轴突细胞(AACs),也被称为大脑皮层中的枝形吊灯细胞(ChCs),是新皮层中描述的最独特的GABA能中间神经元类型,海马体,和基底外侧杏仁核(BLA)。AAC在其轴突初始部分(AIS)选择性神经支配谷氨酸能投射神经元(PNs),因此,可以对PN尖峰施加决定性控制并调节PN功能集合。然而,整个大脑的分布,突触连接,AAC的电路功能仍然知之甚少,主要是由于缺乏具体可靠的实验工具。这里,我们建立了一种交叉遗传策略,根据其谱系(Nkx2.1)和分子(Unc5b,Pthlh)标记。我们发现AAC基本上部署在所有的大脑皮层来源的大脑结构中,不仅包括背侧大脑皮层衍生的新皮质和内侧大脑皮层衍生的海马结构,但也有来自横向的皮层-岛叶复合物,和腹侧大脑皮层衍生的扩展杏仁核复合体和嗅觉中心。嗅前核中也有大量的AAC,taeniatecta,和侧隔。AAC在新皮质区域和层以及海马结构的各个子区域中显示出密度的特征性变化。新皮质AAC包含多个层状亚型,具有不同的树突状和轴突树状模式。来自AACs的逆行单突触追踪穿过新皮质,海马,和BLA区域揭示了突触输入的共享和不同模式。AAC的具体和全面的靶向有助于研究它们的发育遗传程序和跨大脑结构的回路功能。为理解跨大脑区域和物种的真实细胞类型的保护和变化提供了一个基本事实平台。
无论我们是在记忆事实,还是在对一声巨响做出反应,不同大脑区域的神经细胞必须能够通过精确的,有意义的信号。称为中间神经元的特殊神经细胞充当“交通信号灯”,以精确调节这些信息在神经回路中的流动时间和位置。轴突细胞是一种罕见的抑制性中间神经元,被认为对于控制不同组兴奋性神经元之间的信息传递特别重要。这是因为它们只连接到靶细胞的一个关键部分——轴突初始部分——在那里启动了大脑交流所需的电信号(称为动作电位)。由于轴突细胞是抑制性中间神经元,这种联系有效地允许他们“否决”这些信号的产生。尽管已经使用传统的解剖学方法在三个大脑区域中鉴定了轴-轴突细胞,没有现成的“标签”可以可靠地识别它们。因此,关于这些细胞的许多信息仍然未知,包括它们在哺乳动物大脑中的分布。为了解决这个问题,Raudales等人。研究了哪些基因在轴突细胞中打开,而不是在其他细胞中打开,确定一个独特的分子特征,可以用来标记,记录,操纵这些细胞。对小鼠脑组织的显微镜成像显示,轴突细胞已经被鉴定出来,它们存在于比以前认为的更多的大脑区域,包括大脑皮层的几乎所有区域,甚至下丘脑,控制着许多与生俱来的行为。轴突细胞也有不同的“连接”,取决于它们的位置;例如,与记忆和情绪相关的大脑区域比其他区域有更广泛的输入联系。Raudales等人的发现。提供,第一次,一种直接追踪和操纵大脑轴突细胞的方法。由于轴突细胞的功能障碍也与癫痫和精神分裂症等神经系统疾病有关,深入了解它们的分布和连通性可能有助于开发针对这些疾病的更好治疗方法。
Axo-axonic cells (AACs), also called chandelier cells (ChCs) in the cerebral cortex, are the most distinctive type of GABAergic interneurons described in the neocortex, hippocampus, and basolateral amygdala (BLA). AACs selectively innervate glutamatergic projection neurons (PNs) at their axon initial segment (AIS), thus may exert decisive control over PN spiking and regulate PN functional ensembles. However, the brain-wide distribution, synaptic connectivity, and circuit function of AACs remain poorly understood, largely due to the lack of specific and reliable experimental tools. Here, we have established an intersectional genetic strategy that achieves specific and comprehensive targeting of AACs throughout the mouse brain based on their lineage (Nkx2.1) and molecular (Unc5b, Pthlh) markers. We discovered that AACs are deployed across essentially all the pallium-derived brain structures, including not only the dorsal pallium-derived neocortex and medial pallium-derived hippocampal formation, but also the lateral pallium-derived claustrum-insular complex, and the ventral pallium-derived extended amygdaloid complex and olfactory centers. AACs are also abundant in anterior olfactory nucleus, taenia tecta, and lateral septum. AACs show characteristic variations in density across neocortical areas and layers and across subregions of the hippocampal formation. Neocortical AACs comprise multiple laminar subtypes with distinct dendritic and axonal arborization patterns. Retrograde monosynaptic tracing from AACs across neocortical, hippocampal, and BLA regions reveal shared as well as distinct patterns of synaptic input. Specific and comprehensive targeting of AACs facilitates the study of their developmental genetic program and circuit function across brain structures, providing a ground truth platform for understanding the conservation and variation of a bona fide cell type across brain regions and species.
Whether we are memorising facts or reacting to a loud noise, nerve cells in different brain areas must be able to communicate with one another through precise, meaningful signals. Specialized nerve cells known as interneurons act as “traffic lights” to precisely regulate when and where this information flows in neural circuits. Axo-axonic cells are a rare type of inhibitory interneuron that are thought to be particularly important for controlling the passage of information between different groups of excitatory neurons. This is because they only connect to one key part of their target cell – the axon-initial segment – where the electrical signals needed for brain communication (known as action potentials) are initiated. Since axo-axonic cells are inhibitory interneurons, this connection effectively allows them to ‘veto’ the generation of these signals at their source. Although axo-axonic cells have been identified in three brain regions using traditional anatomical methods, there were no ‘tags’ readily available that can reliably identify them. Therefore, much about these cells remained unknown, including how widespread they are in the mammalian brain. To solve this problem, Raudales et al. investigated which genes are switched on in axo-axonic cells but not in other cells, identifying a unique molecular signature that could be used to mark, record, and manipulate these cells. Microscopy imaging of brain tissue from mice in which axo-axonic cells had been identified revealed that they are present in many more brain areas than previously thought, including nearly all regions of the broadly defined cerebral cortex and even the hypothalamus, which controls many innate behaviors. Axo-axonic cells were also ‘wired up’ differently, depending on where they were located; for example, those in brain areas associated with memory and emotions had wider-ranging input connections than other areas. The finding of Raudales et al. provide, for the first time, a method to directly track and manipulate axo-axonic cells in the brain. Since dysfunction in axo-axonic cells is also associated with neurological disorders like epilepsy and schizophrenia, gaining an insight into their distribution and connectivity could help to develop better treatments for these conditions.