Abstract
It has been observed that certain developmental environmental risk factors for schizophrenia when modeled in rodents alter the trajectory of dopaminergic development, leading to persistent behavioural changes in adults. This has recently been articulated as the “dopamine ontogeny hypothesis of schizophrenia”. To test one aspect of this hypothesis, namely that transient dopaminergic effects during development modulate attention-like behavior and arousal in adults, we turned to a small-brain model, Drosophila melanogaster. By applying genetic tools allowing transient activation or silencing of dopaminergic neurons in the fly brain, we investigated whether a critical window exists during development when altered dopamine (DA) activity levels could lead to impairments in arousal states in adult animals. We found that increased activity in dopaminergic neurons in later stages of development significantly increased visual responsiveness and locomotion, especially in adult males. This misallocation of visual salience and hyperactivity mimicked the effect of acute methamphetamine feeding to adult flies, suggesting up-regulated DA signaling could result from developmental manipulations. Finally, brain recordings revealed significantly reduced gamma-band activity in adult animals exposed to the transient developmental insult. Together, these data support the idea that transient alterations in DA signaling during development can permanently alter behavior in adults, and that a reductionist model such as Drosophila can be used to investigate potential mechanisms underlying complex cognitive disorders such as schizophrenia.
Highlights
One of the most enduring hypotheses in schizophrenia research is the proposal that dopamine (DA) signaling is in some way abnormal in patients.[1]
Rodent models will continue to be useful in providing answers as to how genetic and environmental factors shape the developing brain and adult behaviour, other reductionist approaches commonly used in developmental neuroscience have added advantages of faster turnover, efficient genetics, and precise temporal and spatial control of gene expression in a simpler nervous system.[7]
In a first set of experiments on wild-type, we selected flies emerging from the maze following a visual experiment to measure, using high performance liquid chromatography (HPLC), whether DA levels were differentially represented in wild-type flies making different choices in the maze (Figures 1d–f)
Summary
One of the most enduring hypotheses in schizophrenia research is the proposal that dopamine (DA) signaling is in some way abnormal in patients.[1]. Recent studies using rodent models of maternal vitamin D deficiency or maternal infection, both proven epidemiological risk factors for schizophrenia, have provided convergent evidence that the early expression of genes crucial for the normal growth and differentiation of DA neurons in the central nervous system (CNS) may be altered.[4,5] This has led to the proposal that the origins of a range of defective adult behaviours may be due to early alterations in DA ontogeny.[6] rodent models will continue to be useful in providing answers as to how genetic and environmental factors shape the developing brain and adult behaviour, other reductionist approaches commonly used in developmental neuroscience have added advantages of faster turnover, efficient genetics, and precise temporal and spatial control of gene expression in a simpler nervous system.[7] These alternate approaches may allow researchers to investigate molecularly any lead provided by clinical or genetic investigations. For these reasons we have chosen to investigate how interfering with normal DA ontogeny at various developmental stages of fly brain development could affect adult behaviour and brain function
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
