Srivastava Snigdha, Wang I-Ching, Kochukov Mikhail Y, Swanson Jessica L, Costa-Mattioli Mauro, Arenkiel Benjamin R
Genetics and Genomics Graduate Program, Baylor College of Medicine, Houston, TX, United States.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.
Front Behav Neurosci. 2025 Jul 29;19:1646689. doi: 10.3389/fnbeh.2025.1646689. eCollection 2025.
Despite the rise in psychiatric disorders worldwide, the underlying brain circuits responsible for these devastating conditions remain elusive. The lateral habenula (LHb) has emerged as a key brain structure in depression studies due to its hyperactive state in both patients and animal models. While this aligns with known roles in driving aversive states and regulating serotonin release, it is still unclear how acute and transient activity changes in the LHb can influence higher order cognitive processes such as learning, memory, and behavioral adaptation. Given the importance of these processes to psychiatric conditions, understanding how LHb activity impacts cognitive function allows novel insights into the neurobiological mechanisms of disorders like depression.
Towards this goal, we used chemogenetic activation to temporarily excite glutamatergic neurons in the mouse LHb and assessed impacts on associative memory.
Surprisingly, we found that transient activation of LHb impaired long-term memory, without affecting anxiety or depression-like behaviors. Specifically, post-training activation of LHb glutamatergic neurons disrupted object recognition and reward-based associative long-term memory, while sparing fear associated long-term memory. The memory impairment was restricted to a critical temporal window post-training/conditioning that corresponded with the consolidation stage of long-term memory. Strikingly, pairing LHb glutamatergic neuronal activation with systemic ketamine administration rescued the long-term memory deficits, indicating that LHb glutamatergic neurons modulate consolidation of associative memories via a NMDA-mediated mechanism. Together, these findings support a novel role for LHb glutamatergic neuronal activity in the consolidation of associative long-term memories.
尽管全球精神疾病发病率呈上升趋势，但导致这些破坏性疾病的潜在脑回路仍不明确。外侧缰核（LHb）已成为抑郁症研究中的关键脑结构，因为在患者和动物模型中它都处于过度活跃状态。虽然这与已知的驱动厌恶状态和调节血清素释放的作用相符，但目前仍不清楚LHb中急性和短暂的活动变化如何影响诸如学习、记忆和行为适应等高阶认知过程。鉴于这些过程对精神疾病的重要性，了解LHb活动如何影响认知功能有助于深入洞察抑郁症等疾病的神经生物学机制。
为实现这一目标，我们使用化学遗传学激活方法来暂时兴奋小鼠LHb中的谷氨酸能神经元，并评估其对联想记忆的影响。
令人惊讶的是，我们发现LHb的短暂激活会损害长期记忆，而不影响焦虑或类似抑郁的行为。具体而言，训练后激活LHb谷氨酸能神经元会破坏物体识别和基于奖励的联想长期记忆，而不影响与恐惧相关的长期记忆。记忆损害仅限于训练/条件化后的关键时间窗口，该窗口与长期记忆的巩固阶段相对应。引人注目的是，将LHb谷氨酸能神经元激活与全身给予氯胺酮配对可挽救长期记忆缺陷，这表明LHb谷氨酸能神经元通过NMDA介导的机制调节联想记忆的巩固。总之，这些发现支持了LHb谷氨酸能神经元活动在联想长期记忆巩固中的新作用。
