(C) PLOS One
This story was originally published by PLOS One and is unaltered.
 . . . . . . . . . .



A brain-wide form of presynaptic active zone plasticity orchestrates resilience to brain aging in Drosophila [1]

['Sheng Huang', 'Institute For Biology Genetics', 'Freie Universität Berlin', 'Berlin', 'Neurocure Cluster Of Excellence', 'Charité Universitätsmedizin', 'Chengji Piao', 'Christine B. Beuschel', 'Zhiying Zhao', 'Stephan J. Sigrist']

Date: 2022-12 

The brain as a central regulator of stress integration determines what is threatening, stores memories, and regulates physiological adaptations across the aging trajectory. While sleep homeostasis seems to be linked to brain resilience, how age-associated changes intersect to adapt brain resilience to life history remains enigmatic. We here provide evidence that a brain-wide form of presynaptic active zone plasticity (“PreScale”), characterized by increases of active zone scaffold proteins and synaptic vesicle release factors, integrates resilience by coupling sleep, longevity, and memory during early aging of Drosophila. PreScale increased over the brain until mid-age, to then decreased again, and promoted the age-typical adaption of sleep patterns as well as extended longevity, while at the same time it reduced the ability of forming new memories. Genetic induction of PreScale also mimicked early aging-associated adaption of sleep patterns and the neuronal activity/excitability of sleep control neurons. Spermidine supplementation, previously shown to suppress early aging-associated PreScale, also attenuated the age-typical sleep pattern changes. Pharmacological induction of sleep for 2 days in mid-age flies also reset PreScale, restored memory formation, and rejuvenated sleep patterns. Our data suggest that early along the aging trajectory, PreScale acts as an acute, brain-wide form of presynaptic plasticity to steer trade-offs between longevity, sleep, and memory formation in a still plastic phase of early brain aging.

Funding: This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) to S.J.S. (SFB1315 TP A08, NeuroNex2, CoE NeuroCure and FOR2705 TP05). S.H. was supported by the Chinese Scholarship Council (201504910753) as well as by the Leibniz Association (SAW-2019-ISAS-4-SyMetAge). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

We here provide evidence that PreScale operates at the intersection of principal organismal fitness and the formation of new memories during early aging. PreScale peaked at mid-age, changed sleep patterns during the early aging phase, and promoted lifespan but at the same time restricted the extent of forming new memories. Healthy aging paradigms (Spd supplementation, pharmacological induction of excessive sleep) apparently reset the need of triggering PreScale-type plasticity in the Drosophila brain. Thus, PreScale seemingly executes behavioral adaptations and trade-offs during a still plastic phase of early brain aging, illustrating how life strategy manifests on a circuit and synaptic plasticity level.

Previously, a brain-wide form of presynaptic plasticity (PreScale) was described in Drosophila, which is triggered in the course of aging [ 8 ] and also acutely upon experimentally and genetically induced sleep loss [ 33 ]. PreScale is driven by up-regulations of the presynaptic ELKS family scaffold factor Bruchpilot (BRP), which in turn controls the levels of critical synaptic vesicle release factor (m)Unc13-family protein Unc13A at presynaptic active zones [ 8 , 34 ]. Genetically triggering PreScale by increasing brp gene copy number reduced memory formation [ 8 ] and evoked rebound-like additional sleep [ 33 ]. Speaking of healthy aging paradigms, supplementing with the body-endogenous polyamine spermidine (Spd) has prominent cardioprotective and neuroprotective effects across the aging of animal models [ 9 ]. Notably, Spd facilitates memory formation in mid-aged 30-day-old animals [ 10 ] and extends lifespan [ 15 ], and, at the same time attenuates the age-associated emergence of PreScale [ 8 ]. Similarly, bidirectional regulation of mitochondrial Aconitase 1 was found to modulate PreScale-type plasticity in conjunction with its effects on lifespan and age-associated memory decline [ 35 ]. Thus, BRP-driven PreScale seems to operate at a critical intersection of different aspects of brain aging. Still, how exactly PreScale-type plasticity intersects with brain aging, importantly whether in a per se protective or detrimental manner, remained to be investigated.

Aging provokes changes in both sleep pattern and memory, which are suspected to functionally interact [ 5 , 6 , 19 , 20 ]. The fruit fly Drosophila has been widely used in discovering molecular, cellular, and circuit mechanisms of memory formation [ 21 – 23 ], as well as in understanding the mechanisms and functions of sleep [ 24 – 26 ]. Moreover, Drosophila has also been developed into a suitable animal model for studying aging and age-associated sleep pattern alterations [ 27 – 31 ] and memory decline [ 10 , 32 ]. With a relative short lifespan, but not too short, Drosophila allows to explore and causally connect age-associated molecular and behavioral changes that might pave the way for diagnosis and therapy.

The aging of the human societies over the globe, with lifespan extension currently being unmatched by increases in healthspan, urges to better understand the molecular–cellular mechanistic underpinnings underlying the various age-associated alterations [ 1 , 2 ]. The current increase of human lifespan expectancy demands for (i) a better understanding of aging mechanisms [ 1 – 8 ] and (ii) safe paradigms to allow for healthspan extension [ 7 , 9 – 15 ]. While the resilience against the effects of brain aging is an individual trait [ 16 , 17 ], its circuit, neuronal, and molecular basis remains insufficiently understood. Similarly, the resilience relevance of age-associated molecular and behavioral changes observed in humans and in animal models remains largely unclear [ 1 – 4 , 6 , 18 ], and discriminating protective from detrimental changes often remains speculative, impeding the development of safe healthspan extension paradigms.

Results

[END]
---
[1] Url: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001730

Published and (C) by PLOS One
Content appears here under this condition or license: Creative Commons - Attribution BY 4.0.

via Magical.Fish Gopher News Feeds:
gopher://magical.fish/1/feeds/news/plosone/