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Effects of 16p11 chromosomal deletion on attention and motivation
Jordan Lidsky-EversonDr. Nicola Grissom,
Dr. Teresa Reyes, Dr. Ted Abel
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
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
MOUSE MODEL OF 16P11 HEMIDELETION
Mice bred on mixed 129/B6 background Horev et al 2011 PNAS
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.
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 NAcNucleus accumbens mediates motivation to work for reinforcement
Dorsal striatumwhen I see X, I do Y to get Z
GOAL
• To characterize male and female 16p11 deleted mice for striatal rule learning and motivation
• Assess any sex differences
METHODS
Food restrict
Pavlovian Conditioned
Approach
Fixed Ratio 1(center hole)
Progressive Ratio
5-Choice SerialReaction Time
Task
Transitioned to reversed
light/dark cycle
Pre-exposure to rewardPreparation
Striatal Learning Tasks
Attention Tasks
METHODS
METHODS: FIXED RATIO (FR1)
1 response = 1 reward
Basic striatal learning action-outcome
association
DS DS
NAc NAc
Dorsal striatumwhen I see X, I do Y, to get Z
16P11 MALES HAVE STRIATAL DYSFUNCTION
Male 16p11del – Fixed Ratio 1
METHODS: PROGRESSIVE RATIO (PR)
Tests how motivated the animal is to respond
DS DS
NAc NAc
Nucleus accumbens mediates motivation to work for reinforcement
16P11 MALES HAVE IMPAIRED MOTIVATION
METHODS: SUCROSE PREFERENCE
Deficits in operant learning and performance cannot be accounted for
by a disliking for sweetened rewards.
RESULTS: FEMALE VULNERABILITY IN STRIATAL LEARNING
Male fixed ratio training Female fixed ratio training
Effect of Maternal High Fat Diet
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
ACKNOWLEDGMENTS
Dr. Nicola GrissomDr. Teresa Reyes
Dr. Ted AbelAriel Miller
Kevin HersheySarah McKeeBob George
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)
PR in maternal high fat diet
Figure 12: Male progressive ratio trainingFigure 4: Female progressive ratio task
fem del