BIOMED 509. Executive Control UNM SOM. Primate Research Inst. Kyoto,Japan. Cambridge University. JL Brigman

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1 BIOMED 509 Executive Control Cambridge University Primate Research Inst. Kyoto,Japan UNM SOM JL Brigman

2 Symptoms and Assays of Cognitive Disorders Symptoms of Cognitive Disorders Learning & Memory Declarative memory Orienting in time Sequence order memory Spatial memory Working memory Assays of Animal Cognition Learning & Memory Morris Water Maze Serial Learning Tasks Novel Object Recognition Radial Arm Mazes (T,Y,8) Fear Conditioning Paradigms Executive Control Future planning Inhibitory control Attention Control over reward-seeking Cognitive flexibility Working Memory, again (Basically, why you are sitting here now) Executive Control Latent Inhibition Prepulse Inhibition 5-Choice Serial Reaction Time Task Discrimination and Reversal Learning Acquisition & Extinction of an Instrumental Response Reinstatement Learning Reinforcer Devaluation Strategy-Shifting Tasks Delay Non-Match to Location

3 Classic Measures

4 Classical Conditioning Unconditioned Stimulus Unconditioned Response = Conditioned Stimulus Conditioned Response Unconditioned Stimulus Conditioned Response Acquisition Conditioned Stimulus

5 Operant Conditioning Positive Reinforcement = delivery of desired stimulus You won the game, ice cream for everyone! Behavior 1 Behavior 2 Behavior 3 Outcome Negative Reinforcement = removal of undesired stimulus You won the big account, take Friday off! Positive Punishment = delivery of undesired stimulus I m going to wash your mouth out with soap! Negative Punishment = removal of desired stimulus No TV for a week! Note: Reinforcers can be: primary (intrinsically desired) or secondary (not intrinsically valued)

6 Acquisition-Extinction-Reinstatment Acquisition Extinction Response produces reward (& tone, light) Response produces no reward (or tone, light) Reinstatement Rewards delivered during early trials (no tone, light) Response produces tone, light (no reward) Response produces reward (& tone, light) Lederle et al. PloS One, 2011

7 Schedules of reinforcement SCHEDULE REINFORCEMENT EXAMPLE EFFECT Continuous Fixed Ratio Fixed Interval Presented after every response Presented after a designated # of RESPONSES Presented after a designated amount of TIME Soda Machine Factory Piecework Standing Friday Quiz Rapidly Learning Rapid Extinction Rapid Response Rate Response toward end of interval after reinforcement Variable Ratio Presented after random # of RESPONSES Slot Machine Highly resistant to extinction Variable Interval Presented after random amount of TIME Crazy Fishing People Highly resistant to extinction

8 Acquisition-Extinction-Reinstatment AER has multiple components that can be analyzed to tell us: How quickly does an animal learn an instrumental response for a reward (food, drug, etc.)? Once the behavior ceases to deliver the reward, how quickly do they discontinue? Perhaps most importantly, how does a quick burst of reward (or just the secondary reinforcers) re-engage the behavior? Lederle et al., 2011

9 Reinforcer Devaluation A Instrumental training B Sickness pairing Low lever response rate (FR1) C High lever response rate (RR20) Devaluation probe Food paired with LiCl-induced malaise Non-devalued mice lever press Devalued mice do not lever press Lederle et al. PloS One, 2011

10 Lever presses/min FR1(5) FR1(10) FR1(15) RR10 RR20 RR20 RR20 Lever presses/min Number of pellets eaten Reinforcer Devaluation Devaluation tasks are mediated by PFC-Striatal-Amygdala circuits: If designed properly they can measure the formation of a habit. That is, when a response (action) becomes dissociated from the reward (outcome). Non-devalued Devalued * * * 0 Trial 1 Trial 2 GEN RET Head entries/min 0 ND D ND D 0 Lederle et al. PloS One, 2011

11 *p<.01 vs D1, #p<.01 vs D2, p<.05 vs R1, p<.01 vs R2 Attention and Inhibitory Control X

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15 5 Choice Paradigms 5-CSRTT and the 5-Choice CPT (continuous performance task) measure: attention (accuracy) impulsive choice (premature responses) compulsive choice (responses on hold trials) These tasks are acutely sensitive to PCP (and other NMDAR antagonist) treatment. Amitai & Markou, 2010

16 *p<.01 vs D1, #p<.01 vs D2, p<.05 vs R1, p<.01 vs R2 Operant Association Learning

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28 Discrimination Learning Discrimination (regardless of modality) is primarily mediated by the basal ganglia and in particular the dorsal striatum. However, discriminations that are difficult due to the need to carefully attend to the features of the stimuli or interference from previous are also mediated by prefrontal cortex, and the ventral mpfc in particular. Brigman et al., 2008

29 *p<.01 vs D1, #p<.01 vs D2, p<.05 vs R1, p<.01 vs R2 Working Memory

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35 Hold that one in working memory!

36 Delay Non-Match to Location Delay Matching and Non-Matching tasks require intact hippocampal function: Task difficulty (cognitive load) depends primarily on: Separation: How distinct are the locations? Delay: How long do you have to hold the representation in working memory? Brady et al., 2012

37 Delay Non-Match to Location Delay Matching and Non-Matching tasks require intact hippocampal function: Task difficulty (cognitive load) depends primarily on: Separation: How distinct are the locations? Delay: How long do you have to hold the representation in working memory? Talpos et al, 2010

38 *p<.01 vs D1, #p<.01 vs D2, p<.05 vs R1, p<.01 vs R2 Cognitive Flexibility (stimulus) Ct

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46 OFC c-fos-positive cells (per 360x460 µm) Perseverative errors Reversal Learning Reversal learning is a hallmark test of behavioral flexibility across species and modalities. The behavior is heavily dependent on the lateral orbitofrontal cortex which is thought to act as an expectancy-monitor * # # * * D early D late R early R mid R late Discrimination Reversal * # * # D early D lat e 0 D early D late R early R mid R late R early R mid R late Brigman et al. Nat. Neurosci, 2013

47 Reversal Learning Hamilton & Brigman, 2015

48 *p<.01 vs D1, #p<.01 vs D2, p<.05 vs R1, p<.01 vs R2 Cognitive Flexibility (Rule) ?

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59 Attentional Set-Shifting Tasks Based on the hallmark task of prefrontal function in humans the Wisconsin Card Sorting Task (which you just took), these tasks require subjects to make choices based on a rule. The rule relates to the features (or dimensions) of the stimuli, not the stimulus themselves (as in reversal). The rule governs what you attend to (i.e. color) and what you can ignore (shape and number and therefore this focus is called an Attentional Set. It should be harder to shift your attention to a new set (Extra-Dimensional) than learn a new discrimination in the previous set (Intra-Dimensional). This is the basis for all attentional set-shifting tasks across species no matter what stimuli compose the dimensions (visual, olfactory, tactile, auditory) and is mediated by the dlpfc in primates and the mpfc in rodents. Seriously, you re lumping me in with these guys?

60 Attentional Set-Shifting Tasks Marquardt et al., G2B 2014 Thompson et al., Beh. Neurosci 2015

61 Attentional Set-Shifting Tasks

62 Set-shifting Hamilton & Brigman, 2015

63 Problems, Pitfalls and Controls Genetic Variation Lack of sufficient control Order and stress effects Laboratory effects

64 roblems, Pitfalls and Controls This should look familiar: Differences between strains and parental genotype: Choose background strain carefully. Breed mutation onto congenic background(s). Differences between tests: Employ multiple and varied tests, consider non-behavioral adjuncts. Differences between labs: Validate pharmacologically in-house, and keep conditions constant. Behavior isn t Enough: Strong face and predictive validity does not mean circuits are analogous. How you would solve a problem is OFTEN not how a rodent would. Data with strong translational potential shows neural correlates across species.

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