Functional role of dual neurotransmission in aggression

摘要 双重神经传递有可能改变我们认为神经元信号和 信息在电路和网络中的传输。双重传播的重要性从以下几个方面可见一斑 在每个系统中识别出的双传递神经元的数量越来越多。然而，我们仍然 对共同传播的监管和功能影响的洞察力有限。在我们之前的 资助期内，我们建立了：1)大多数章鱼(OA，无脊椎动物的类似物 去甲肾上腺素)，神经元共表达谷氨酸，2)OA和谷氨酸有重叠，也有明显的， 在生殖和攻击行为中的作用，以及3)操纵谷氨酸-骨关节炎神经元亚群导联 到高强度的攻击性。尽管攻击性是社会行为的重要组成部分 物种，当表达水平上升时，对人类的攻击性可能威胁生命并导致经济损失 给社会带来的负担。鉴于保持攻击性和攻击性之间关键平衡的重要性 了解双传输信令的一般含义，在此建议中，我们 确定限制攻击性的分子和生理机制以及 动态监管共递质的释放。利用我们对攻击性的深刻理解- 为了促进神经元、遗传工具和功能成像，我们将在三个具体目标上测试我们的假设。 首先，使用荧光生物传感器来可视化神经递质的释放，并使用钙离子成像来量化神经元 活性，我们将检验谷氨酸能和肾上腺素能受体由谷氨酸-OA表达的假设 神经元是调节共同传递所必需的。第二，使用表位标记的囊泡 转运体和抗体我们将检验性别二态谷氨酸-OA神经元表现出的假设 VGLUT水平随年龄的动态变化。最后，我们将确定VMAT-VGLUT终端 表型依赖于突触后神经元的外部信号。我们研究的意义在于 它解决了一个基本的神经科学问题，即分子和潜在的性二型性 对双重传播现象的管制，以及可能导致以 谷氨酸-单胺能神经元内的谷氨酸能系统作为一种未被检查的疾病的治疗策略 攻击性。

ABSTRACT Dual neurotransmission has the potential to transform the way we consider neuronal signaling and the transmission of information within circuits and networks. The importance of dual transmission is evident by the large and increasing number of identified dual transmitting neurons in every system. However we still have only limited insight into the regulation and functional effects of co-transmission. During our previous funding period, we established: 1) the majority of octopamine (OA, the invertebrate analogue of norepinephrine), neurons co-express glutamate, 2) OA and glutamate have overlapping, as well as distinct, roles in reproductive and aggressive behaviors, and 3) manipulation of a glutamate-OA neuronal subset leads to high intensity aggression. Although aggression is a critical component of social behavior observed across species, when expressed at elevated levels aggression in humans can threaten lives and incur economic burdens on society. Given the importance of maintaining a critical balance of aggression and understanding the implications of dual transmission signaling in general, in this proposal we are identifying the molecular and physiological mechanisms that constrain aggression as well as dynamically regulate the release of co-transmitters. Leveraging our deep understanding of aggression- promoting neurons, genetic tools, and functional imaging, we will test our hypothesis in three specific aims. First, using fluorescent biosensors to visualize neurotransmitter release and Ca2+ imaging to quantify neuron activity, we will test the hypothesis that glutamatergic and adrenergic receptors expressed by glutamate-OA neurons are required for the regulation of co-transmission. Second, using epitope-tagged vesicular transporters and antibodies we will test the hypothesis that sexually dimorphic glutamate-OA neurons exhibit dynamic age-related changes in VGLUT levels. Finally, we will determine if VMAT-VGLUT terminal phenotypes are dependent on external cues from postsynaptic neurons. The significance of our study is that it addresses a fundamental neuroscience question, namely the molecular and potentially sexually dimorphic regulation of the dual transmission phenomenon, as well as potentially leading to the targeting of the glutamatergic system within glutamate-monoamine neurons as a therapeutic strategy for unchecked aggression.