ABSTRACT A major goal in clinical neuroscience is to develop efficient treatments to prevent or minimize the loss of brain function caused by pathological decreases or increases of neuronal activity, which are hallmarks of a wide variety of neurological disorders. Interestingly, in some instances, the brain has evolved mechanisms to partially correct abnormal neuronal function. Understanding the adaptive mechanisms that restore brain function would not only provide insight into the functioning of the normal brain but also guide future approaches to ameliorate loss of brain function caused by disease or injury. We propose to start a research program to investigate the cellular and circuit mechanisms by which the brain maintains constant behavioral output, even when neuronal activity is naturally variable or it is perturbed. Our preliminary evidence with songbirds indicate that the brain circuits involved in song production demonstrate a high level of behavioral resilience both at short and long timescales. At the short timescale the patterns of firing of premotor neurons directly involved in song production vary from day to day, although there is no measurable variability in the song. At the long timescale, we genetically perturbed the activity of these premotor neurons and this caused a dramatic disruption of song. However, manipulated birds fully recovered from the perturbation, and were able to produce their original song after around 10 days. We will build on these results to explore the neuronal mechanisms that ensure behavioral resilience in a brain circuit involved in a complex behavior using gene delivery, optogenetics, in vivo functional imaging, behavioral analysis, and computational modelling.

PROJECT NARRATIVE The brain has limited ability to recover from damage, and in most cases, functional losses after neurological disease or injury are irreversible. Nonetheless, in some instances, the brain can adapt to these disturbances and normal behavior is recovered. We propose to investigate the mechanisms by which the brain maintains stable behaviors after perturbation of neuronal function, and anticipate that this research will provide new avenues for the treatment for neurological diseases.