November 08, 2017; Volume 37,Issue 45

细胞/分子

【标题】1. Foxp1在前脑锥体神经元控制空间学习和突触可塑性所需的基因表达(Foxp1 in Forebrain Pyramidal Neurons Controls Gene Expression Required for Spatial Learning and Synaptic Plasticity)

【作者】Daniel J. Araujo, Kazuya Toriumi, Christine O. Escamilla, Ashwinikumar Kulkarni, Ashley G. Anderson, Matthew Harper, Noriyoshi Usui, Jacob Ellegood, Jason P. Lerch, Shari G. Birnbaum, Haley O. Tucker, Craig M. Powell and Genevieve Konopka

【链接】https://doi.org/10.1523/JNEUROSCI.1005-17.2017

【关键词】自闭症，基因表达，海马，空间学习，突触可塑性(autism, gene expression, hippocampus, spatial learning, synaptic plasticity)

【摘要】转录因子Forkhead Box P1（FOXP1）的遗传扰动是通常伴有智力障碍的严重形式的自闭症谱系障碍的致病因素。最近的工作已经开始显示FoxP1在大脑发育中的重要作用，但是Foxp1对自闭症和智力障碍表型的脑区特异性贡献尚未完全确定。在这里，我们描述Foxp1有条件的敲除（Foxp1cKO）的雄性和雌性小鼠与新皮层的锥体神经元和海马的CA1 / CA2子域中的Foxp1的损失。 Foxp1cKO小鼠表现出与自闭症谱系障碍潜在相关的行为表型，包括活动过度，焦虑增加，交流障碍和社交能力下降。另外，Foxp1cKO小鼠在与智力障碍有关的学习和记忆任务中具有严重缺陷。使用全基因组的方法，我们确定了与突触功能和发育相关的Foxp1cKO小鼠的海马中差异表达的基因。此外，使用磁共振成像，我们发现整个海马体积以及Foxp1cKO小鼠的单个海马亚区的体积显着减少。最后，我们观察到这些突变小鼠海马CA1区LTP的维持减少。总之，这些数据表明Foxp1在前脑锥体神经元中的正确表达对于调节基因表达途径是重要的，所述基因表达途径有助于使人想起在自闭症和智力障碍中看到的那些特定行为。特别地，Foxp1基因表达的调节似乎对正常海马发育，CA1可塑性和空间学习至关重要。(Genetic perturbations of the transcription factor Forkhead Box P1 (FOXP1) are causative for severe forms of autism spectrum disorder that are often comorbid with intellectual disability. Recent work has begun to reveal an important role for FoxP1 in brain development, but the brain-region-specific contributions of Foxp1 to autism and intellectual disability phenotypes have yet to be determined fully. Here, we describe Foxp1 conditional knock-out (Foxp1cKO) male and female mice with loss of Foxp1 in the pyramidal neurons of the neocortex and the CA1/CA2 subfields of the hippocampus. Foxp1cKO mice exhibit behavioral phenotypes that are of potential relevance to autism spectrum disorder, including hyperactivity, increased anxiety, communication impairments, and decreased sociability. In addition, Foxp1cKO mice have gross deficits in learning and memory tasks of relevance to intellectual disability. Using a genome-wide approach, we identified differentially expressed genes in the hippocampus of Foxp1cKO mice associated with synaptic function and development. Furthermore, using magnetic resonance imaging, we uncovered a significant reduction in the volumes of both the entire hippocampus as well as individual hippocampal subfields of Foxp1cKO mice. Finally, we observed reduced maintenance of LTP in area CA1 of the hippocampus in these mutant mice. Together, these data suggest that proper expression of Foxp1 in the pyramidal neurons of the forebrain is important for regulating gene expression pathways that contribute to specific behaviors reminiscent of those seen in autism and intellectual disability. In particular, Foxp1 regulation of gene expression appears to be crucial for normal hippocampal development, CA1 plasticity, and spatial learning.)

【标题】2. 腹侧被盖区GABA神经元CB1依赖型长期抑制：大麻新靶(CB1-Dependent Long-Term Depression in Ventral Tegmental Area GABA Neurons: A Novel Target for Marijuana)

【作者】Lindsey Friend, Jared Weed, Philip Sandoval, Teresa Nufer, Isaac Ostlund and Jeffrey G. Edwards

【链接】https://doi.org/10.1523/JNEUROSCI.0190-17.2017

【关键词】anandamide，endocannabinoid，mGluR5，THC，TRPV1，戒断(anandamide, endocannabinoid, mGluR5, THC, TRPV1, withdrawal)

【摘要】VTA是奖励行为的必要条件，多巴胺细胞关键涉及奖励信号。多巴胺细胞又受到神经支配，并受邻近的抑制性GABA细胞调节。使用全细胞电生理学青少年GAD67-GFP雄性小鼠，我们审查兴奋性可塑性荧光VTA GABA细胞。在依赖于代谢型谷氨酸受体5和大麻素受体1（CB1）的GABA细胞中诱导新型CB1依赖性LTD。 LTD在CB1基因敲除小鼠中不存在，但保存在杂合的同窝出生体中。应用Δ9-四氢大麻酚的浴抑制GABA细胞活性，因此下游的多巴胺细胞将被去除抑制;因此，这可能会导致奖励增加。与载体注射相比，慢性注射△9-四氢大麻酚吸收的LTD;然而，一次曝光不足以做到这一点。由于滥用药物的突触修饰通常与成瘾有关，所以这些数据提示了Δ9-四氢大麻酚在青少年青少年中的成瘾作用的可能机制，其可能改变奖励行为的结果。(The VTA is necessary for reward behavior with dopamine cells critically involved in reward signaling. Dopamine cells in turn are innervated and regulated by neighboring inhibitory GABA cells. Using whole-cell electrophysiology in juvenile-adolescent GAD67-GFP male mice, we examined excitatory plasticity in fluorescent VTA GABA cells. A novel CB1-dependent LTD was induced in GABA cells that was dependent on metabotropic glutamate receptor 5, and cannabinoid receptor 1 (CB1). LTD was absent in CB1 knock-out mice but preserved in heterozygous littermates. Bath applied Δ9-tetrahydrocannabinol depressed GABA cell activity, therefore downstream dopamine cells will be disinhibited; and thus, this could potentially result in increased reward. Chronic injections of Δ9-tetrahydrocannabinol occluded LTD compared with vehicle injections; however, a single exposure was insufficient to do so. As synaptic modifications by drugs of abuse are often tied to addiction, these data suggest a possible mechanism for the addictive effects of Δ9-tetrahydrocannabinol in juvenile-adolescents, by potentially altering reward behavioral outcomes.)

【标题】3. 树突状和轴索L型钙通道在果蝇幼虫运动中协同增强运动神经元的射出量(Dendritic and Axonal L-Type Calcium Channels Cooperate to Enhance Motoneuron Firing Output during Drosophila Larval Locomotion)

【作者】Dimitrios Kadas, Aylin Klein, Niklas Krick, Jason W. Worrell, Stefanie Ryglewski and Carsten Duch

【链接】https://doi.org/10.1523/JNEUROSCI.1064-17.2017

【关键词】钙通道，果蝇，L型通道，运动，运动神经元(calcium channel, Drosophila, L-type channel, locomotion, motoneuron)

【摘要】行为上充足的神经元放电模式严重依赖于特定类型的离子通道表达和亚细胞定位。这项研究结合了原位电生理学和遗传和药理干预两性在幼虫果蝇，以解决L型钙通道在运动神经元的定位和功能。我们证明Dmca1D（Cav1同系物）L型钙通道本地化的幼虫爬行运动神经元的躯体树突和轴突室。遗传马赛克中的原位膜片钳记录显示，Dmca1D通道在半完好的动物爬行状运动模式期间增加了爆发持续时间和最大的爆发内发射频率。遗传和急性药理操作表明，延长爆发持续时间是由树突局部化Dmca1D渠道，胆碱能突触输入激活和放大EPSPs，从而表明从树突状L型通道从果蝇到脊椎动物保守功能。相比之下，最大的爆发内速率需要通过Dmca1D通道轴突钙内流，可能通过BK通道活化通过快速超极化来增强钠通道失活。因此，在无髓鞘的果蝇运动神经元中，轴突和树突状L型钙通道的不同功能可能协同作用以最大化运动期间的发射输出。(Behaviorally adequate neuronal firing patterns are critically dependent on the specific types of ion channel expressed and on their subcellular localization. This study combines in situ electrophysiology with genetic and pharmacological intervention in larval Drosophila melanogaster of both sexes to address localization and function of L-type like calcium channels in motoneurons. We demonstrate that Dmca1D (Cav1 homolog) L-type like calcium channels localize to both the somatodendritic and the axonal compartment of larval crawling motoneurons. In situ patch-clamp recordings in genetic mosaics reveal that Dmca1D channels increase burst duration and maximum intraburst firing frequencies during crawling-like motor patterns in semi-intact animals. Genetic and acute pharmacological manipulations suggest that prolonged burst durations are caused by dendritically localized Dmca1D channels, which activate upon cholinergic synaptic input and amplify EPSPs, thus indicating a conserved function of dendritic L-type channels from Drosophila to vertebrates. By contrast, maximum intraburst firing rates require axonal calcium influx through Dmca1D channels, likely to enhance sodium channel de-inactivation via a fast afterhyperpolarization through BK channel activation. Therefore, in unmyelinated Drosophila motoneurons different functions of axonal and dendritic L-type like calcium channels likely operate synergistically to maximize firing output during locomotion.)

发育/可塑性/修复

【标题】4. 激活的ErbB2选择性过度活化损伤的雪旺氏细胞的损伤后诱导和促进强大的背根神经轴突再生(Postinjury Induction of Activated ErbB2 Selectively Hyperactivates Denervated Schwann Cells and Promotes Robust Dorsal Root Axon Regeneration)

【作者】Seung Baek Han, Hyukmin Kim, Hyunkyoung Lee, Matthew Grove, George M. Smith and Young-Jin Son

【链接】https://doi.org/10.1523/JNEUROSCI.0903-17.2017

【关键词】背根再生，ErbB2，GDNF，神经调节蛋白，周围神经再生，许旺细胞(dorsal root regeneration, ErbB2, GDNF, neuregulin, peripheral nerve regeneration, Schwann cell)

【摘要】在神经损伤之后，失神经雪旺细胞（SC）转化为修复SC，这使得能够再生周围轴突。然而，SC的修复能力和外周神经轴突的再生能力是有限的。在目前的研究中，我们研究了增强SC的修复能力的潜在治疗策略，并测试了其增强再生能力特别薄弱的背根（DR）轴突的再生的功效。我们使用强力霉素诱导的转基因系的雄性和雌性小鼠在DR挤压或横切后在SC中选择性诱导组成性活化的ErbB2（caErbB2）的表达。受伤两周后，诱导动物的受伤DR包含更多的SC和SC过程。这些SC没有再分化并继续扩散。诱导动物受伤的DRs也含有更多的轴突，沿着SC过程重新经过横切或挤压位点。值得注意的是，未损伤DR中的SC和轴突保持静止，表明caErbB2增强了受损DR的再生，而没有异常激活完整神经中的SC和轴突。我们还发现，脊髓内表达神经胶质细胞源性神经营养因子（GDNF），但不是硫酸软骨素蛋白多糖的去除，大大增强caErbB2表达SCs脊髓内迁移，使强大的DR轴突渗透到脊髓。这些发现表明，SC选择性，损伤后ErbB2的激活提供了一种新的策略，有力地提高SC和轴突再生修复能力，没有实质性的脱靶损伤。他们还强调，通过GDNF促进caErbB2表达的SCs的定向迁移可能有助于在非允许的环境中使轴突再生。(Following nerve injury, denervated Schwann cells (SCs) convert to repair SCs, which enable regeneration of peripheral axons. However, the repair capacity of SCs and the regenerative capacity of peripheral axons are limited. In the present studies we examined a potential therapeutic strategy to enhance the repair capacity of SCs, and tested its efficacy in enhancing regeneration of dorsal root (DR) axons, whose regenerative capacity is particularly weak. We used male and female mice of a doxycycline-inducible transgenic line to induce expression of constitutively active ErbB2 (caErbB2) selectively in SCs after DR crush or transection. Two weeks after injury, injured DRs of induced animals contained far more SCs and SC processes. These SCs had not redifferentiated and continued to proliferate. Injured DRs of induced animals also contained far more axons that regrew along SC processes past the transection or crush site. Remarkably, SCs and axons in uninjured DRs remained quiescent, indicating that caErbB2 enhanced regeneration of injured DRs, without aberrantly activating SCs and axons in intact nerves. We also found that intraspinally expressed glial cell line-derived neurotrophic factor (GDNF), but not the removal of chondroitin sulfate proteoglycans, greatly enhanced the intraspinal migration of caErbB2-expressing SCs, enabling robust penetration of DR axons into the spinal cord. These findings indicate that SC-selective, post-injury activation of ErbB2 provides a novel strategy to powerfully enhance the repair capacity of SCs and axon regeneration, without substantial off-target damage. They also highlight that promoting directed migration of caErbB2-expressing SCs by GDNF might be useful to enable axon regrowth in a non-permissive environment.)

系统/环路

【标题】5. 大鼠原发性和继发性运动皮层神经元Int and和锥体束投影的前肢运动表征的显着侧面性(Distinct Laterality in Forelimb-Movement Representations of Rat Primary and Secondary Motor Cortical Neurons with Intratelencephalic and Pyramidal Tract Projections)

【作者】Shogo Soma, Akiko Saiki, Junichi Yoshida, Alain Ríos, Masanori Kawabata, Yutaka Sakai and Yoshikazu Isomura

【链接】https://doi.org/10.1523/JNEUROSCI.1188-17.2017

【关键词】通道视紫红质-2，碰撞试验，健侧/同侧，皮质层次，锥体细胞，大鼠(channelrhodopsin-2, collison test, contralateral/ipsilateral, cortical hierarchy, pyramidal cell, rat)

【摘要】两个不同的运动区域，主要和次要运动皮层（M1和M2），在啮齿动物的自主运动中发挥关键作用。这项研究的目的是表征左，右前肢运动的运动皮质代表性的偏侧性。为了实现这个目标，我们开发了一个新颖的行为任务，即左右踏板任务，在这个任务中，头部受限制的雄性老鼠用对应的前肢操纵右或左踏板。这项任务使我们能够以高时空分辨率监测两个前肢的独立运动。我们在孤立的单侧运动中观察到阶段性运动相关的神经元活动（Go型）和强直性持有相关活动（Hold型）。在M1和M2中，Go型神经元表现出偏向于对侧偏好，而Hold型神经元没有偏见。 M2的对侧偏差比M1要弱。此外，我们区分intratelencephalic（IT）和锥体束（PT）神经元使用optogenetically诱发尖峰碰撞表达channelrhodopsin-2大鼠。即使在识别的PT和IT神经元中，保持型神经元也没有表现出侧向偏差。 Go型PT神经元表现出偏向对侧偏好，而IT神经元没有偏见。我们的研究结果表明M1和M2在运动表征方面有不同的偏侧性，其中IT神经元参与双边运动的合作，而PT神经元控制对侧运动。(Two distinct motor areas, the primary and secondary motor cortices (M1 and M2), play crucial roles in voluntary movement in rodents. The aim of this study was to characterize the laterality in motor cortical representations of right and left forelimb movements. To achieve this goal, we developed a novel behavioral task, the Right-Left Pedal task, in which a head-restrained male rat manipulates a right or left pedal with the corresponding forelimb. This task enabled us to monitor independent movements of both forelimbs with high spatiotemporal resolution. We observed phasic movement-related neuronal activity (Go-type) and tonic hold-related activity (Hold-type) in isolated unilateral movements. In both M1 and M2, Go-type neurons exhibited bias toward contralateral preference, whereas Hold-type neurons exhibited no bias. The contralateral bias was weaker in M2 than M1. Moreover, we differentiated between intratelencephalic (IT) and pyramidal tract (PT) neurons using optogenetically evoked spike collision in rats expressing channelrhodopsin-2. Even in identified PT and IT neurons, Hold-type neurons exhibited no lateral bias. Go-type PT neurons exhibited bias toward contralateral preference, whereas IT neurons exhibited no bias. Our findings suggest a different laterality of movement representations of M1 and M2, in each of which IT neurons are involved in cooperation of bilateral movements, whereas PT neurons control contralateral movements.)

【标题】6. 随机网络中的Hebbian学习捕捉前额叶皮质的选择性特性(Hebbian Learning in a Random Network Captures Selectivity Properties of the Prefrontal Cortex)

【作者】Grace W. Lindsay, Mattia Rigotti, Melissa R. Warden, Earl K. Miller and Stefano Fusi

【链接】https://doi.org/10.1523/JNEUROSCI.1222-17.2017

【关键词】混合选择性，前额叶皮层，随机连通性，理论模型(mixed selectivity, prefrontal cortex, random connectivity, theoretical models)

【摘要】前额皮层（PFC）支持复杂的认知行为，如上下文切换和规则跟随。 PFC中的神经活动因此必须专门用于特定的任务，同时保持灵活性。非线性“混合”选择性是一个重要的神经生理学特征，能够实现复杂的和背景依赖的行为。在这里，我们研究（1）PFC在多大程度上表现出与计算相关的特性，例如混合选择性，以及（2）如何通过电路机制产生这样的特性。我们表明，在复杂的任务期间从男性和女性恒河猴记录的PFC细胞显示中等水平的专业化和结构，不被细胞接收随机前馈输入的模型复制。虽然随机连接可以有效地产生混合选择性，但是数据显示出比具有其他匹配参数的模型所预测的更多的混合选择性。然而，一个适用于随机连接的简单的Hebbian学习规则增加了混合选择性，使模型更准确地匹配数据。为了解释学习如何实现这一目标，我们提供了分析以及对学习对选择性影响的清晰的几何解释。在学习之后，该模型还匹配噪声测量，响应密度，聚类和选择性分布的数据。两种样式的Hebbian学习测试，更简单和更生物合理的选择更好地匹配的数据。这些建模结果提供了线索关于如何神经属性重要的认知可以出现在电路中，并作出明确的实验预测如何各种措施的选择性将在动物训练过程中演变。(Complex cognitive behaviors, such as context-switching and rule-following, are thought to be supported by the prefrontal cortex (PFC). Neural activity in the PFC must thus be specialized to specific tasks while retaining flexibility. Nonlinear “mixed” selectivity is an important neurophysiological trait for enabling complex and context-dependent behaviors. Here we investigate (1) the extent to which the PFC exhibits computationally relevant properties, such as mixed selectivity, and (2) how such properties could arise via circuit mechanisms. We show that PFC cells recorded from male and female rhesus macaques during a complex task show a moderate level of specialization and structure that is not replicated by a model wherein cells receive random feedforward inputs. While random connectivity can be effective at generating mixed selectivity, the data show significantly more mixed selectivity than predicted by a model with otherwise matched parameters. A simple Hebbian learning rule applied to the random connectivity, however, increases mixed selectivity and enables the model to match the data more accurately. To explain how learning achieves this, we provide analysis along with a clear geometric interpretation of the impact of learning on selectivity. After learning, the model also matches the data on measures of noise, response density, clustering, and the distribution of selectivities. Of two styles of Hebbian learning tested, the simpler and more biologically plausible option better matches the data. These modeling results provide clues about how neural properties important for cognition can arise in a circuit and make clear experimental predictions regarding how various measures of selectivity would evolve during animal training.)

【标题】7. 运动处理中的抑制和对比度归一化(Suppression and Contrast Normalization in Motion Processing)

【作者】Christian Quaia, Lance M. Optican and Bruce G. Cumming

【链接】https://doi.org/10.1523/JNEUROSCI.1572-17.2017

【关键词】屏蔽，运动，标准化(masking, motion, normalization)

【摘要】感觉神经元被一系列据说被调整的刺激激活。通常情况下，他们也受到另一组孤立的影响不大的刺激的抑制。优先和抑制刺激之间的相互作用往往是相当复杂的，即使在一个单一的区域内也是不同的，因此很难推断它们对神经元群体活动介导的行为反应的集体效应。在这里，我们通过在人类受试者（三个男性）中测量静态掩模对由移动刺激引起的眼睛随后的响应的抑制效果来调查这个问题。我们发现了各种各样的效应，这些效应依赖于非线性和不可分的方式对刺激和掩模的空间频率，对比度和空间位置。在某些情况下，面具的存在可以看作是缩放驾驶刺激的对比度。在其他条件下，效果更为复杂，也涉及行为反应的直接缩放。在行为层面的所有这些复杂性都可以通过一个简单的模型来捕捉，在这个模型中，刺激和面具在两个阶段非线性地相互作用，一个单眼和一个双眼。相互作用的性质与在灵长类动物单个神经元层面观察到的相一致，通常被广泛地描述为分裂的归一化，而不必调用任何标度机制。(Sensory neurons are activated by a range of stimuli to which they are said to be tuned. Usually, they are also suppressed by another set of stimuli that have little effect when presented in isolation. The interactions between preferred and suppressive stimuli are often quite complex and vary across neurons, even within a single area, making it difficult to infer their collective effect on behavioral responses mediated by activity across populations of neurons. Here, we investigated this issue by measuring, in human subjects (three males), the suppressive effect of static masks on the ocular following responses induced by moving stimuli. We found a wide range of effects, which depend in a nonlinear and nonseparable manner on the spatial frequency, contrast, and spatial location of both stimulus and mask. Under some conditions, the presence of the mask can be seen as scaling the contrast of the driving stimulus. Under other conditions, the effect is more complex, involving also a direct scaling of the behavioral response. All of this complexity at the behavioral level can be captured by a simple model in which stimulus and mask interact nonlinearly at two stages, one monocular and one binocular. The nature of the interactions is compatible with those observed at the level of single neurons in primates, usually broadly described as divisive normalization, without having to invoke any scaling mechanism.)

行为/认知

【标题】8. 侧耳Habenula及其对Rostromedial Tegmental核的输入介导结果特异性条件抑制(The Lateral Habenula and Its Input to the Rostromedial Tegmental Nucleus Mediates Outcome-Specific Conditioned Inhibition)

【作者】Vincent Laurent, Felix L. Wong and Bernard W. Balleine

【链接】https://doi.org/10.1523/JNEUROSCI.3415-16.2017

【关键词】外侧缰核，阴性预测误差，结果特异性条件抑制，巴甫洛夫器官转移，逆转学习，rostromedial被膜盖核(lateral habenula, negative prediction error, outcome-specific conditioned inhibition, Pavlovian-instrumental transfer, reversal learning, rostromedial tegmental nucleus)

【摘要】动物可以很容易地知道刺激预测没有特定的食欲结果;然而，这种结果特异性条件抑制的神经基础在很大程度上仍然是未知的。在这里，使用雌性和雄性大鼠作为受试者，我们研究了外侧缰核（LHb）及其输入参与抑制性学习中的rostromedial被盖核（RMTg）。在这些实验中，我们使用后向调节和应急逆转来建立针对两种不同的食欲结果的成果特异性条件抑制剂。然后，使用巴甫洛夫器乐转移范例，我们评估了操纵LHb和LHb-RMTg通路对抑制性编码的影响。在对照动物中，我们发现一个结果特定的条件抑制剂偏离选择行动提供的结果和行动赚取其他结果。重要的是，这种偏见被LHb的电解损伤和LHb神经元的选择性消除所消除，Cre表达神经元中的Cre依赖性Caspase3表达投射到RMTg。这种缺陷是特定的条件抑制;一个特定的结果偏向选择的兴奋性预测因子，可以使得LHb或LHb-RMTg网络完整与否，达到相同的结果。 LHb损伤也破坏了动物在逆转之后抑制先前编码的刺激 - 结果意外事件的能力，指出LHb及其投入在RMTg中的关键作用，在食欲环境中的结果特异性条件抑制中。这些发现与发展中的观点相一致，即LHb在巴甫洛夫条件下促进了负面报酬预测误差。(Animals can readily learn that stimuli predict the absence of specific appetitive outcomes; however, the neural substrates underlying such outcome-specific conditioned inhibition remain largely unexplored. Here, using female and male rats as subjects, we examined the involvement of the lateral habenula (LHb) and of its inputs onto the rostromedial tegmental nucleus (RMTg) in inhibitory learning. In these experiments, we used backward conditioning and contingency reversal to establish outcome-specific conditioned inhibitors for two distinct appetitive outcomes. Then, using the Pavlovian-instrumental transfer paradigm, we assessed the effects of manipulations of the LHb and the LHb–RMTg pathway on that inhibitory encoding. In control animals, we found that an outcome-specific conditioned inhibitor biased choice away from actions delivering that outcome and toward actions earning other outcomes. Importantly, this bias was abolished by both electrolytic lesions of the LHb and selective ablation of LHb neurons using Cre-dependent Caspase3 expression in Cre-expressing neurons projecting to the RMTg. This deficit was specific to conditioned inhibition; an excitatory predictor of a specific outcome-biased choice toward actions delivering the same outcome to a similar degree whether the LHb or the LHb–RMTg network was intact or not. LHb lesions also disrupted the ability of animals to inhibit previously encoded stimulus–outcome contingencies after their reversal, pointing to a critical role of the LHb and of its inputs onto the RMTg in outcome-specific conditioned inhibition in appetitive settings. These findings are consistent with the developing view that the LHb promotes a negative reward prediction error in Pavlovian conditioning.)

【标题】9. 动态试验性审判重新编码的任务表示在Frontoparietal皮层介导行为的灵活性(Dynamic Trial-by-Trial Recoding of Task-Set Representations in the Frontoparietal Cortex Mediates Behavioral Flexibility)

【作者】Lei Qiao, Lijie Zhang, Antao Chen and Tobias Egner

【链接】https://doi.org/10.1523/JNEUROSCI.0935-17.2017

【关键词】认知控制，认知灵活性，功能磁共振成像，额顶皮质，代表相似性分析，任务切换(cognitive control, cognitive flexibility, fMRI, frontoparietal cortex, representational similarity analysis, task switching)

【摘要】认知灵活性是人类适应能力非凡的核心，但是我们在任务集之间灵活转换能力的精确神经机制仍然知之甚少。最近使用多体素模式分析（MVPA）的功能磁共振成像（fMRI）研究已经表明，目前相关的任务组可以从顶下皮层的活动模式解码，但是这些区域是否支持任务组从试验到试验的动态转换不清楚。在这里，我们结合了人类（两性）功能磁共振成像任务切换协议，并利用代表性相似性分析（RSA），以促进神经任务集表示的审判试验变化的新颖评估。我们首先使用MVPA来定义任务敏感的前额叶和视觉区域，发现开关试验中的神经任务组表示比重复试验编码稳定。然后，我们利用RSA来表明，对于开关试验，连续试验中的神经表现模式差异比重复试验更大，并且这种模式不相似的程度预测了行为。此外，代表性差异的总体神经模式遵循重复集与开关集相比导致更强的神经任务表示的假设。最后，在试验中从提示到目标阶段，模式差异跟踪从先前的试验任务表示到当前相关的集合的转换。这些结果为任务集惯性阻碍了任务集重新配置过程的长期假设提供了神经依据，并且它们证明了顶前端和刺激处理区域支持“动态自适应编码”，在试验中灵活地表示不断变化的任务集时尚。(Cognitive flexibility forms the core of the extraordinary ability of humans to adapt, but the precise neural mechanisms underlying our ability to nimbly shift between task sets remain poorly understood. Recent functional magnetic resonance imaging (fMRI) studies employing multivoxel pattern analysis (MVPA) have shown that a currently relevant task set can be decoded from activity patterns in the frontoparietal cortex, but whether these regions support the dynamic transformation of task sets from trial to trial is not clear. Here, we combined a cued task-switching protocol with human (both sexes) fMRI, and harnessed representational similarity analysis (RSA) to facilitate a novel assessment of trial-by-trial changes in neural task-set representations. We first used MVPA to define task-sensitive frontoparietal and visual regions and found that neural task-set representations on switch trials are less stably encoded than on repeat trials. We then exploited RSA to show that the neural representational pattern dissimilarity across consecutive trials is greater for switch trials than for repeat trials, and that the degree of this pattern dissimilarity predicts behavior. Moreover, the overall neural pattern of representational dissimilarities followed from the assumption that repeating sets, compared with switching sets, results in stronger neural task representations. Finally, when moving from cue to target phase within a trial, pattern dissimilarities tracked the transformation from previous-trial task representations to the currently relevant set. These results provide neural evidence for the longstanding assumptions of an effortful task-set reconfiguration process hampered by task-set inertia, and they demonstrate that frontoparietal and stimulus processing regions support “dynamic adaptive coding,” flexibly representing changing task sets in a trial-by-trial fashion.)

神经疾病

【标题】10. 增强脊柱可塑性，增强康复训练的益处，改善卒中的康复(Enhancing Spinal Plasticity Amplifies the Benefits of Rehabilitative Training and Improves Recovery from Stroke)

【作者】Anna M. Wiersma, Karim Fouad and Ian R. Winship

【链接】https://doi.org/10.1523/JNEUROSCI.0770-17.2017

【关键词】硫酸软骨素蛋白多糖，软骨素酶ABC，皮质脊髓束，康复，感觉运动皮层，熟练掌握(chondroitin sulfate proteoglycans, chondroitinase ABC, corticospinal tract, rehabilitation, sensorimotor cortex, skilled reaching)

【摘要】中风后有限的恢复发生几乎完全在伤后头几周。而且，在这个狭窄的时间框架之外，康复训练的效果是有限的。在脊髓逆行脊髓中出芽的皮质脊髓束轴突对感觉运动恢复有重要贡献，但是这种结构可塑性也限于中风后头几周。在这里，我们测试了在慢性中风期间诱导脊髓可塑性可以改善持续感觉运动损伤的恢复的假设。我们通过椎管内注射软骨素酶ABC在雄性Sprague-Dawley大鼠中，在最初的缺血性损伤后数周，在慢性中风期间增强脊柱可塑性。我们的数据显示，在中风后28天施用软骨素酶注射入颈髓脊髓灰质物质中，可以诱发起源于梗塞周围皮层的皮质脊髓轴突的显着发芽。软骨素酶ABC注射在慢性卒中没有额外的训练导致感觉运动缺陷的适度改善。重要的是，这种疗法显着增强了在熟练的前肢接近任务中慢性卒中期间康复训练的功效。这些新的数据表明，慢性卒中期间的脊髓治疗可以放大延迟康复训练的好处，有可能减少中风幸存者的永久性残疾。(The limited recovery that occurs following stroke happens almost entirely in the first weeks postinjury. Moreover, the efficacy of rehabilitative training is limited beyond this narrow time frame. Sprouting of spared corticospinal tract axons in the contralesional spinal cord makes a significant contribution to sensorimotor recovery, but this structural plasticity is also limited to the first few weeks after stroke. Here, we tested the hypothesis that inducing plasticity in the spinal cord during chronic stroke could improve recovery from persistent sensorimotor impairment. We potentiated spinal plasticity during chronic stroke, weeks after the initial ischemic injury, in male Sprague-Dawley rats via intraspinal injections of chondroitinase ABC. Our data show that chondroitinase injections into the contralesional gray matter of the cervical spinal cord administered 28 d after stroke induced significant sprouting of corticospinal axons originating in the peri-infarct cortex. Chondroitinase ABC injection during chronic stroke without additional training resulted in moderate improvements of sensorimotor deficits. Importantly, this therapy dramatically potentiated the efficacy of rehabilitative training delivered during chronic stroke in a skilled forelimb reaching task. These novel data suggest that spinal therapy during chronic stroke can amplify the benefits of delayed rehabilitative training with the potential to reduce permanent disability in stroke survivors.)

【标题】11. 内源性黄体酮通过神经特异性缺失揭示脑卒中的保护作用(A Role of Endogenous Progesterone in Stroke Cerebroprotection Revealed by the Neural-Specific Deletion of Its Intracellular Receptors)

【作者】Xiaoyan Zhu, Magalie Fréchou, Philippe Liere, Shaodong Zhang, Antoine Pianos, Neïké Fernandez, Christian Denier, Claudia Mattern, Michael Schumacher and Rachida Guennoun

【链接】https://doi.org/10.1523/JNEUROSCI.3874-16.2017

【关键词】衰老，内源性，神经保护，黄体酮受体，性别差异，类固醇(aging, endogenous, neuroprotection, progesterone receptors, sex differences, steroids)

【摘要】孕酮治疗可保护雄性和雌性大脑免受大脑中动脉闭塞（MCAO）后的损伤。然而，无论男女，大脑都含有大量的内源性黄体酮。目前尚不清楚内源性孕酮是否能增强大脑对缺血性损伤的抵抗力。在这里，我们用气相色谱 - 串联质谱（GC-MS / MS）进行类固醇分析，探索MCAO后黄体酮及其代谢物脑水平的适应性和性别特异性变化。我们发现在雄性小鼠脑中，黄体酮主要通过5α-还原反应生成5α-二氢黄体酮（5α-DHP），也是神经细胞中的孕激素受体（PR）激动剂配体，然后是3α，5α-四氢黄体酮3α，5α-THP）。在雌性小鼠脑中，5α-DHP和3α，5α-THP水平较低，20α-DHP水平高于男性。 MCAO后，孕激素和5α-DHP的水平在男性中迅速上调至妊娠样水平，而在女性脑中则不如此。为了评估内源性孕酮和5α-DHP是否有助于神经细胞对缺血性损伤的抵抗，我们在CNS中选择性地使PR失活。脑部PR的缺失降低了其对MCAO的抗性，导致梗塞体积增加和两性的神经功能缺陷。重要的是，内源性PR配体继续保护衰老小鼠的大脑。这些结果揭示了内源性黄体酮及其代谢物在脑保护中意外的重要性。他们还揭示雌性生殖激素黄体酮是两性的内源性脑保护性神经甾体。(Treatment with progesterone protects the male and female brain against damage after middle cerebral artery occlusion (MCAO). However, in both sexes, the brain contains significant amounts of endogenous progesterone. It is not known whether endogenously produced progesterone enhances the resistance of the brain to ischemic insult. Here, we used steroid profiling by gas chromatography-tandem mass spectrometry (GC-MS/MS) for exploring adaptive and sex-specific changes in brain levels of progesterone and its metabolites after MCAO. We show that, in the male mouse brain, progesterone is mainly metabolized via 5α-reduction leading to 5α-dihydroprogesterone (5α-DHP), also a progesterone receptor (PR) agonist ligand in neural cells, then to 3α,5α-tetrahydroprogesterone (3α,5α-THP). In the female mouse brain, levels of 5α-DHP and 3α,5α-THP are lower and levels of 20α-DHP are higher than in males. After MCAO, levels of progesterone and 5α-DHP are upregulated rapidly to pregnancy-like levels in the male but not in the female brain. To assess whether endogenous progesterone and 5α-DHP contribute to the resistance of neural cells to ischemic damage, we inactivated PR selectively in the CNS. Deletion of PR in the brain reduced its resistance to MCAO, resulting in increased infarct volumes and neurological deficits in both sexes. Importantly, endogenous PR ligands continue to protect the brain of aging mice. These results uncover the unexpected importance of endogenous progesterone and its metabolites in cerebroprotection. They also reveal that the female reproductive hormone progesterone is an endogenous cerebroprotective neurosteroid in both sexes.)