PSYC318-Lecture#5

1. Pavlovian Conditioned Approach: Goal Tracking vs. Sign Tracking
   1. goal-tracking

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      •   Upon seeing the lever, some animals immediately run over to the food port. This is called goal-tracking, b/c the animal is fixated on the goal, the food  
   2. sign tracking

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      •   Upon seeing the lever, some animals immediately run over to the lever. This is called sign tracking, because the animal is fixated on the reward-predictive cues, the lever.   

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• In Parkinson’s patients this is called paradoxical movement. I.e. Parkinson’s patients will perfectly catch a ball that is thrown int heir face, but their movements just cant be consciously initiated, but they do have the ability to move

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• Tyrosine hydroxylase, which is needed to make L-dopa  tyrosine-> {tyrosine hydroxylase} ->  L-dopa > {aromatic L-amino acid Decarboxylase} —>  dopamine  

1. dopamine neurone develop isn't hindered

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   • Preventing dopamine neurones from making dopamine, doesn’t greatly influence how dopamine neurones develop and survive
   1. LDopa Injections

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      •  When L-dopa is given to the mice (stomach injection), it is taken up by dopamine neurones and converted into dopamine just normally. Then these neurones start to release dopamine as they would normally.
      1. Movement is restored

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         •  Movement and motivation is then largely restored for a few hours. Their movements are awkward, hyperactive. In the three hours they move, they eat a day’s worth of food.

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•  They removed the TH gene (ability to make dopamine) from all neurones, that express the dopamine transporter gene, which is most but not all dopamine neurones. It appears that 5% of normal dopamine provides enough system gain to enable movement and motivation. These mice are slow but can preform simple actions

1. crossing two different kinds of transgenic mice
   1. 1st type of transgenic mouse A:

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      • Conditional dopamine knock-out mouse; LoxP sites added to either site of dopamine-synthesizing enzyme (TH) (when you buy it is a fine, healthy mouse)  
   2. 2nd type of transgenic mouse B

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      • Other mouse has cre-recombinase under control of dopamine transporter (re-uptake) (a.k.a. dopamine transporter cre mouse) gene promotor. (This gene is transcribed in almost all dopamine neurones as they need to re-uptake and reuse the dopamine they release). The only cells that aren't making dopamine are the ones that don't make the re-uptake transporter. 95% make cre-recombinase and remove dopmaine, the only cells (5%) that still make dopamine are cells that do not produce ‘cre’    
2. Pavlovian Learning Trial

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   • For 5 days, 25 trials per day, research try to teach ThKO mice, presentation of lever means food is about to be delivered. The lever comes out for 10 seconds and food is delivered at the end of this period. They measure the number of time Head entries into the ‘food hopper’ during the cue (lever) presentation (more so than during any other time) indicate the mouse has learned the cue-reward association. The authors calculate this conditioned approach behaviour as head entires during cue period minus head entries during inter-trial interval (during 10 seconds). 
   1. wild type vs. KO mouse

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      • WT mouse are four time as likely (compared to KO 5% dopamine mice) to check food hopper during the cue presentation (when the lever is out) than otherwise.   
   2. conclusion
      1. ThKO mice don’t have Pavlovian learning

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         • They regularly check the food hooper and eat all the food, but don’t use presentation of lever cue to guide their behaviour
      2. hypothesis

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         • Hypothesis 1: they aren't check the food hopper b/ they are obsessed w/ sign tracking. Maybe, they walk over to the cue (i.e. lever) a.k.a. sign tracking?  instead of walking to the food port a.k.a. goal tracking? Hypothesis 2: Do 5% dopamine mice ThKO have knowledge of cue-reward association but maybe not enough motivation to jump into action during the 10 seconds long cue presentation?  
   3. Test#2: LDopa injections given to KO mice

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      • Let’s give L-dopa after ten days of training to suddenly restore dopamine levels in these mice.  The first day L-dopa injections are stopped, mice still preform fine on learning tests. However, soon without L-dopa, cue-reward association soon extinguishes, even though mice are still getting food.   
      1. conclusion

         Annotations:

         • ThKO mice can move and eat, but not sufficient to learn simple cue-reward associations. If mice first learn a cue-reward associations, and then dopamine levels are reduced to 5% they will initially demonstrate knowledge of cue-reward associations, but their behavioural response will soon extinguish. More than 5% of normal dopamine somewhere in the brain is need to learn and maintain Pavlovian cue-reward associations. 
   4. Test#3
      1. Restoring dopamine synthesis to select populations of neurones in the dopamine- deficient mice
      2. CAV

         Annotations:

         • Canine adenovirus (CAV) infects axon terminals. Here it is used to drive cre-recombinase expression in all neurones that project to either the dorsal or ventral striatum. Place virus into dopamine deficient mice, which can’t make dopamine unless ‘cre’ is present. ( these mice have 0% dopamine prior to introduction of ‘cre’.  
         1. 40% Dopamine

            Annotations:

            •  This viral restoration restores dopamine levels to 40% of normal at the cre-virus injection site.  A portion of dopamine neurones that project to the dorsal striatum also project to the ventral striatum, and vice versa. 5% of dopamine levels are restored to the region (which region is this? NAc) that was not infect with the the virus. However, we know from the last experiments that 5% of dopamine is not enough to learn this task.
   5. test#4
      1. Restoring dopamine synthesis to select population of neurones in the dopamine-deficient mice
      2. staining dopamine-positive axons red in the striatum

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         •  immunohistochemistry was used to stain dopamine-positive axons red in the striatum. The ‘sham’ image is from a wild type mouse. The other two are showing that a small amount of dopamine has been restored to the top or bottom of the striatum. (vrDD-DS = viral restoration in dopamine-deficient mice in dorsal striatum)   
      3. conclusion

         Annotations:

         • Restoring dopamine synthesis to ventral  but not dorsal striatum-projecting dopamine neurones restores learning