Aldh1a1 neurons are a subtype of gamma-aminobutyric acid (GABA) inhibitory neurons that use Aldh1a1 rather than glutamate decarboxylase (GAD) as an enzyme for synthesizing GABA transmitters. However, the behaviors and circuits of this newly identified subtype of inhibitory interneurons remain unknown. We generated a mutant mouse line in which cyclization recombination enzyme (CRE) was expressed under the control of the Aldh1a1 promotor (Aldh1a1-CRE mice). Using this mutant strain of mice together with the heterozygous male Alzheimer’s disease (AD) related model mice (APPswe/PSEN1dE9, or AD mice) and a genetically modified retrograde and anterograde synaptic tracing strategy, we have studied a specific synaptic circuit of Aldh1a1 neurons with system-level function and disease progression in AD mice. We demonstrate that Aldh1a1 neurons encode delay of gratification that measures self-control skills in decision making by projecting inhibitory synapses directly onto excitatory glutamate neurons in the intermediate lateral septum (EGNIS) and receiving synaptic inputs from layer 5b pyramidal neurons in the medial prefrontal cortex (L5PN). L5PN → Aldh1a1 synaptic transmission undergoes long-term potentiation (LTP). Pathway specific inhibition by either genetic silencing presynaptic terminals or antagonizing postsynaptic receptors impairs delay of gratification, resulting in the impulsive behaviors. Further studies show that reconstitution of Aldh1a1-deficient neurons with the expression of exogenous Aldh1a1 (eAldh1a1) restores Aldh1a1 → EGNIS synaptic transmission and rescues the impulsive behaviors in AD mice. These results not only identify a specific function and circuit of Aldh1a1 neurons but also provide a cellular point of entry to an important but understudied synaptic mechanism for the induction of impulsive behaviors at an early stage of AD.

中文翻译：

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腹侧被盖区 Aldh1a1 神经元的突触功能障碍导致冲动行为

Aldh1a1 神经元是γ-氨基丁酸 (GABA) 抑制性神经元的一种亚型，它使用 Aldh1a1 而不是谷氨酸脱羧酶 (GAD) 作为合成 GABA 递质的酶。然而，这种新发现的抑制性中间神经元亚型的行为和回路仍然未知。我们生成了一个突变小鼠系，其中环化重组酶 (CRE) 在 Aldh1a1 启动子（Aldh1a1-CRE 小鼠）的控制下表达。使用这种小鼠突变品系与杂合雄性阿尔茨海默氏病 (AD) 相关模型小鼠（APPswe/PSEN1dE9 或 AD 小鼠）和转基因逆行和顺行突触追踪策略，我们研究了 Aldh1a1 神经元的特定突触回路AD 小鼠的系统级功能和疾病进展。我们证明，Aldh1a1 神经元编码延迟满足，通过将抑制性突触直接投射到中间外侧隔膜 (EGNIS) 中的兴奋性谷氨酸神经元并接收来自内侧前额叶皮层 5b 层锥体神经元的突触输入来衡量决策制定中的自我控制技能。 L5PN）。L5PN → Aldh1a1 突触传递经历长期增强 (LTP)。通过遗传沉默突触前末端或拮抗突触后受体的途径特异性抑制会损害满足延迟，从而导致冲动行为。进一步的研究表明，用外源性 Aldh1a1 (eAldh1a1) 的表达重建 Aldh1a1 缺陷神经元可恢复 Aldh1a1 → EGNIS 突触传递并挽救 AD 小鼠的冲动行为。