Department of Biology, Volen National Center for Complex Systems, Brandeis University, Waltham, Massachusetts 02454-9110.
Department of Biology, Volen National Center for Complex Systems, Brandeis University, Waltham, Massachusetts 02454-9110
J Neurosci. 2020 Nov 18;40(47):9066-9077. doi: 10.1523/JNEUROSCI.0782-20.2020. Epub 2020 Oct 26.
Dissociation between the output of the circadian clock and external environmental cues is a major cause of human cognitive dysfunction. While the effects of ablation of the molecular clock on memory have been studied in many systems, little has been done to test the role of specific clock circuit output signals. To address this gap, we examined the effects of mutations of () and its receptor, , on associative memory in male and female Loss of PDF signaling significantly decreases the ability to form associative memory. Appetitive short-term memory (STM), which in wild-type (WT) is time-of-day (TOD) independent, is decreased across the day by mutation of or , but more substantially in the morning than in the evening. This defect is because of PDFR expression in adult neurons outside the core clock circuit and the mushroom body (MB) Kenyon cells (KCs). The acquisition of a TOD difference in mutants implies the existence of multiple oscillators that act to normalize memory formation across the day for appetitive processes. Interestingly, aversive STM requires PDF but not PDFR, suggesting that there are valence-specific pathways downstream of PDF that regulate memory formation. These data argue that the circadian clock uses circuit-specific and molecularly diverse output pathways to enhance the ability of animals to optimize responses to changing conditions. From humans to invertebrates, cognitive processes are influenced by organisms' internal circadian clocks, the pace of which is linked to the solar cycle. Disruption of this link is increasingly common (e.g., jetlag, social jetlag disorders) and causes cognitive impairments that are costly and long lasting. A detailed understanding of how the internal clock regulates cognition is critical for the development of therapeutic methods. Here, we show for the first time that olfactory associative memory in requires signaling by Pigment-dispersing factor (PDF), a neuromodulatory signaling peptide produced only by circadian clock circuit neurons. We also find a novel role for the clock circuit in stabilizing appetitive sucrose/odor memory across the day.
生物钟输出与外部环境线索的脱节是人类认知功能障碍的主要原因。虽然许多系统已经研究了分子钟缺失对记忆的影响，但很少有研究测试特定时钟电路输出信号的作用。为了弥补这一空白，我们研究了 () 和其受体 () 的突变对雄性和雌性果蝇的联想记忆的影响。PDF 信号的缺失显著降低了形成联想记忆的能力。在野生型（WT）中，与奖赏有关的短期记忆（STM）不受时间的影响，但突变 或 后，其在一天中的变化与时间相关，而且在早晨比晚上更显著。这一缺陷是由于 PDFR 在核心时钟电路和蘑菇体（MB）Kenyon 细胞（KC）之外的成年神经元中的表达。在突变体中，TOD 差异的获得表明存在多个振荡器，这些振荡器作用于全天的记忆形成，使动物能够对变化的条件做出正常反应。有趣的是，厌恶 STM 需要 PDF，但不需要 PDFR，这表明 PDF 下游存在与效价特异性相关的通路，调节记忆形成。这些数据表明，生物钟利用特定于电路的分子多样性输出途径来增强动物优化对变化条件的反应能力。从人类到无脊椎动物，认知过程都受到生物体内部生物钟的影响，生物钟的节奏与太阳周期有关。这种联系的中断越来越常见（例如，时差、社交时差障碍），并导致代价高昂且持久的认知障碍。详细了解内部时钟如何调节认知对于治疗方法的发展至关重要。在这里，我们首次表明，果蝇的嗅觉联想记忆需要由生物钟电路神经元产生的神经调质信号肽 Pigment-dispersing factor (PDF) 来传递信号。我们还发现，时钟电路在稳定一天中与奖赏有关的蔗糖/气味记忆方面发挥了新的作用。
