Complex neuromodulatory processes in the locus coeruleus neuron-astrocyte network

蓝斑神经元星形胶质细胞网络中复杂的神经调节过程

• 批准号: RGPIN-2020-05514
• 负责人: Ballanyi, Klaus
• 金额: $ 2.62万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=740577
• 关键词: Complex; neuromodulatory; processes; locus; coeruleus

The locus coeruleus (LC) in the brainstem innervates most brain areas with synapses that release the chemical neurotransmitter noradrenaline (NA) to control behaviors like memory, anxiety, pain sensation or breathing. It is thought that the LC is a `simple' brain circuit in which spontaneous action potential (`spike') discharge is synchronous to facilitate rhythmic NA release in the target areas. However, recent in vivo studies indicate that the LC is rather a complex network capable of generating different spike `burst' patterns within neuron clusters that receive from other brain areas synaptic input involving diverse neurotransmitters. Accordingly, such presumptive `LC modules' may express different neurotransmitters receptors, e.g. for glutamate, dopamine or endogenous opioids that are all pivotal for brain cell communication. Astrocytic glial cells in the vicinity of the neurons might contribute to complex LC activities as in other brain areas. Indeed, there is evidence that LC neurons are excited by lactate released from adjacent astrocytes. All this indicates that the LC is NOT a simple circuit. The proposed research aims at testing the Overarching Hypothesis: The LC is a complex neuromodulatory network in which neurotransmitters and neuron-astrocyte interactions shape spike burst output patterns and thus the efficacy of pulsed NA release. We are qualified for this research based on our previous extensive in vitro studies of spontaneously active neuron-astrocyte networks, e.g. in the spinal cord, hippocampus, cortex or breathing center. For this, we combine pharmacological manipulations with electrophysiological recording of local field potentials (LFP) and membrane potential from an individual cell plus imaging of signaling factors. For example, we image changes of intracellular calcium or membrane potential with chemical dyes and, since several years, with genetically-engineered fluorescent protein sensors. Regarding the proposed research, we reported recently that LC neurons in newborn rat brain slices spontaneously generate phase-locked, non-synchronous spikes. Moreover, spikes in single neurons overlap to form bell-shaped LFP bursts and this LC population burst pattern changes profoundly in response to glutamate or activators of ionotropic glutamate receptor (iGluR) subtypes. Our preliminary findings show that activation of opioid and NA receptor subtypes transforms the LC burst pattern in different fashion. Here, we will identify mechanisms by which (i) neurotransmitter receptors modulate LC activity and (ii) lactate released from astrocytes stimulates LC neurons. Our research will show that the LC has intrinsic mechanisms for adapting its discharge pattern under the influence of specific neurotransmitters and signals from astrocytes. This complex behavior is likely pivotal to enable this small brain structure to affect specifically the different activities of numerous target brain areas that are involved in distinct behaviors.

脑干中的蓝斑(LC)通过突触支配大脑的大部分区域，这些突触释放化学神经递质去甲肾上腺素(NA)来控制记忆、焦虑、痛感或呼吸等行为。一般认为，LC是一种“简单”的脑回路，其中自发动作电位(“棘波”)的放电是同步的，以促进靶区有节律性的NA释放。然而，最近的活体研究表明，LC是一个相当复杂的网络，能够在从其他脑区接受突触输入的神经元簇中产生不同的峰“爆发”模式，涉及不同的神经递质。因此，这种假定的“LC模块”可能表达不同的神经递质受体，例如谷氨酸、多巴胺或内源性阿片类药物，这些都是脑细胞通讯的关键。与其他脑区一样，神经元附近的星形胶质细胞可能参与了复杂的LC活动。事实上，有证据表明LC神经元是由邻近星形胶质细胞释放的乳酸兴奋的。所有这些都表明LC不是一个简单的电路。这项研究旨在验证这一最重要的假说：LC是一个复杂的神经调节网络，其中神经递质和神经元-星形胶质细胞的相互作用塑造了棘波爆发的输出模式，从而影响了脉冲NA释放的效果。根据我们之前对自发活跃的神经元-星形胶质细胞网络进行的广泛的体外研究，例如在脊髓、海马体、皮质或呼吸中心，我们有资格进行这项研究。为此，我们将药物操作与局部场电位(LFP)和单个细胞的膜电位的电生理记录以及信号因子的成像相结合。例如，我们使用化学染料成像细胞内钙离子或膜电位的变化，并在几年后使用基因工程荧光蛋白传感器。关于拟议的研究，我们最近报道了新生大鼠脑片中的LC神经元自发地产生锁相的、非同步的尖峰电位。此外，单个神经元中的棘波重叠形成钟状LFP爆发，这种LC群体爆发模式因谷氨酸或离子谷氨酸受体(IGluR)亚型的激活剂而发生深刻变化。我们的初步发现表明，阿片和NA受体亚型的激活以不同的方式改变LC猝发模式。在这里，我们将确定(I)神经递质受体调节LC活动的机制和(Ii)星形胶质细胞释放的乳酸刺激LC神经元的机制。我们的研究将表明，在特定神经递质和星形胶质细胞信号的影响下，LC具有适应其放电模式的内在机制。这种复杂的行为可能是关键，使这个小的大脑结构能够特别地影响与不同行为有关的许多目标大脑区域的不同活动。