results   5.  Alternative  outcomes  if  you  do  obtain  the  expected  results   6.  Literature  cited     Note:    Providing  definitions  of  the  techniques  you  would  use  is  NOT  a  sufficient  answer.    Use  your   training   in   neuroscience   and   pharmacology   to   provide   an   answer   that   demonstrates   critical   thinking  and  appropriate  experimental  design.

NAME:                         Question  3           You  have  created  a  transgenic  mouse  which  expresses  an  inhibitory  Gi-­‐coupled  DREADD  from  the   GFAP  promoter.  Long-­‐term  administration  of  CNO  from  P0-­‐P21  during  brain  development  leads   to   the  reduction   in   the  density  of  excitatory  synpases   in  CA1  of   the  hippocampus.  Given  that   astrocytes  are  known  to  secrete  many  proteins  which  regulate  synapse  formation,  you  suspect   that  there  is  an  activity-­‐dependent  protein  that  is  secreted  by  astrocytes  that  increases  synapse   density.

1)   Design   an   experiment   to   prove   that   an   astrocyte-­‐secreted   factor   is   involved   in   the   phenotype  of  the  GFAP-­‐inhibitory  DREADD  mouse.

2)   Assuming  that  you  have  proven  that  a  secreted  factor  is  responsible,  design  experiments   to  identify  this  secreted  factor.

 

NAME:                         Question  4           In  the  CNS,  myelin  is  produced  by  oligodendrocytes.  Recently,  we  found  that  the  brain-­‐derived   neurotrophic  factor  (BDNF)  is  important  for  oligodendrocyte  development.  Propose  a  research   project  to  investigate  the  role  of  one  of  BDNF  in  neuron-­‐oligodendroglia  interaction,  myelination,   and  neural  circuit  development  in  the  CNS.  Design  a  research  project  including  the  rationale  (or   hypothesis),  the  experimental  approaches  (methods  and  techniques),  the  expected  results,  and   the  possible  explanation  (their  roles  in  the  brain).

NAME:                         Question  5         You  have  found  a  novel  therapeutic  compound  and  are  concerned  that   it  may  have  off-­‐target   effects   in   the   hippocampus.   Provide   three   distinct   approaches   (i.e.   behavioral   and   non-­‐ behavioral)   you  would   use   to   evaluate   these   potentially   deleterious   effects.   Please   include   a   detailed  rationale,  experimental  design,  and  potential  conclusions  for  each.

NAME:                         Question  6

You  have   isolated   a   substance   from   fire   ants   that   produces   a   profound  mechanical   allodynia   when  injected  into  mice.    The  initial  pharmacology  studies  demonstrate  the  following  properties:

 

1.   Design  a  series  of  experiments  to  determine  the  site  of  action  of  this  substance:

2.   Design  additional  experiments  to  determine  its  mechanism  of  action.

 

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