2026-06-04 バージニア工科大学（VirginiaTech）
◆研究を主導したJarome教授らは、恐怖記憶が脳内でどのように形成・固定化されるかに注目し、特定の分子機構がトラウマ記憶の長期維持に重要な役割を果たすことを明らかにした。PTSDでは、本来は時間とともに弱まるはずの恐怖記憶が過剰に保持され、フラッシュバックや強い不安症状を引き起こす。研究では、記憶形成や再固定化（reconsolidation）に関与する分子経路を解析し、その制御によって病的な恐怖記憶を弱められる可能性が示された。これにより、単に症状を抑えるのではなく、PTSDの根本原因である異常な記憶プロセスに直接介入する治療戦略への道が開かれる。
◆研究チームは、将来的に薬物療法や心理療法と組み合わせることで、より効果的なPTSD治療の実現が期待できるとしている。本成果は、精神疾患の神経生物学的理解と治療法開発を前進させる重要な研究である。
＜関連情報＞
- https://news.vt.edu/articles/2026/05/cals-jarome-PTSD.html
- https://www.sciencedirect.com/science/article/pii/S0166432826001713
非標準的なK27ポリユビキチン化は、海馬における文脈的恐怖記憶の性特異的な調節因子であるが、扁桃体ではそうではない Non-canonical K27 polyubiquitination is a sex-specific regulator of contextual fear memory in the hippocampus but not the amygdala
Morgan B. Patrick, Shannon E. Kincaid, Kaiser C. Arndt, Yeeun Bae, Olivia N. Ball, Adam Cummings, Jennifer R. Abraham, Gitali Bhanot, W. Keith Ray, Timothy J. Jarome
Behavioural Brain Research Available online: 27 March 2026
DOI:https://doi.org/10.1016/j.bbr.2026.116195
Highlights
- K27 polyubiquitination increased in the female hippocampus, but not amygdala, following contextual fear conditioning.
- K27 polyubiquitination levels remained unchanged in the male hippocampus and amygdala following fear conditioning.
- Knockdown of K27 polyubiquitination in the hippocampus impaired contextual fear memory in females, but not males.
- ACAT1 was the only target of K27 polyubiquitination in the female hippocampus following contextual fear conditioning.
Abstract
Polyubiquitination is a process whereby multiple ubiquitin proteins link to each other on a target substrate, marking that substate for various cellular processes of which protein degradation via the proteasome is the most common. Recently, evidence has emerged suggesting that the most common forms of proteasome-dependent (K48) and proteasome-independent (K63, M1) polyubiquitination have sex-specific roles in contextual fear memory formation in the amygdala and hippocampus. However, there are 8 different linkage sites at which polyubiquitin chains can form, most of which have not been studied in the brain. Lysine 27 (K27) polyubiquitination is a less common, non-canonical mark that has not been well studied and may be connected to the protein degradation process. To date, K27 polyubiquitination has never been examined in the brain under any condition. Here, we found that K27 polyubiquitination was selectively increased in the hippocampus after contextual fear conditioning in female, but not male, rats, though neither sex showed changes in this polyubiquitin mark in the amygdala. Consistent with this, CRISPR-dCas13-mediated knockdown of K27 polyubiquitination in the hippocampus selectively impaired contextual fear memory retention in the hippocampus of females, but not males. Proteomic analyses revealed ACAT1 as a target of K27 polyubiquitination in the female hippocampus following fear conditioning, though this mark was not associated with degradation of the target protein. Together, these data suggest that K27 polyubiquitination has a sex-selective role in fear memory formation in the hippocampus. These findings advance our understanding of molecular mechanisms of fear memory formation and the importance of sex as a biological variable in this process
