Characterisation of a novel interneuron type in the higher order thalamus

丘脑是由间脑前体2(P2)1-3发育而来的前脑结构，主要由皮质投射的兴奋性丘脑皮质(TC)神经元组成，在哺乳动物4-6中分为30多个单独的核团。丘脑的功能历来被描述为将感觉信息传递到大脑皮层7-13。考虑到丘脑皮质回路5，14-17的输入和输出特征的多样性，最近的研究表明，丘脑不仅是一个中继器，而且对允许行为灵活性17-25，包括注意力转移和唤醒的关键计算也有贡献。与皮质网络相反，丘脑中的兴奋性神经元不相互连接，4，25-27。相反，丘脑皮质回路中的局部连接和计算由常驻的抑制性GABA释放神经元(中间神经元)27-30主导。中间神经元的数量和分布在不同物种之间差异很大，这表明它们在丘脑皮质结构和功能的进化中起着至关重要的作用。特别是，对所有羊膜动物(爬行动物、鸟类和哺乳动物)的比较研究描述了中间神经元的比例与兴奋性丘脑31、33的大小和连通性之间的相关性。在大脑较小的有袋类动物、蝙蝠和老鼠中，中间神经元主要局限于视觉丘脑，在这些动物中，它们只占神经元总数的6%，33-35。另一方面，在灵长类动物中，由皮质输入驱动的高阶(HO)核相对于感觉中继(一级，FO)区域33，36-39扩展，中间神经元存在于整个丘脑，其比例增加到约30%31，40。由Alessio Delogu领导的宿主实验室之一先前已经表明，在小鼠中，FO丘脑中最大比例的中间神经元起源于中脑EN1+Gata2+OTX2+Sox14+谱系41。Delogulab的最新发现表明，在前脑中存在另一类来自Nkx2.1-Dlx5+前体区域的中间神经元。有趣的是，这两类小鼠中间神经元根据它们的个体发育被组织在一个空间模式中，这样中脑出生的中间神经元主要存在于主要的感觉中继核和与通道相关的HO核，而前脑产生的中间神经元存在于HO丘脑，包括背内侧(MD)、背外侧(LD)和后侧(LP；又名枕区)。基因构筑学证据支持非人灵长类绒猴丘脑中丘脑中间神经元的保守基本结构，推测中脑产生的中间神经元富含FO和HO核，并得到一个独特且更受限的中间神经元类别的补充，这些中间神经元富含选定的HO相关TC核。综上所述，Delogu Labhasidity的先前工作在小鼠丘脑中发现了比先前报道的31，34，35更广泛的GABA中间神经元的分布和多样性，包括FO感觉中继核和HO丘脑核，包括在灵长类中最大的联合HO核。陈述主要研究问题，并在适当的情况下测试主要假设博士项目的总体目标是了解前脑衍生的Nkx2.1-Dlx5+抑制中间神经元谱系对丘脑组织和功能的具体贡献。我们假设，与之前在感觉丘脑41中描述的中脑衍生的中间神经元相比，前脑衍生的丘脑中间神经元具有更适合支持更高认知功能的独特特性。

The thalamus is a forebrain structure that develops from the diencephalic prosomere 2 (p2) 1-3and is primarily composed of cortically projecting excitatory thalamocortical (TC) neurons, divided into more than 30 individual nuclei in mammals 4-6. The function of the thalamus has been historically described as relay of sensory information to the cortex 7-13. Taking into account the diversity of input and output features of thalamocortical circuits 5,14-17, more recent work has shown that the thalamus is notjust a relay, but also contributesto criticalcomputations thatallowfor behavioural flexibility 17-25, including shifts in attention and arousal.In contrast to cortical networks, excitatory neurons in the thalamus do not connect with each other 4,25-27. Instead, local connections and computations within thalamocortical circuits are dominated by the resident inhibitory, GABA-releasing neurons (interneurons) 27-30. Interneuron numbers and distribution vary widely across species, suggesting that they are critically involved in the evolution of thalamocortical structure and function 25,31,32. In particular, comparative studies across all amniotes (reptiles, birds and mammals) have described a correlation between the proportion of interneurons and the size and connectivity of the excitatory thalamus 31,33. Interneurons are largely restricted to the visual thalamus in smaller-brained marsupials, bats and mice, where they represent only 6% of the total neuronal population 33-35. In primates, on the other hand, where higher order (HO) nuclei driven by cortical inputs are expanded relative to sensory relay (first order, FO) regions 33,36-39, interneurons are present across the entire thalamus and their proportion increases to around 30% 31,40.One of the host labs, headed by Alessio Delogu,hadpreviously shown that in the mouse, the largest proportion of interneurons in the FO thalamusoriginate in the midbrain from an En1+Gata2+Otx2+Sox14+lineage 41.A recent discovery in the Delogulab revealed thatthere is an additional classof interneuronsthat derives from the Nkx2.1-Dlx5+inhibitory progenitor domains in the forebrain. Intriguingly, the two classes ofmouse interneurons are organized in a spatial pattern according to their ontogeny, such that midbrain-born interneurons are largely found in the principal sensory relays and modality-related HO nuclei, while the forebrain-generated interneurons reside in the HO thalamus, including medio dorsal (MD), laterodorsal (LD) and lateral posterior (LP; aka pulvinar). Genoarchitectonicevidence supports a conserved basic organization of thalamic interneurons in the non-human primate marmoset thalamus, where putative midbrain-generated interneurons are abundant in FO and HO nuclei and complemented by a distinct and more restricted interneuron class enriched in selected HO associative TC nuclei.Insummary,previous work in the Delogu labhasidentifieda wider distributionand diversityof GABAergicinterneurons in the thalamus of the mouse than previously reported 31,34,35, encompassing both FO sensory relay and HO thalamic nuclei, including associative HO nuclei that are most enlarged in primates. State primary research question and where appropriate the primary hypotheses being testedThe overall aim of thePhD project is to understand the specific contribution of the forebrain-derivedNkx2.1-Dlx5+inhibitory interneuron lineage to thalamic organisation and function. We hypothesise that forebrain-derived thalamic interneurons possess unique properties that are bettersuited to supportinghigher cognitive functionsas compared to the midbrain-derived interneurons that were previously described in the sensory thalamus 41.