Abstract
There is evidence of a link between the circadian system and psychiatric diseases. Studies in humans and mammals suggest that environmental and/or genetic disruption of the circadian system leads to an increased liability to psychiatric disease. Disruption of clock genes and/or the clock network might be related to the etiology of these pathologies; also, some genes, known for their circadian clock functions, might be associated to mental illnesses through clock-independent pleiotropy. Here, we examine the features which we believe make Drosophila melanogaster a model apt to study the role of the circadian clock in psychiatric disease. Despite differences in the organization of the clock system, the molecular architecture of the Drosophila and mammalian circadian oscillators are comparable and many components are evolutionarily related. In addition, Drosophila has a rather complex nervous system, which shares much at the cell and neurobiological level with humans, i.e., a tripartite brain, the main neurotransmitter systems, and behavioral traits: circadian behavior, learning and memory, motivation, addiction, social behavior. There is evidence that the Drosophila brain shares some homologies with the vertebrate cerebellum, basal ganglia, and hypothalamus-pituitary-adrenal axis, the dysfunctions of which have been tied to mental illness. We discuss Drosophila in comparison to mammals with reference to the: organization of the brain and neurotransmitter systems; architecture of the circadian clock; clock-controlled behaviors. We sum up current knowledge on behavioral endophenotypes, which are amenable to modeling in flies, such as defects involving sleep, cognition, or social interactions, and discuss the relationship of the circadian system to these traits. Finally, we consider if Drosophila could be a valuable asset to understand the relationship between circadian clock malfunction and psychiatric disease.
Highlights
Mental health diseases make up about 20% of all illnesses and approximately one person in four is afflicted by one form or other of this kind of disease during their lifetime
The main reasons which justify this choice are that: (i) flies show a relatively simple brain, which shows interesting functional homologies with important regions of the mammalian brain; (ii) the fundamental neurobiological processes and neurotransmitter systems are conserved; (iii) flies are characterized by a set of complex behaviors such as sleep/wake cycles, learning and memory (LM) and social interactions, which can be modulated by experience
In the study of the possible link between psychiatric diseases and the circadian clock, the use of Drosophila might provide an advantage for three main reasons: (i) the Drosophila circadian system organization is simpler compared to that of mammals; (ii) genetic mutations at the level of circadian clock genes, which cause modifications in the timing of the circadian clock, are available such as, for example, the two dper gene mutants, which show shortening or lengthening of the clock periodicity [190]; (iii) Drosophila has homologs to most of the candidate genes associated with psychiatric diseases, as reported in case-control and genome-wide associations (GWA) studies [212, 214, 215]
Summary
Mental health diseases (i.e., depressive syndromes, bipolar disorders, and schizophrenia) make up about 20% of all illnesses and approximately one person in four is afflicted by one form or other of this kind of disease during their lifetime. The organism’s circadian clock-controlled phenotypes, such as the sleep/wake cycle, body temperature, and metabolism, are synchronized with the 24 h environmental variations. Clinical observations have shown that many psychiatric patients display abnormalities in circadian parameters such as cycles in body temperature, melatonin levels, blood pressure, cortisol secretion, and sleep/wake cycles [4, 10, 11]. Several single nucleotide polymorphisms at the level of genes involved in the control of the circadian clock have been associated to different forms of psychiatric disorders [4, 12, 13]. A postmortem transcriptome analysis performed in individuals affected by depressive disorders showed that in different brain regions several circadian clock genes oscillate with a lower amplitude with respect to controls [14]. Studies in mammalian models have shown that some genes such as mPeriod, www.frontiersin.org
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