Dissecting asymmetric habenular neural circuit formation and function in vivo

神经网络的形成需要严格控制，以避免从精神疾病到运动性疾病等对有机体的毁灭性后果。神经元是一种特殊的细胞，在网络发育过程中，突起(轴突)在所有动物的身体中延伸到不同的距离。在他们的途中，轴突受到外部信号的影响，以寻找并最终精确地支配他们的目标。我们研究斑马鱼缰核回路作为神经网络形成和功能的活体模型。保守的双侧缰核由背侧和腹侧缰核(dHb和vHb)不同的神经元群组成。有趣的是，dHb在许多脊椎动物的中线上是不对称的，例如关于神经元亚群的细胞数量。DHB神经元从前脑的前体细胞池中发育而来。我们最近的工作揭示了Wnt信号影响前体细胞内这一发育程序的基本机制，这对建立脑不对称非常重要。我们还可以证明，同样的途径对于VHB的形成是必不可少的，我们的目标是解决潜在的机制。通常的神经元发出纵向投射，这些投射在大脑的两侧似乎是协调的，最终在大约300微米的距离内神经支配它们的靶点。我们应用双光子显微镜长期成像和计算深度颜色编码来跟踪缰核神经网络在单个轴突水平上的三维体积形成。我们将这一多功能系统与激光消融神经元相结合，阐明了在4天内网络形成过程中的关键事件，并研究了其组件的功能相关性。这让我们发现了一种有趣的机制，即缰核轴突使用连接大脑两侧的第二个网络来协调它们的伸长。现在不可避免的目标是找到大脑半球间信息交换的重要分子。缰核网络整合了嗅觉和视觉信息等认知输入，参与从恐惧到奖励反应的各种行为。功能障碍会导致病理生理综合征。我们现在知道缰核神经回路是如何在活胚胎中发育的，我们有工具和资源来从基因和物理上操纵它的不对称性和侧向性。这使我们在阐明用于整合认知刺激的轴突通路方面处于领先地位。缰核轴突将这些神经元从前脑转移到中脑和后脑。通过建立这些连接的功能投影图，我们可以分析精确网络操作的功能后果。这些研究将有助于我们理解神经网络的功能和大脑的功能偏侧化。

Neural network formation needs to be tightly controlled to avoid devastating consequences for the organism ranging from mental illnesses to motoric diseases. Neurons are specialized cells, which during network development extend protrusions (axons) over various distances through the body of all animals. On their way, the axons are influenced by extrinsic signals to find and eventually precisely innervate their targets. We study the zebrafish habenular circuitry as an in vivo model for neural network formation and function. The conserved bilaterally formed habenulae consist of distinct groups of neurons named dorsal and ventral habenulae (dHb and vHb). Intriguingly, the dHb are established asymmetrically across the midline in many vertebrates regarding for instance the cell number of neuronal subpopulations. dHb neurons develop from pools of precursor cells in the forebrain. Our recent work has uncovered a fundamental mechanism by which Wnt signaling influences this developmental program within precursor cells important for the establishment of brain asymmetry. We can also show that the same pathway is essential for the formation of the vHb and we aim to address the underlying mechanism.Habenular neurons send out longitudinal projections, which elongate seemingly coordinated on either side of the brain and eventually innervate their targets in about 300 µm distance. We apply 2-photon microscopy long-term imaging and computational depth colour coding to follow habenular neural network formation on a single axon level in the 3-D volume. We combine this versatile system with laser ablations of neurons elucidating the key-events during network formation over 4 days and to study the functional relevance of its components. This allowed us to uncover an intriguing mechanism by which habenular axons use a second network connecting the two sides of the brain to coordinate their elongation. The inevitable goal now is to find the molecules important for the interhemispheric exchange of information.The habenular network integrates cognitive input such as olfactory and visual information and is involved in various behaviors ranging from fear to reward responses. Functional impairment causes pathophysiological syndromes. We now know how the habenular neural circuit develops in the living embryo and we have the tools and resources to manipulate its asymmetry and laterality genetically and physically. This puts us in a headstart position to elucidate the axonal pathways used to integrate cognitive stimuli. Habenular axons transfer these from the forebrain into the mid- and hindbrain. By establishing a functional projection map of these connections, we can analyse the functional consequences of precise network manipulations. These studies will substantially contribute to our understanding of neural network function and functional lateralization of the brain.