Vertebrates can change their behavior upon detection of visual stimuli according to the outcome their actions produce. Such goal-directed behavior involves evolutionary conserved brain structures like the striatum and optic tectum, which receive ascending visual input from the periphery. In mammals, however, these structures also receive descending visual input from visual cortex (VC), via neurons that give rise to cortico-fugal projections. The function of cortico-fugal neurons in visually guided, goal-directed behavior remains unclear. Here, we address the impact of two populations of cortico-fugal neurons in mouse VC in the learning and performance of a visual detection task. We show that the ablation of striatal projecting neurons reduces learning speed, whereas the ablation of superior colliculus projecting neurons does not impact learning but reduces detection sensitivity. This functional dissociation between distinct cortico-fugal neurons in controlling learning speed and detection sensitivity suggests an adaptive contribution of cortico-fugal pathways even in simple goal-directed behavior.

Cytoplasmic accumulation of TDP-43 in motor neurons is the most prominent pathological feature in amyotrophic lateral sclerosis (ALS). A feedback cycle between nucleocytoplasmic transport (NCT) defect and TDP-43 aggregation was shown to contribute to accumulation of TDP-43 in the cytoplasm. However, little is known about cellular factors that can control the activity of NCT, thereby affecting TDP-43 accumulation in the cytoplasm. Here, we identified via FRAP and optogenetics cytosolic calcium as a key cellular factor controlling NCT of TDP-43. Dynamic and reversible changes in TDP-43 localization were observed in Drosophila sensory neurons during development. Genetic and immunohistochemical analyses identified the cytosolic calcium-Calpain-A-Importin α3 pathway as a regulatory mechanism underlying NCT of TDP-43. In C9orf72 ALS fly models, upregulation of the pathway activity by increasing cytosolic calcium reduced cytoplasmic accumulation of TDP-43 and mitigated behavioral defects. Together, these results suggest the calcium-Calpain-A-Importin α3 pathway as a potential therapeutic target of ALS.