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Research Symposium '14
- 1. Effects of 16p11 chromosomal deletion on attention and motivation Jordan Lidsky-Everson Dr. Nicola Grissom, Dr. Teresa Reyes, Dr. Ted Abel
- 2. AUTISM IS SEX-SPECIFIC • Autism is a sex-specific neurological disorder, affecting males much more commonly than females • Multiple studies have found that males display a greater severity of autistic traits
- 3. 16P11.2 IS A RISK FACTOR FOR AUTISM • Deletions and duplications of the 16p11.2 gene are risk factors for autism spectrum disorder. Horev et al 2011 PNAS
- 4. MOUSE MODEL OF 16P11 HEMIDELETION Mice bred on mixed 129/B6 background Horev et al 2011 PNAS
- 5. REWARD LEARNING AND MOTIVATION Could some ASD deficits be related to disrupted reward learning or motivation, not decreased preference for rewards? Social interaction deficits and restricted interests and repetitive behaviors are core symptoms of autism.
- 6. WHY DOES STRIATAL FUNCTION MATTER? Operant learning (When I see X, I do Y behavior, to cause Z outcome) is dependent on striatal function. DS DS NAc NAc Nucleus accumbens mediates motivation to work for reinforcement Dorsal striatum when I see X, I do Y to get Z
- 7. GOAL • To characterize male and female 16p11 deleted mice for striatal rule learning and motivation • Assess any sex differences
- 8. METHODS Food restrict Pavlovian Conditioned Approach Fixed Ratio 1 (center hole) Progressive Ratio 5-Choice Serial Reaction Time Task Transitioned to reversed light/dark cycle Pre-exposure to rewardPreparation Striatal Learning Tasks Attention Tasks
- 9. METHODS
- 10. METHODS: FIXED RATIO (FR1) 1 response = 1 reward Basic striatal learning action-outcome association DS DS NAc NAc Dorsal striatum when I see X, I do Y, to get Z
- 11. 16P11 MALES HAVE STRIATAL DYSFUNCTION Male 16p11del – Fixed Ratio 1
- 12. METHODS: PROGRESSIVE RATIO (PR) Tests how motivated the animal is to respond DS DS NAc NAc Nucleus accumbens mediates motivation to work for reinforcement
- 13. 16P11 MALES HAVE IMPAIRED MOTIVATION
- 14. METHODS: SUCROSE PREFERENCE Deficits in operant learning and performance cannot be accounted for by a disliking for sweetened rewards.
- 15. RESULTS: FEMALE VULNERABILITY IN STRIATAL LEARNING Male fixed ratio training Female fixed ratio training Effect of Maternal High Fat Diet
- 16. CONCLUSION: 16P11 MALE MICE ARE EXTREMELY IMPAIRED DURING OPERANT BEHAVIOR TASKS • 16p11.2 male deleted mice are extremely impaired during operant behavior tasks while the females showed no evidence of impairments • Future directions: social behavior tasks, social operant tasks, examination of specific genes
- 17. ACKNOWLEDGMENTS Dr. Nicola Grissom Dr. Teresa Reyes Dr. Ted Abel Ariel Miller Kevin Hershey Sarah McKee Bob George
- 18. REFERENCES • Horev G, Ellegood J, Lerch JP, Son YE, Muthuswamy L, Vogel H, et al. Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism. Proc Natl Acad Sci U S A.2011;108:17076–17081. • Canales, J. J. & Graybiel, A. M. A measure of striatal function predicts motor stereotypy. Nature Neurosci. 3, 377–383 (2000)
- 20. PR in maternal high fat diet Figure 12: Male progressive ratio training Figure 4: Female progressive ratio task
- 21. fem del
Hinweis der Redaktion
- My research looked at the effects of the 16p11 chromosomal deletion on attention and motivation I worked directly under Nicola Grissom in Dr. Teresa Reyes’s lab in collaboration on this project with Dr. Ted Abel’s lab. Thank you (). Today I’m going to talk about striatal learning and motivation in autism modeled mice.
- However, the cause of a majority of autism spectrum disorder cases is unknown. About 3% of autism spectrum disorders are caused by chromosome abnormalities.
- One of those chromosomal abnormalities is a copy number variation in the 16p11.2 region which is highlighted here in red. These approximately 30 genes in the same order show up in mouse chromosome 7.
- Draw a box around CIS …giving us an opportunity to create a model of autism. You can see by looking at this CIS model these hemideleted mice have one normal copy of mouse chromosome 7 and one where the approximately 30 genes of the 16p11.2 region are deleted. This is our model so now we can talk about the autism phenotype. deleted in mice to create a model for autism and help assess whether the 16p11 microdeletion causes the type of cognitive impairments that are typically associated with autism these same genes can be deleted in mice to create a model for autism and help assess whether the 16p11 microdeletion causes the type of cognitive impairments that are typically associated with autism The mice were bred on a 129/B6 background As I just said, the 16p11 chromosomal abnormality can be achieved through deletion or duplication. If you look at these animals labeled CIS, they have one normal copy of chromosome 7 and one where these approximately 30 genes of region 16p11.2 are deleted. This is our mouse model so let’s talk about autism phenotypes. Specific reason for this strain? -> do knockout on pure B6 then they are deaf, physiological abnormalities, mixed background is better to introduce genetic diversity so we can look at the genetic knockout and not other genetic effects Mitigate potential effects of behavior specific to pure strain of mouse, mixed background is better Why the deletion and not the duplication? -> literature suggests duplication is more commonly associated with schizophrenia, this is not always the case but the this is the tendency
- The core symptoms of autism are social interaction deficits and restricted interests and repetitive behaviors. Repetitive behavior is known to be regulated by striatal dysfunction and the striatum is turns out plays a really big role in reward learning and motivation. People are used to thinking about autism in relation to social preference but there is also an important component involving learning how to interact with people and being motivated to seek out social interaction.
- We use operant learning tasks because they are dependent on striatal function. The striatum has two parts. The dorsal half regulates the ability to learn rules such as when I see X, I do Y to get Z and the nucleus accumbens regulates motivation to work for reinforcement.
- The preparation, operant striatal tasks and operant attention tasks are a long process that takes several months to complete. I’m not going to go through the PCA because we are still analyzing the data and I’m not going to go through the attention tasks but I am going to explain the striatal learning tasks in detail. First however, animals were transitioned in a room whose lights operated on 9am-9pm dark cycle and behavior tasks were completed during the dark cycles. The animals were food restricted to maintain 85-90% of their free-feeding weight in order to ensure that they would be motivated to complete the behavioral tasks. The animals were pre-exposed to the food reward (Yoohoo) before the experiment began. Food restriction was maintained throughout the course of the experiment.
- This is a schematic of the chamber. There are 9 holes in the back of the chamber which illuminate in accordance with the specific tasks being tested. Responses are recorded when nose pokes break the infrared beams at the back of the chamber. Yoohoo is dispensed into the magazine at the front of the chamber when the animals complete the task correctly.
- The fixed ratio task is a basic striatal learning action-outcome association task. A hole in the rear of the chamber is illuminated and the mouse must nose poke at the correct hole in order to receive the reward. Once the mouse collects the yoohoo from the magazine, a new trial begins. This is clearly implicated with striatal learning because the mouse must learn “when I nosepoke, I get yoohoo.” If we see any deficits during this task, then we know the mouse has impairments in the striatum. Criterion: greater than 70 responses in 30 minutes for two consecutive days
- Here are the results for the fixed ratio. The y-axis shows the number of responses in a 30 minutes session and the x-axis shows the number of days of fr1 training. As you can see the 16p11 deleted males show significant deficits compared to the wildtypes whereas the females show evidence of impairments. Suggests dorsomedial striatum dysfunction due to inability to predict reward from behavior. Why does the male show 8 days of training and females show 14?
- The progressive ratio task is significantly more challenging. The mice are expected to respond progressively more times before the are rewarded and at some point they abandon the task. This is a measure of how motivated the mice and how hard they willing to work for a reward.
- The results of the progressive ratio follow the same trend as the fixed ratio. On the y-axis we have the breakpoint and the x-axis we have the wildtype and deleted mice. The 16p11 deleted mice showed significant impairment during this task while the females, again, showed no evidence of impairment. 16p11 males have impaired motivation
- Before we started the behavior, we administered a sucrose preference test through a two bottle choice task. The mice cages are given a bottle of yoohoo and a bottle of water and we observe which they drink out of more. As you can see here, the y-axis shows percent preference for sucrose and the x-axis shows wild type and deleted mice. Neither wild type or deleted 16p11 showed an decreased preference for sucrose so we know that any deficits in operant learning cannot be accounted for by a disliking for sweetened rewards. Different set of animals are given access are given sucrose water bottle and regular water bottle and we observe how much sucrose water they drink over regular water Freely drink it without working for it, they don’t have any deficits An important control for the performance deficits seen in operant responding is to ensure that 16p11 deletion does not alter preference for sweetened liquid, such as those used as reinforcers in operant chambers. A separate cohort of animals was tested for three days in a two-bottle choice task, comparing consumption of 4% sucrose to water. Dotted line at 50% marks equal preference for water and sucrose. No differences in sucrose preference were seen between genotypes. Therefore, deficits in operant learning and performance are not due to a disliking for sweetened rewards.
- I was involved in another project in the lab that looked at fr1 learning in maternal high fat diet. These results showed that both males and females had significant deficits during the fixed ratio tasks but females may have more severe impairments. It is not the case that female mice in general aren’t vulnerable to striatal deficits during the fr1 task but rather there is something specific about 16p male mice that is having a profound effect on their behavior during these cognitive tasks. Gestational high fat diet causes greater or equal vulnerability in striatal learning between males and females Even females are doing better than 16p males even though they have a significant impairment “effective maternal high fat diet”
- 16p11 deleted mice are extremely impaired during operant behavior tasks while females showed no evidence of impairments. This indicated that the effects of this particular genetic problem are much more overt in males and supports the evidence that males are diagnosed with autism more frequently than women. Currently, the 16p’s are undergoing social behavior tasks but there are other important avenues to explore such as social operant tasks because this data suggests that males and not females would have deficits with social reward. Also trying to discern which specific gene or group of genes in the 16p11 region is contributing to striatal development or ongoing deficits. Future: which one or more of the genes is affected differently and why? Social operant task, molecular Suggests males would have deficits with social reward presumably
- Thank you…to Nicola for being the best mentor I could have asked for. To Teresa and Ted…this project wouldn’t have happened without you…and to Ariel, Kevin, Sarah, and Bob who spent many hours in the dark room helping me with the behavior.
- Deficits in “response accuracy”, or incorrect responses in the absence of overt impulsivity, can be caused entirely by a dorsal striatal deficit (Nishizawa et al, 2012) such that striatum cannot appropriately integrate cortical inputs (Agnoli et al, 2013). These data are most consistent with primary striatal dysfunction.