Projects / Programmes
Influence of gonadal hormones on sex differences in autism spectrum disorders on mouse model
| Code |
Science |
Field |
Subfield |
| 3.09.00 |
Medical sciences |
Psychiatry |
|
| Code |
Science |
Field |
| B640 |
Biomedical sciences |
Neurology, neuropsychology, neurophysiology |
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
Sex differences, mice, autism, hormones
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
24348 |
PhD Neža Grgurevič |
Veterinarian medicine |
Head |
2013 - 2015 |
0 |
Organisations (1)
Abstract
Autism is a devastating nevrodevelopmental disorder which starts very early in life and continues in adulthood in most cases without remission. Autism is not a single disease entity, but rather a spectrum of different autistic-like phenotypes collectively termed as autism spectrum disorder (ASD). ASD is generally characterized as difficulties in reciprocal social interaction and communication, strongly repetitive behavior and unusually narrow interest. Genetic factors are highly involved in ASD incidence either causing ASD or just increasing the risk for ASD. Less prominent but not less important are epigenetic and environmental factors that could also contribute to the development of ASD. Sexual dimorphism is one of the most consistently reported features of ASD indicating greater incidence in males than in females. It has been hypothesized that ASD is an extreme expression of the male brain observed as a lack of empathy and language deficit, but increase in so called systemizing behaviors such as attention to detail, to collecting and a preference to interaction with strict rules. One of the biological explanations for extreme maleness is organizational effect of fetal testosterone (T) which is present during development in males but not in females. It was proposed that androgens induce the release of arousal-related neurotransmitters secreted from the nerve endings in amygdala. Therefore male amygdala could become hypersensitive to exogenous stressors. Contrary to males, females are not exposed to high levels of androgens therefore their amygdala does not become as sensitive as male amygdala. Moreover they are exposed to high levels of estrogens which could act neuroprotective and oxytocin known for its pro-social activity. Interestingly animal studies focusing on gender differences in ASD are still limited and little is known about mechanisms by which males become more susceptible for ASD than females. Even hypothesis mentioned above has not yet been tested on animal models for autism. Therefore the aim of our proposal is to explore whether T during development has a major role in susceptibility for ASD and whether autistic-like behaviors could be modulated by estradiol (E) treatment in adulthood. In our studies we will use mice prenatally exposed to antiepileptic drug, valproic acid (VPA) that was reported as good animal model for autism. Pregnant females will be divided into four groups and exposed during critical period of fetal development to: VPA together with T, T only, VPA only and control treatment with vehicles. Treatment with T will serve as a control for masculinization while treatment with VPA will serve as a control for sex different autistic-like behavior. Offspring will be subsequently observed in set of behavioral tests that have been shown to be the most relevant for ASD studies. Mice will be tested either intact or gonadectomized and treated with E. The first group of intact mice will be used to explore whether females exposed to T and VPA during development develop similar autistic-like behaviors than VPA males. The second group will be used to explore whether gonadectomized males exposed to VPA during development display reduced autistic like behaviors after E treatment in adult life. After sacrifice blood will be used to measure corticosterone and oxytocin levels and brain will be examine for either imumunoexpression of estrogen, serotonin and oxytocin receptors (OTR) or for RNA analyses for androgen and OTR and oxytocin as well. Since human studies are very limited, animal studies provide an important alternative in research of neuropsychiatric disorders. As far as we know, this will be the first study on animal model for autism that will examine autistic-like behaviors in the context of different hormonal treatment during development and in adulthood. Therefore our results will provide new insights about gender-specific mechanism involved in etiology of ASD.
Significance for science
Autism is devastating, incurable disorder which starts very early in the childhood. Our study is focused specially on process of sexual differentiation in the context of autism causing factors and will provide new answers to questions regarding etiology of autism in particular from the perspective of sex differences. Since mice are widely used in different studies and numerous genetic models are available for ASD, our results could provide a base for further studies of sex differences in ASD. In the future sex differences could be explored with mice models for hormonal independent sexual differentiation. This would be particularly interesting since influence of sex chromosomes on ASD was also implicated in humans. With improved knowledge about gender-specific mechanisms making males more susceptible for ASD and females less susceptible to ASD further research on mice models could provide new targets for drugs.
Significance for the country
Research project is important for development of basic interdisciplinary projects in Slovenia which are at the moment very poorly present especially in the use of animal models for psychiatric research
Most important scientific results
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Most important socioeconomically and culturally relevant results
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