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.