Suh Junghyup, Flanagan-Burt Quilla C, Moon Byung Kwon, Pasqualini Amanda L, Zambrano Maria A, Ressler Kerry J
Division of Depression and Anxiety Disorders, McLean Hospital, Department of Psychiatry, Harvard Medical School, Belmont, MA, 02478, USA.
Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, 98195, USA.
Mol Psychiatry. 2025 Aug 29. doi: 10.1038/s41380-025-03184-w.
Alcohol seeking during abstinence is mediated in part by strong associations between the pharmacological effects of alcohol and the environment within which alcohol is administered. The amygdala, particularly the basolateral amygdala (BLA), is a key neural substrate of environmental cue and reward associations since it is involved in associative learning and memory recall. However, we still lack a clear understanding of how alcohol affects the activity of BLA neurons, which may encode information that drives environmental cue-dependent, alcohol-related behaviors. We previously demonstrated that a subset of BLA neurons which express the calcium/calmodulin-dependent protein kinase II (CaMKII) and thymus cell antigen 1 (Thy1) markers project preferentially to the nucleus accumbens (NAcc), rather than the central amygdala; and these neurons mediate fear inhibition rather than fear acquisition or expression, suggesting a specific role in positive valence processing. We now demonstrate that Pavlovian conditioning with alcohol administration increases the activity of these Thy1-expressing (Thy1+) excitatory neurons in mouse BLA, which is necessary for the conditioned appetitive response. In vivo calcium imaging indicates that the temporal activity profile of these neurons is also correlated with alcohol-induced motivated behavior in response to environmental cues. Optogenetic inhibition of BLA Thy1+ neuronal activity at cell body disrupts both the formation and expression of alcohol-induced conditioned place preference. Furthermore, selective axonal inhibition of BLA-Thy1+ efferents reveals that the activity of their NAcc and prefrontal cortex (PFC) projections are differentially necessary for alcohol cue association vs. recall, respectively. Together, these findings provide insights into a molecularly distinct subset of BLA neurons that regulates environmental cue-reward associations and drives alcohol-induced motivated behaviors in a projection-specific manner.
戒酒期间对酒精的寻觅部分是由酒精的药理作用与饮酒环境之间的强烈关联介导的。杏仁核，尤其是基底外侧杏仁核（BLA），是环境线索与奖赏关联的关键神经基质，因为它参与联想学习和记忆回忆。然而，我们仍然不清楚酒精如何影响BLA神经元的活动，而这些神经元可能编码驱动环境线索依赖的、与酒精相关行为的信息。我们之前证明，表达钙/钙调蛋白依赖性蛋白激酶II（CaMKII）和胸腺细胞抗原1（Thy1）标记物的一部分BLA神经元优先投射到伏隔核（NAcc），而不是中央杏仁核；并且这些神经元介导恐惧抑制而非恐惧习得或表达，这表明它们在正性效价加工中具有特定作用。我们现在证明，酒精给药的巴甫洛夫条件反射增加了小鼠BLA中这些表达Thy1（Thy1+）的兴奋性神经元的活动，这是条件性食欲反应所必需的。体内钙成像表明，这些神经元的时间活动模式也与酒精诱导的对环境线索的动机行为相关。对BLA Thy1+神经元胞体活动的光遗传学抑制会破坏酒精诱导的条件性位置偏好的形成和表达。此外，对BLA-Thy1+传出纤维的选择性轴突抑制表明，它们对伏隔核和前额叶皮质（PFC）投射的活动分别对酒精线索关联与回忆有不同的必要性。总之，这些发现为BLA神经元中一个分子上不同的亚群提供了见解，该亚群以投射特异性方式调节环境线索-奖赏关联并驱动酒精诱导的动机行为。
