2016 Fiscal Year Research-status Report
Neural circuit and molecular mechanisms for noradrenergic modulation of fear learning and memory
| Project/Area Number |
16K21620
|
|---|
| Research Institution | Institute of Physical and Chemical Research |
|---|
Principal Investigator |
Tan BaoZhen 国立研究開発法人理化学研究所, 脳科学総合研究センター, 国際特別研究員 (80756784)
|
|---|
| Project Period (FY) |
2016-04-01 – 2018-03-31
|
| Keywords | amygdala / noradrenaline / fear conditioning / optogenetics / neural circuits |
|---|
| Outline of Annual Research Achievements |
Noradrenaline in the lateral amygdala (LA) modulates Hebbian plasticity mechanisms via beta-adrenergic (b-AR) receptors to facilitate the formation of auditory fear memories. It is unclear if locus coeruleus-noradrenaline (LC-NA) projections to LA modulate learning, and the intracellular changes that are triggered by NA release and b-AR activation in LA to facilitate this learning. By injecting retrograde canine adenovirus expressing Cre recombinase in LA, and AAV virus expressing Cre-dependent ArchT into the LC in rats, we are able to specifically inhibit the LC-NA projections in the LA during auditory fear conditioning. We found that inhibition of LC-NA projections in the LA, specifically during the aversive shock period of fear conditioning, significantly reduced fear memory formation.
|
| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
We have successfully tested the first hypothesis proposed, in that LC activity and activation of LC terminals in the LA, specifically during the aversive experience, is required for and facilitates fear memory formation and associative neural plasticity in the LA. Our second hypothesis, that NA release from the LC terminals in the LA regulates fear conditioning through actions on b-ARs and CRTC1 is also progressing smoothly. We found that fear learning produced a significant increase in CRTC1 nuclear accumulation in the LA neurons, and that expression of dominant-negative version of CRTC1 or shRNA targeting CRTC1 could reduce long term fear memory formation, implicating CRTC1 as a potential mechanism for transducing noradrenergic signaling in the LA neurons into long term fear memories.
|
| Strategy for Future Research Activity |
We plan to examine the role of b-ARs in the LA during auditory fear conditioning, by viral expression of shRNAs targeting specific subtypes of b-ARs and examine the effects on behavioral fear learning and nuclear accumulation of CRTC1, a sensitive readout of synaptic activity. We also plan to test the third hypothesis - if activation of CRTC1 in a specific subset of LA neurons that project to the central amygdala (CeA) is necessary for and facilitates fear conditioning. To do so, we will inject CAV2-Cre virus to the CeA to retrogradely express Cre recombinase in LA neurons that project to the CeA and Cre-dependent virus expressing DNCRTC1 in the LA.
|
| Causes of Carryover |
I wasn't able to find a suitable candidate for assistance with project.
|
| Expenditure Plan for Carryover Budget |
I will continue to look out for good candidates, as the project is progressing smoothly. And I plan to attend more international conferences this year for exchange of scientific ideas and networking.
|
