BRAin-wide Neuron quantification Tool reveals strong sexual dimorphism in the evolution of fear memory

Abstract

Fear responses are functionally adaptive behaviors that are strengthened as memories. Indeed, a detailed knowledge of the neural circuitry modulating fear and fear memory could be the turning point for the comprehension of this emotion and its pathological states. A comprehensive understading of the neural circuits mediating memory encoding, consolidation, and retrieval over time presents the fundamental technological challenge of analyzing activity in the entire brain with single-neuron resolution. In this context, we developed the BRAin-wide Neuron quantification Toolkit (BRANT) for mapping whole-brain neuronal activation at micron-scale resolution, combining tissue clearing, high-resolution light-sheet microscopy, and automated 3D image analysis. The robustness and scalability of this method allowed us to quantify the evolution of neuronal activation patterns across multiple phases of memory in mice. This approach highlighted a strong sexual dimorphism in the circuits recruited during memory recall, which had no counterpart in the behaviour. The methodology presented here paves the way for a comprehensive functional characterization of the evolution of fear memory.