Recovery of a learned behavior despite partial restoration of neuronal dynamics after chronic inactivation of inhibitory neurons

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Maintaining motor skills is crucial for an animal’s survival, enabling it to endure diverse perturbations throughout its lifespan, such as trauma, disease, and aging. What mechanisms orchestrate brain circuit reorganization and recovery to preserve the stability of behavior despite the continued presence of a disturbance? To investigate this question, we chronically silenced a fraction of inhibitory neurons in a pre-motor circuit necessary for singing in zebra finches. This manipulation altered brain activity and severely perturbed their song, a complex learned behavior, for around two months, after which it was precisely restored. Electrophysiology recordings revealed abnormal offline dynamics resulting from chronic inhibition loss, while subsequent recovery of the behavior occurred despite partial normalization of brain activity. Single-cell RNA sequencing revealed that chronic silencing of interneurons leads to elevated levels of microglia and MHC I. These experiments demonstrate that the adult brain can overcome extended periods of drastic abnormal activity. The reactivation of mechanisms employed during learning, including offline neuronal dynamics and upregulation of MHC I and microglia, could facilitate the recovery process following perturbation of the adult brain. These findings indicate that some forms of brain plasticity may persist in a dormant state in the adult brain until they are recruited for circuit restoration.

Abstract Figure

Graphical Abstract:

Schematic overview of the experiments performed in this study.

To investigate how a complex motor behavior recovers after chronic loss of inhibitory tone, we blocked the function of zebra finch HVC inhibitory neurons by bilateral stereotaxic injection of an AAV viral vector into HVC. Throughout various timepoints in this perturbation paradigm, we recorded song behavioral data, electrophysiological measurements (chronic and acute within HVC), and measured changes in gene expression at single-cell resolution.

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