2021 Fiscal Year Annual Research Report
Circuit based genome editing for the treatment of stress related psychiatric disorders
Publicly Offered Research
| Project Area | Constructive understanding of multi-scale dynamism of neuropsychiatric disorders |
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| Project/Area Number |
21H00219
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
JOHANSEN JOSHUA 国立研究開発法人理化学研究所, 脳神経科学研究センター, チームリーダー (80625351)
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| Project Period (FY) |
2021-04-01 – 2023-03-31
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| Keywords | adrenergic receptor / noradrenaline / PTSD / stress / amygdala / locus coeruleus |
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| Outline of Annual Research Achievements |
Trauma produces alterations in molecular signaling in specific neural circuits in the brain resulting in post-traumatic stress disorder (PTSD) in vulnerable individuals. While neural circuit based measurement and perturbation approaches have been developed to study these processes, techniques to study molecular signaling in specific neural circuits are not fully realized. In the past year we have developed molecular perturbation approaches to knockdown adrenergic receptors and downstream intracellular targets of adrenergic receptor activation. We have used these in the amygdala to knockdown adrenergic receptors in specific neuronal subtypes (GABAergic and glutamatergic cells) and shown their importance in reformatting trauma memories. Furthermore, we've shown that under conditions of stress traumatic memories are enhanced and this is recapitulated by stimulating adrenergic receptors in specific amygdala neurons during memory recall. Furthermore, we've demonstrated the role of inputs from the locus coeruleus noradrenaline system in the brainstem in regulating traumatic memories when they are recalled. This work demonstrates the viability of circuit specific molecular targeting for regulating traumatic memories.
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| Current Status of Research Progress |
Current Status of Research Progress
1: Research has progressed more than it was originally planned.
Reason
We developed molecular approaches for circuit specific molecular targeting which allows for a studying molecular signaling in brain circuits. We have succesfully applied this technique to modulate traumatic memories.
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| Strategy for Future Research Activity |
We will use cell type specific targeting based on anatomical connectivity of neurons to modify adrenergic signaling in distinct connectivity defined populations of amygdala pyramidal neurons and study the link between amygdala adrenergic signaling and inputs from the locus coeruleus noradrenaline system. Furthermore, we will develop new cell type specific techniques for controlling intracellular signaling molecules and use these to identify proteins that are regulated by adrenergic signaling to control gene transcription in amygdala neurons to control traumatic memories.
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