Bianca Silva

Brain circuits for fear attenuation

Abstract

How are consolidated memories modified on the basis of experience? In this project we aimed to unravel the neural mechanisms at the basis of memory update. Understanding this biological process allows us to decipher how new information is constantly incorporated into existing memory, how a newly formed memory is integrated into previous knowledge and how the fine balance between memory stability and memory flexibility is maintained.

By using fear memory extinction as a model of memory update, we combined neuronal circuit mapping, fiber photometry, chemogenetic and closed-loop optogenetic manipulations in mice, and showed that the extinction of remote (30-day old) fear memories depends on thalamic nucleus reuniens (NRe) inputs to the basolateral amygdala (BLA). We find that remote, but not recent (1-day old), fear extinction activates NRe to BLA inputs, which become potentiated upon fear reduction. Both monosynaptic NRe to BLA, and total NRe activity increase shortly before freezing cessation, suggesting that the NRe registers and transmits safety signals to the BLA.

Accordingly, pan-NRe and pathway-specific NRe to BLA inhibition impairs, while their activation facilitates fear extinction. These findings identify the NRe as a crucial BLA regulator for extinction, and provide the first functional description of the circuits underlying the experience-based modification of consolidated fear memories.

Biography

Since the beginning of her career, Bianca was interested in understanding the neural basis of emotions. After obtaining a master degree in medical biotechnology at the University of Milan, where she studied oxytocin receptors, Bianca joined Cornelius Gross’ group at EMBL-Rome for her doctoral training. During her PhD, she investigated how the brain processes innate fear. Using chemogenetic manipulations she discovered that social and predator fear, two evolutionarily conserved and highly ethologically relevant stimuli, are not mediated by classic amygdalar fear circuits, but depend instead on distinct hypothalamic networks. Interestingly, this study revealed that fear is processed by separate circuits depending on the nature of the threat.

For her postdoctoral research she decided to move to a more translational aspect of basic neuroscience and investigated how long-lasting fear memories can be attenuated. She joined Johannes Gräff’s group at the Swiss Federal Institute of Technology in Lausanne (EPFL) with an EMBO postdoctoral fellowship. There, she used chemogenetics, optogenetics, functional connectivity analysis, calcium imaging and viral tracing and uncovered a thalamo-amygdalar circuit mediating attenuation of remote (i.e. 30 days old) but not recent (i.e. 1 day old) fear memories.

Since February 2021, Bianca is a principal investigator at the Institute of Neuroscience of the National Research Council of Italy.