Male-specific deficits in natural reward learning in a mouse model of neurodevelopmental disorders
Open accessAbstract
Neurodevelopmental disorders, including autism spectrum disorders, are highly male biased, but the underpinnings of this are unknown. Striatal dysfunction has been strongly implicated in the pathophysiology of neurodevelopmental disorders, raising the question of whether there are sex differences in how the striatum is impacted by genetic risk factors linked to neurodevelopmental disorders. Here we report male-specific deficits in striatal function important to reward learning in a mouse model of 16p11.2 hemideletion, a genetic mutation that is strongly associated with the risk of neurodevelopmental disorders, particularly autism and attention-deficit hyperactivity disorder. We find that male, but not female, 16p11.2 deletion animals show impairments in reward-directed learning and maintaining motivation to work for rewards. Male, but not female, deletion animals overexpress mRNA for dopamine receptor 2 and adenosine receptor 2a in the striatum, markers of medium spiny neurons signaling via the indirect pathway, associated with behavioral inhibition. Both sexes show a 50% reduction of mRNA levels of the genes located within the 16p11.2 region in the striatum, including the kinase extracellular-signal related kinase 1 (ERK1). However, hemideletion males show increased activation in the striatum for ERK1, both at baseline and in response to sucrose, a signaling change associated with decreased striatal plasticity. This increase in ERK1 phosphorylation is coupled with a decrease in the abundance of the ERK phosphatase striatum-enriched protein-tyrosine phosphatase in hemideletion males. In contrast, females do not show activation of ERK1 in response to sucrose, but notably hemideletion females show elevated protein levels for ERK1 as well as the related kinase ERK2 over what would be predicted by mRNA levels. These data indicate profound sex differences in the impact of a genetic lesion linked with neurodevelopmental disorders, including mechanisms of male-specific vulnerability and female-specific resilience impacting intracellular signaling in the brain.
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Male 16p11.2+/− mice (Mills) exhibit sleep deficits and impairments in a reward-directed learning task, while females do not.
“Additionally, male 16p11.2+/− mice (Mills) exhibit sleep deficits [70], and impairments in a reward-directed learning task [67], while females do not.”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [67]
All three lines of 16p11.2+/− mice display social deficits in various testing paradigms and an array of cognitive deficits.
“All 3 lines of 16p11.2+/− mice display social deficits in various testing paradigms [59–64], and an array of cognitive deficits [4, 59, 62–68].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [67]
An elevated number of MSNs and increased expression of Drd2 in striatum are found in male 16p11.2+/− mice (Mills).
“An elevated number of MSNs and the increased expression of Drd2 in striatum are found in male 16p11.2+/− mice (Mills) [4, 67].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [67]
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References 86 · Cited by 92
Research works printed but not linked: 1
- Syndrome D, Portmann T, Yang M, Mao R, Panagiotakos G, Ellegood J et al. Article behavioral abnormalities and circuit defects in the basal ganglia of a mouse model. Cell Rep 2014 7: 1077–1092. PMC4251471 24794428
- Authors
- Grissom, N. M., McKee, S. E., Schoch, H., Bowman, N., Havekes, R., O'Brien, W. T., Mahrt, E., Siegel, S., Commons, K., Portfors, C., Nickl-Jockschat, T., Reyes, T. M., & Abel, T.
- Affiliations
- University of Pennsylvania (US)
- Washington State University Vancouver (US)
- Boston Children's Hospital (US)
- Corresponding author
- Abel, T
- Venue
- Molecular Psychiatry
- Published
- 2017-10-17
- Volume
- 23
- Issue
- 3
- Pages
- 544-555
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC5822461
- OpenAlex
- W2766825691
- Cited by
- 92
- References
- 86
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 14 · 2023: 11 · 2022: 7 · 2021: 11 · 2020: 12 · 2019: 10 · 2018: 15 · 2017: 1
- FWCI
- 5.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Psychiatry (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RWTH Publications (RWTH Aachen) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-nd)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Simons Foundation (248429)
- University of Pennsylvania
- Simons Foundation Autism Research Initiative (345034, 248429)
- National Institutes of Health (5t32mh017168-34)
- National Institute of Mental Health (T32 MH-017168)
- National Institute of Environmental Health Sciences (T32ES019851, P30ES013508)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD086984)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- sex differences, striatum, neurodevelopmental disorders, autism spectrum disorder, attention deficit hyperactivity disorder, dopamine D2 receptor, medium spiny neurons, indirect pathway, ERK1, ERK2, sucrose reward, striatal plasticity, male vulnerability, women's resilience
- MeSH terms
- Autism Spectrum Disorder, Animals, Autistic Disorder, Chromosome Deletion, Corpus Striatum, Disease Models, Animal, Female, Learning, Male, Motivation, Phosphorylation, Reward, Sex Factors, Signal Transduction, MAP Kinase Signaling System, Extracellular Signal-Regulated MAP Kinases, Mitogen-Activated Protein Kinase 3, Mice, Neurodevelopmental Disorders
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