Role of morphologically and developmentally diverse dopaminergic neurons in olfactory circuit processing

包括人类在内的哺乳动物的大脑由高度互联的神经元细胞网络组成。神经元通过产生小电流来相互交流，这些电流通过称为突触的特殊连接中心发送给其他神经元。突触通讯构成了信息传递的基础，并允许大脑计算来自环境的输入（如气味），并将其转化为适当的行为（如觅食，或避免有毒物质）。与皮肤细胞等其他细胞不断产生和替换不同，神经元只有在动物胚胎发育期间才会诞生。然后，它们形成并完善适当的突触连接，并在整个生命周期中保持不变。产生神经元的时间窗口很窄，这意味着大脑在受伤后无法在成年期自我修复。另一方面，这种固定的发育时期具有提供细胞、网络和突触连接的稳定框架的优势，这将有助于以一致的方式处理信息。然而，正如生物学中经常出现的情况一样，这一普遍规律也有例外：在动物的一生中，有三种类型的神经元能够持续产生。其中一类“打破规则”的神经元被称为多巴胺能神经元，位于嗅觉球中，这是大脑中编码气味的关键区域之一。直到最近，科学家们才相信所有的球多巴胺能神经元都能终生生成，但最近的证据表明情况并非如此。事实上，嗅球中共存着两类多巴胺能神经元：一种是“打破规则”的神经元，可以在整个生命过程中产生，体积很小；另一种是“遵守规则”的神经元，只在动物胚胎发育期间产生，体积相当大。这两种多巴胺能神经元的作用是什么？这个项目将通过观察(1)嗅觉网络中的哪些其他神经元通过突触向多巴胺能神经元的亚型发送信息来回答这个问题；(2)嗅觉网络中的其他神经元通过突触接收来自多巴胺能神经元亚型的信息；(3)多巴胺能神经元的两种亚型对动物处理和反应气味的能力有何影响。我们的假设是，在动物的一生中，能够产生的小多巴胺能神经元通过突触与很少的近邻连接在一起，并有助于动物对气味的敏感性——例如，区分新鲜薄荷茶的大量薄荷气味和口香糖的少量薄荷气味的能力。另一方面，我们预测在胚胎发育过程中产生的大多巴胺能细胞，并在动物的一生中稳定存在，与嗅觉网络中大量的近邻和远邻神经元建立许多突触连接。在行为层面上，我们认为这些影响深远且发育稳定的多巴胺能神经元促进了动物区分不同气味的能力——例如，区分新鲜薄荷茶和咖啡的能力。研究嗅觉、神经元发育和细胞多样性的神经科学家，以及研究嗅觉疾病（包括covid - 19）的临床医生，将对这些结果感兴趣。此外，通过研究嗅觉区域中可以终生再生的神经元群（如上所述，这是一种非常罕见的能力），我们将为转化研究提供有价值的见解，这些研究旨在用功能性细胞替代退化的脑细胞。

The brain of mammals, humans included, consists of highly interconnected networks of cells called neurons. Neurons communicate with each other by producing small electrical currents, which they send to other neurons at specialized connection hubs called synapses. Synaptic communication forms the basis of information transfer, and allows the brain to compute inputs coming from the environment (such as smells) and to transform them into appropriate behaviours (such as foraging for food, or avoiding toxic substances). Contrary to other cells such as those in the skin, which are continuously produced and replaced, neurons are born only during the animal's embryonic development. They then form and refine the appropriate synaptic connections, and stay in place for the entire lifespan. This narrow time window to generate neurons means that the brain cannot repair itself in adulthood following injury. On the other hand, this fixed developmental period has the advantage of providing a stable framework of cells, networks and synaptic connections that will be instrumental to process information in a consistent way. However, as it is often the case in biology, this general rule has exceptions: three types of neurons have the ability to be continuously generated during the animal's lifetime. One class of these "rule-breaking" neurons are called dopaminergic and are located in the olfactory bulb, one of the key brain areas that encode smells. Up until recently scientists believed that all bulbar dopaminergic neurons were capable of lifelong generation, but recent evidence has demonstrated that this is not the case. Indeed, two classes of dopaminergic neurons co-exist in the olfactory bulb: the "rule-breaker" ones who can be generated throughout life and are quite small, and the "rule-follower" ones which are born only during the animal's embryonic development and are fairly large. What do these two subtypes of dopaminergic neurons do? This project will answer this question by looking at (1) which other neurons in the smell network send information via synapses to the subtypes of dopaminergic neurons; (2) which other neurons in the smell network receive information via synapses from the subtypes of dopaminergic neurons; (3) what is the effect of the two subtypes of dopaminergic neurons on the animal's ability to process and respond to smells. Our hypothesis is that the small dopaminergic neurons capable of being born during the lifespan of the animals are connected via synapses with few close neighbours, and contribute to the animal's sensitivity to smells - for example, the ability to distinguish between a lot of menthol odour coming from a fresh mint tea, versus a little menthol odour coming from a chewing gum. On the other hand we predict that the large dopaminergic cells born during embryonic development, and which stably persist throughout the animals' life, make many synaptic connections with a large number of near and far neighbouring neurons in the olfactory network. At the behavioural level, we believe that these far-reaching and developmentally-stable dopaminergic neurons facilitate the animal's ability to discriminate different smells - for example, the ability to distinguish between a fresh mint tea and a coffee. These results will be of interest to neuroscientists working on olfaction, neurons development and cell diversity, as well as to clinicians working on disorders involving the sense of smell (including Covid19). Moreover, by studying a population of neurons in the olfactory areas that can regenerate throughout life (which, as mentioned above, is a very rare ability), we will provide valuable insights to translational research that looks into replacing brain cells that have degenerated with functional ones.