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