Characterisation of a novel interneuron type in the higher order thalamus

丘脑是前脑结构，从间脑原体节2（p2）1- 3发育而来，主要由皮质投射的兴奋性丘脑皮质（TC）神经元组成，在哺乳动物中分为30多个单独的核4-6。丘脑的功能在历史上被描述为将感觉信息传递到皮层7-13。考虑到丘脑皮层回路的输入和输出特征的多样性5，14 -17，最近的研究表明，丘脑不仅是一个中继器，而且还有助于关键计算，使行为灵活性17-25，包括注意力和唤醒的转移。与皮层网络相反，丘脑中的兴奋性神经元并不相互连接4，25 -27。相反，丘脑皮层回路内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）支配27-30。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25，31，32。特别是，在所有爬行动物（爬行动物，鸟类和哺乳动物）的比较研究已经描述了中间神经元的比例和兴奋性丘脑的大小和连接之间的相关性31，33。中间神经元在很大程度上局限于大脑较小的有袋动物，蝙蝠和小鼠的视觉丘脑，它们仅占总神经元群体的6% 33-35。另一方面，在灵长类动物中，由皮层输入驱动的高阶（HO）核相对于感觉中继被扩展，（一级，FO）区域33，36 -39，中间神经元存在于整个丘脑中，其比例增加到约30% 31，40。由Alessio Delogu领导的一个宿主实验室先前表明，在小鼠中，FO丘脑中最大比例的中间神经元起源于中脑，来自En 1 + Gata 2 + Otx 2 + Sox 14+谱系41. Delogulab的最近发现揭示了存在另外一类中间神经元，其来源于前脑中的Nkx2.1-Dlx 5+抑制性祖细胞结构域。有趣的是，这两类小鼠中间神经元根据它们的个体发育以空间模式组织，使得中脑产生的中间神经元主要存在于主要的感觉中继和模态相关的HO核中，而前脑产生的中间神经元存在于HO丘脑中，包括背内侧（MD），背外侧（LD）和背外侧（LP; aka枕）。基因结构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组织，其中假定的中脑产生的中间神经元在FO和HO核中丰富，并由在选定的HO相关TC核中富集的独特且更受限制的中间神经元类补充。以前在Delogu labhas的工作发现，小鼠丘脑中GABA能中间神经元的分布和多样性比以前更广泛报道31，34，35，包括FO感觉中继和HO丘脑核，包括在灵长类动物中最大的联合HO核。陈述主要的研究问题，并在适当的情况下验证主要的假设博士项目的总体目标是了解前脑衍生的Nkx2.1-Dlx 5+抑制性中间神经元谱系对丘脑组织和功能的具体贡献。我们假设前脑衍生的丘脑中间神经元具有独特的特性，与先前在感觉丘脑中描述的中脑衍生的中间神经元相比，这些特性更适合于支持更高的认知功能41。

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.