Aging and Autophagic Function Influences the Progressive Decline of Adult Drosophila Behaviors

Abstract

Multiple neurological disorders are characterized by the abnormal accumulation of protein aggregates and the progressive impairment of complex behaviors. Our Drosophila studies demonstrate that middle-aged wild-type flies (WT, ~4-weeks) exhibit a marked accumulation of neural aggregates that is commensurate with the decline of the autophagy pathway. However, enhancing autophagy via neuronal over-expression of Atg8a (Atg8a-OE) reduces the age-dependent accumulation of aggregates. Here we assess basal locomotor activity profiles for single- and group-housed male and female WT flies and observed that only modest behavioral changes occurred by 4-weeks of age, with the noted exception of group-housed male flies. Male flies in same-sex social groups exhibit a progressive increase in nighttime activity. Infrared videos show aged group-housed males (4-weeks) are engaged in extensive bouts of courtship during periods of darkness, which is partly repressed during lighted conditions. Together, these nighttime courtship behaviors were nearly absent in young WT flies and aged Atg8a-OE flies. Previous studies have indicated a regulatory role for olfaction in male courtship partner choice. Coincidently, the mRNA expression profiles of several olfactory genes decline with age in WT flies; however, they are maintained in age-matched Atg8a-OE flies. Together, these results suggest that middle-aged male flies develop impairments in olfaction, which could contribute to the dysregulation of courtship behaviors during dark time periods. Combined, our results demonstrate that as Drosophila age, they develop early behavior defects that are coordinate with protein aggregate accumulation in the nervous system. In addition, the nighttime activity behavior is preserved when neuronal autophagy is maintained (Atg8a-OE flies). Thus, environmental or genetic factors that modify autophagic capacity could have a positive impact on neuronal aging and complex behaviors.

Social behavior and aging: A fly model

“…As flies do not internally regulate their body temperature, even subtle differences in environmental temperature exposure can alter their lifespan. 13,[51][52][53][54] Despite the lack of a closed circulatory system, even tissues such as heart muscle change with age in a similar manner as human cardiac aging. 44 As far back as the 1920s, D. melanogaster was used as a model of aging to demonstrate that lifespan can be heritable and that metabolic rate inversely correlates with lifespan, the basis for the rate-of-living hypothesis.…”

“…[47][48][49][50] As in other animals, aging in D. melanogaster has been shown to affect motor behavior, mating activity, and brain morphology. 13,[51][52][53][54] Despite the lack of a closed circulatory system, even tissues such as heart muscle change with age in a similar manner as human cardiac aging. 55 When genes underlying human neurodegeneration due to protein aggregation are expressed in D. melanogaster, age-related protein aggregation occurs by the same mechanism as in human brains.…”

Moving to the Rhythm with Clock (Circadian) Genes, Autophagy, mTOR, and SIRT1 in Degenerative Disease and Cancer

“…Studies with Drosophila show that the accumulation of neural aggregates observed with aging is associated with a reduction in the autophagy pathway. These neural aggregates lead to behavior impairments that can be resolved with the maintenance of autophagy pathways in neurons (62). In animal models of Alzheimer's disease, a basal circadian rhythm that controls macroautophagy may be necessary to limit cognitive decline and amyloid deposition (63).…”

Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors

“…Studies with Drosophila demonstrate that neural aggregate accumulation observed with aging is linked to a reduction in the autophagy pathway. These neural aggregates lead to behavior impairments that can be resolved with the maintenance of autophagy pathways in neurons (99). In addition, autophagy is involved in a number of degenerative disorders such as cognitive decline (14, 56, 100), AD (40, 48, 83, 101, 102), Parkinson’s disease (11, 87, 98, 103), Huntington’s disease (59, 104, 105), DM (14, 17, 40, 89, 106, 107), and aging processes (8, 40, 85, 91, 108–111).…”