Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
PLoS Biol. 2023 Nov 20;21(11):e3002386. doi: 10.1371/journal.pbio.3002386. eCollection 2023 Nov.
Defensive responses to visually threatening stimuli represent an essential fear-related survival instinct, widely detected across species. The neural circuitry mediating visually triggered defensive responses has been delineated in the midbrain. However, the molecular mechanisms regulating the development and function of these circuits remain unresolved. Here, we show that midbrain-specific deletion of the transcription factor Brn3b causes a loss of neurons projecting to the lateral posterior nucleus of the thalamus. Brn3b deletion also down-regulates the expression of the neuropeptide tachykinin 2 (Tac2). Furthermore, Brn3b mutant mice display impaired defensive freezing responses to visual threat precipitated by social isolation. This behavioral phenotype could be ameliorated by overexpressing Tac2, suggesting that Tac2 acts downstream of Brn3b in regulating defensive responses to threat. Together, our experiments identify specific genetic components critical for the functional organization of midbrain fear-related visual circuits. Similar mechanisms may contribute to the development and function of additional long-range brain circuits underlying fear-associated behavior.
针对视觉威胁刺激的防御反应代表了一种基本的与恐惧相关的生存本能，这种本能在广泛的物种中都有发现。介导视觉触发防御反应的神经回路已在中脑描绘出来。然而，调节这些回路的发育和功能的分子机制仍未解决。在这里，我们表明，中脑特异性缺失转录因子 Brn3b 会导致投射到丘脑外侧后核的神经元丧失。Brn3b 缺失还下调了神经肽速激肽 2（Tac2）的表达。此外，Brn3b 突变小鼠对社交隔离引发的视觉威胁表现出防御性冻结反应受损。这种行为表型可以通过过表达 Tac2 得到改善，表明 Tac2 在调节对威胁的防御反应中是 Brn3b 的下游作用。总的来说，我们的实验确定了特定的遗传成分对于中脑与恐惧相关的视觉回路的功能组织至关重要。类似的机制可能有助于恐惧相关行为的其他长程脑回路的发育和功能。
