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Brain aging is characterized by cognitive decline related to progressive synaptic degradation. In zebrafish, aging progression resembles human one, making these fish an intriguing model to explore the interplay among aging, behaviour, synaptic integrity and environmental stress. We combined zebrafish deep learning based behavioral analysis of the two phases of behavioral experiment (habituation followed by sociability test) with confocal microscopy based synaptic reconstruction, to correlate behavioral and synaptic changes at different ages, in particular those emerging in response to the social isolation stress paradigm. Through DeepLabCut and Keypoint-MoSeq tools and custom Python pipeline, we observed that social deprivation significantly increased anxiety related behaviors in juvenile and adult fish compared to their controls, while this effect was not present in aged ones. Furthermore, second order Markov based entropy analysis revealed that social isolation yielded a restricted state space with more predictable transitions leading to an age-dependent stereotyped behavior. Such behavioral modification was coupled with a significant increment in glutamatergic synapses, indicative for long term synaptic plasticity, in brain regions related to stress (the homologue of mammalian amygdala) as revealed by Golgi-Cox staining and immunostaining for excitatory synaptic markers. When investigating social behavior, we found that the juvenile isolated fish were less social in respect to their control, presenting conspecific avoidance and enhanced freezing behavior, an effect not detected in adult and aged individuals. Latent Confirmatory factor model revealed that juvenile fish sociability latent factor was inversely predicted by the anxiety latent factor modeled in the habituation phase ($\beta = -0.54$).
Our findings indicate that social isolation has an age-dependent effect on animals’ behavior and related neural substrates, with younger animals exhibiting greater behavioral adaptability and neural plasticity respect to aged ones, which, in opposition, result in less responsiveness to environmental perturbations.
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