No abstract

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 inhibitory neurons, which altered brain activity and severely perturbed 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.

Reliable execution of behaviors requires that brain circuits correct for variations in neuronal dynamics. Genetic perturbation of the majority of excitatory neurons in a brain region involved in song production in adult songbirds with stereotypical songs triggered severe degradation of their songs. The song fully recovered within two weeks, and substantial improvement occurred even when animals were prevented from singing during the recovery period, indicating that offline mechanisms enable recovery in an unsupervised manner. Song restoration was accompanied by increased excitatory synaptic inputs to unmanipulated neurons in the same region. A model inspired by the behavioral and electrophysiological findings suggests that a combination of unsupervised single-cell and population-level homeostatic plasticity rules can support the observed functional restoration after large-scale disruption of networks implementing sequential dynamics. In the model the sequence is restored through a parallel homeostatic process, rather than regrown serially, and predicts that sequences should recover in a saltatory fashion. Correspondingly, we observed such recovery in the songs of manipulated animals, with syllables that rapidly alternate between abnormal and normal durations from rendition to rendition until eventually they permanently settled into their original length. These observations indicate the existence of cellular and systems-level restorative mechanisms that ensure behavioral resilience.