2017 Fiscal Year Research-status Report
Neural circuit and molecular mechanisms for noradrenergic modulation of fear learning and memory
| Project/Area Number |
16K21620
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| Research Institution | Institute of Physical and Chemical Research |
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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)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | noradrenaline / amygdala / fear conditioning / optogenetics / neural circuits / locus coeruleus |
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| Outline of Annual Research Achievements |
The locus coeruleus (LC) is traditionally thought to modulate global brain states and diverse behaviors through a homogeneous, highly collateralized noradrenergic (NA) cell population that respond uniformly to salient stimuli and broadcast an arousal throughout the brain. Surprisingly, I found that distinct populations of LC-NA neurons project to amygdala or to medial prefrontal cortex (mPFC). Using retrograde virus to express an inhibitory opsin in the cell bodies that project to the amygdala and their synaptic terminals in the amygdala, I discovered that activity in this cell population was critical during the aversive shock period for fear learning. However, the mPFC projecting cell population was not important for for learning but was critical for initiating extinction learning.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
I have successfully tested the first hypothesis proposed, in that LC activity and activation of LC terminals in the lateral amgydala (LA), specifically during the aversive shock, is required for and facilitates fear memory learning in the LA. I also tested our second hypothesis that NA released from the LC terminals in the LA regulates fear conditioning through actions on beta-adrenergic receptors (b-ARs) and CREB coactivators and found that fear learning produced a significant increase in CRTC1 nuclear accumulation in the LA neurons and that expression of dominant-negative CRTC1 or shRNA targeting CRTC1 could reduce fear memory formation, suggesting that CRTC1 is a potential mechanism for transducing noradrenergic signaling in the LA neurons into long term memories.
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| Strategy for Future Research Activity |
To test the role of b-ARs in the LA during auditory fear conditioning, I have designed shRNAs targeting specific subtypes of b-ARs and packaged them in AAVs. Preliminary data suggest that viral expression of these shRNAs in the LA to knockdown b-ARs reduces auditory fear learning. I am currently examining if these manipulations have effect on nuclear accumulation of CRTC1, a sensitive readout of synaptic activity. I also have started on testing 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. I 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.
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| Causes of Carryover |
I wasn't able to find a suitable candidate for assistance with project. 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.
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