Behavior-related visual activations in the auditory cortex of nonhuman primates

非人灵长类动物听觉皮层中与行为相关的视觉激活

While it is well established that sensory cortical regions traditionally thought to be unimodal can be activated by stimuli from modalities other than the dominant one, functions of such foreign-modal activations are still not clear. Here we show that visual activations in early auditory cortex can be related to whether or not the monkeys engaged in audio-visual tasks, to the time when the monkeys reacted to the visual component of such tasks, and to the correctness of the monkeys' response to the auditory component of such tasks. These relationships between visual activations and behavior suggest that auditory cortex can be recruited for visually-guided behavior and that visual activations can prime auditory cortex such that it is prepared for processing future sounds. Our study thus provides evidence that foreign-modal activations in sensory cortex can contribute to a subject's ability to perform tasks on stimuli from foreign and dominant modalities.

虽然众所周知，传统上被认为是单峰的感觉皮层区域可以被来自主导模式以外的其他模式的刺激激活，但这种外来模式激活的功能仍不清楚。在这里，我们表明，早期听觉皮层中的视觉激活可能与猴子是否从事视听任务，猴子对此类任务的视觉成分做出反应的时间以及猴子的正确性有关。对此类任务的听觉成分的反应。视觉激活与行为之间的这些关系表明，可以招募听觉皮层进行视觉引导的行为，并且视觉激活可以激发听觉皮层，以便为处理未来的声音做好准备。因此，我们的研究提供了证据，表明感觉皮层中的外来模态激活可以促进受试者根据外来和主导模态的刺激执行任务的能力。

REF: Huang Y, Brosch M. Behavior-related visual activations in the auditory cortex of nonhuman primates. Prog Neurobiol. 2024;240:102637. doi:10.1016/j.pneurobio.2024.102637 PMID: 38879074

Adolescent cannabinoid exposure rescues phencyclidine-induced social deficits through modulation of CA2 transmission

青少年大麻素暴露通过调节CA2传播来挽救苯环利定引起的社会缺陷

Psychotic disorders entail intricate conditions marked by disruptions in cognition, perception, emotions, and social behavior. Notably, psychotic patients who use cannabis tend to show less severe deficits in social behaviors, such as the misinterpretation of social cues and the inability to interact with others. However, the biological underpinnings of this epidemiological interaction remain unclear. Here, we used the NMDA receptor blocker phencyclidine (PCP) to induce psychotic-like states and to study the impact of adolescent cannabinoid exposure on social behavior deficits and synaptic transmission changes in hippocampal area CA2, a region known to be active during social interactions. In particular, adolescent mice underwent 7 days of subchronic treatment with the synthetic cannabinoid, WIN 55, 212-2 (WIN) followed by one injection of PCP. Using behavioral, biochemical, and electrophysiological approaches, we showed that PCP persistently reduced sociability, decreased GAD67 expression in the hippocampus, and induced GABAergic deficits in proximal inputs from CA3 and distal inputs from the entorhinal cortex (EC) to CA2. Notably, WIN exposure during adolescence specifically restores adult sociability deficits, the expression changes in GAD67, and the GABAergic impairments in the EC-CA2 circuit, but not in the CA3-CA2 circuit. Using a chemogenetic approach to target EC-CA2 projections, we demonstrated the involvement of this specific circuit on sociability deficits. Indeed, enhancing EC-CA2 transmission was sufficient to induce sociability deficits in vehicle-treated mice, but not in animals treated with WIN during adolescence, suggesting a mechanism by which adolescent cannabinoid exposure rescues sociability deficits caused by enhanced EC-CA2 activity in adult mice.

精神障碍需要以认知，感知，情感和社交行为中断为特征的复杂状况。值得注意的是，使用大麻的精神病患者往往在社交行为方面表现出较不严重的缺陷，例如对社交线索的误解和无法与他人互动。然而，这种流行病学相互作用的生物学基础仍不清楚。在这里，我们使用NMDA受体阻滞剂苯环利定 (PCP) 来诱导精神病样状态，并研究青少年大麻素暴露对海马区CA2的社交行为缺陷和突触传递变化的影响，该区域在社交互动中活跃。特别是，青春期小鼠用合成大麻素WIN 55，212-2 (WIN) 进行了7天的亚慢性治疗，然后注射了一次PCP。使用行为，生化和电生理方法，我们发现PCP持续降低社交能力，降低海马中GAD67的表达，并在CA3的近端输入和内嗅皮层 (EC) 到ca2的远端输入中诱导gaba能缺陷。值得注意的是，青春期的WIN暴露可特别恢复成人的社交能力缺陷，GAD67的表达变化以及EC-CA2回路中gaba能损伤，但CA3-CA2回路中却没有。使用化学遗传学方法来针对EC-CA2预测，我们证明了这种特定电路对社交能力缺陷的参与。实际上，增强EC-CA2传播足以在媒介物治疗的小鼠中诱导社交性缺陷，但在青春期用WIN治疗的动物中则没有，这表明青春期大麻素暴露可挽救成年小鼠EC-CA2活动增强引起的社交性缺陷的机制。

REF: Barrera-Conde M, Ramon-Duaso C, González-Parra JA, et al. Adolescent cannabinoid exposure rescues phencyclidine-induced social deficits through modulation of CA2 transmission. Prog Neurobiol. 2024;240:102652. doi:10.1016/j.pneurobio.2024.102652 PMID: 38955325

Astrocyte-secreted C3 signaling impairs neuronal development and cognition in autoimmune diseases

星形胶质细胞分泌的C3信号在自身免疫性疾病中损害神经元发育和认知

Neuromyelitis optica (NMO) arises from primary astrocytopathy induced by autoantibodies targeting the astroglial protein aquaporin 4 (AQP4), leading to severe neurological sequelae such as vision loss, motor deficits, and cognitive decline. Mounting evidence has shown that dysregulated activation of complement components contributes to NMO pathogenesis. Complement C3 deficiency has been shown to protect against hippocampal neurodegeneration and cognitive decline in neurodegenerative disorders (e.g., Alzheimer's disease, AD) and autoimmune diseases (e.g., multiple sclerosis, MS). However, whether inhibiting the C3 signaling can ameliorate cognitive dysfunctions in NMO remains unclear. In this study, we found that the levels of C3a, a split product of C3, significantly correlate with cognitive impairment in our patient cohort. In response to the stimulation of AQP4 autoantibodies, astrocytes were activated to secrete complement C3, which inhibited the development of cultured neuronal dendritic arborization. NMO mouse models exhibited reduced adult hippocampal newborn neuronal dendritic and spine development, as well as impaired learning and memory functions, which could be rescued by decreasing C3 levels in astrocytes. Mechanistically, we found that C3a engaged with C3aR to impair neuronal development by dampening β-catenin signalling. Additionally, inhibition of the C3-C3aR-GSK3β/β-catenin cascade restored neuronal development and ameliorated cognitive impairments. Collectively, our results suggest a pivotal role of the activation of the C3-C3aR network in neuronal development and cognition through mediating astrocyte and adult-born neuron communication, which represents a potential therapeutic target for autoimmune-related cognitive impairment diseases.

视神经脊髓炎 (NMO) 是由靶向星形胶质细胞蛋白水通道蛋白4 (AQP4) 的自身抗体诱导的原发性星形细胞病引起的，导致严重的神经系统后遗症，例如视力丧失，运动缺陷和认知能力下降。越来越多的证据表明，补体成分的异常激活有助于NMO发病。已显示补体C3缺乏可防止神经退行性疾病 (例如，阿尔茨海默氏病，AD) 和自身免疫性疾病 (例如，多发性硬化症，MS) 中的海马神经变性和认知下降。然而，抑制C3信号是否可以改善NMO的认知功能障碍仍不清楚。在这项研究中，我们发现C3a (C3的分裂产物) 的水平与我们的患者队列中的认知障碍显著相关。响应AQP4自身抗体的刺激，星形胶质细胞被激活以分泌补体C3，从而抑制了培养的神经元树突状的发展。NMO小鼠模型表现出成年海马新生神经元树突和脊柱发育减少，以及学习和记忆功能受损，这可以通过降低星形胶质细胞中的C3水平来挽救。从机制上讲，我们发现C3a与C3aR通过抑制 β-catenin信号传导而损害神经元发育。此外，C3-C3aR-GSK3β/β-连环蛋白级联的抑制恢复了神经元发育并改善了认知障碍。总的来说，我们的研究结果表明，通过介导星形胶质细胞和成年出生的神经元通讯，C3-C3aR网络激活在神经元发育和认知中的关键作用，这代表了自身免疫相关认知障碍疾病的潜在治疗靶标。

REF: Zhu F, He P, Jiang W, et al. Astrocyte-secreted C3 signaling impairs neuronal development and cognition in autoimmune diseases [published correction appears in Prog Neurobiol. 2024 Aug 12:102659. doi: 10.1016/j.pneurobio.2024.102659]. Prog Neurobiol. 2024;240:102654. doi:10.1016/j.pneurobio.2024.102654 PMID: 38945516

Population coding for figure-ground texture segregation in macaque V1 and V4

猕猴V1和V4中图形-地面纹理分离的种群编码

Object recognition often involves the brain segregating objects from their surroundings. Neurophysiological studies of figure-ground texture segregation have yielded inconsistent results, particularly on whether V1 neurons can perform figure-ground texture segregation or just detect texture borders. To address this issue from a population perspective, we utilized two-photon calcium imaging to simultaneously record the responses of large samples of V1 and V4 neurons to figure-ground texture stimuli in awake, fixating macaques. The average response changes indicate that V1 neurons mainly detect texture borders, while V4 neurons are involved in figure-ground segregation. However, population analysis (SVM decoding of PCA-transformed neuronal responses) reveal that V1 neurons not only detect figure-ground borders, but also contribute to figure-ground texture segregation, although requiring substantially more principal components than V4 neurons to reach a 75 % decoding accuracy. Individually, V1/V4 neurons showing larger (negative/positive) figure-ground response differences contribute more to figure-ground segregation. But for V1 neurons, the contribution becomes significant only when many principal components are considered. We conclude that V1 neurons participate in figure-ground segregation primarily by defining the figure borders, and the poorly structured figure-ground information V1 neurons carry could be further utilized by V4 neurons to accomplish figure-ground segregation.

对象识别通常涉及大脑将对象与周围环境隔离。图形-地面纹理分离的神经生理学研究产生了不一致的结果，特别是在V1神经元是否可以执行图形-地面纹理分离或仅检测纹理边界方面。为了从种群的角度解决这个问题，我们利用双光子钙成像同时记录了V1和V4神经元的大样本对清醒，固定猕猴的图形纹理刺激的响应。平均响应变化表明V1神经元主要检测纹理边界，而V4神经元参与图形-地面分离。然而，群体分析 (PCA转换的神经元响应的SVM解码) 表明，V1神经元不仅检测图形-地面边界，而且还有助于图形-地面纹理分离，尽管需要比V4神经元多得多的主成分才能达到75% 的解码精度。单独地，显示较大 (负/正) 图形地面响应差异的V1/V4神经元对图形地面隔离的贡献更大。但是对于V1神经元，仅当考虑许多主成分时，贡献才变得重要。我们得出的结论是，V1神经元主要通过定义图形边界来参与图形-地面隔离，并且V4神经元可以进一步利用结构不良的图形-地面信息V1神经元来完成图形-地面隔离。

REF: Zhao XN, Dong XS, Jiang DQ, Wu S, Tang SM, Yu C. Population coding for figure-ground texture segregation in macaque V1 and V4. Prog Neurobiol. 2024;240:102655. doi:10.1016/j.pneurobio.2024.102655 PMID: 38969016

Orientation selectivity mapping in the visual cortex

视觉皮层中的方向选择性映射

The orientation map is one of the most well-studied functional maps of the visual cortex. However, results from the literature are of different qualities. Clear boundaries among different orientation domains and blurred uncertain distinctions were shown in different studies. These unclear imaging results will lead to an inaccuracy in depicting cortical structures, and the lack of consideration in experimental design will also lead to biased depictions of the cortical features. How we accurately define orientation domains will impact the entire field of research. In this study, we test how spatial frequency (SF), stimulus size, location, chromatic, and data processing methods affect the orientation functional maps (including a large area of dorsal V4, and parts of dorsal V1) acquired by intrinsic signal optical imaging. Our results indicate that, for large imaging fields, large grating stimuli with mixed SF components should be considered to acquire the orientation map. A diffusion model image enhancement based on the difference map could further improve the map quality. In addition, the similar outcomes of achromatic and chromatic gratings indicate two alternative types of afferents from LGN, pooling in V1 to generate cue-invariant orientation selectivity.

方向图是视觉皮层研究得最多的功能图之一。然而，来自文献的结果具有不同的品质。在不同的研究中显示了不同方向域之间的清晰边界和模糊的不确定区别。这些不清楚的成像结果将导致描绘皮质结构的不准确性，并且在实验设计中缺乏考虑也将导致对皮质特征的描绘有偏差。我们如何准确定义方向域将影响整个研究领域。在这项研究中，我们测试了空间频率 (SF) 、刺激大小、位置、色度和数据处理方法如何影响通过本征信号光学成像获取的定向功能图 (包括大面积的背侧V4和部分背侧V1)。我们的结果表明，对于较大的成像场，应考虑具有混合SF分量的较大光栅刺激以获取方向图。基于差异图的扩散模型图像增强可以进一步提高图的质量。此外，消色差光栅和彩色光栅的类似结果表明LGN有两种替代类型的传入，在V1中池以生成线索不变的方向选择性。

REF: Liu ML, Liu YP, Guo XX, et al. Orientation selectivity mapping in the visual cortex. Prog Neurobiol. 2024;240:102656. doi:10.1016/j.pneurobio.2024.102656 PMID: 39009108

A free intravesicular C-terminal of otoferlin is essential for synaptic vesicle docking and fusion at auditory inner hair cell ribbon synapses

otoferlin的游离囊泡C末端对于听觉内毛细胞带状突触的突触小泡对接和融合至关重要

Our understanding of how otoferlin, the major calcium sensor in inner hair cells (IHCs) synaptic transmission, contributes to the overall dynamics of synaptic vesicle (SV) trafficking remains limited. To address this question, we generated a knock-in mouse model expressing an otoferlin-GFP protein, where GFP was fused to its C-terminal transmembrane domain. Similar to the wild type protein, the GFP-tagged otoferlin showed normal expression and was associated with IHC SV. Surprisingly, while the heterozygote Otof+/GFP mice exhibited a normal hearing function, homozygote OtofGFP/GFP mice were profoundly deaf attributed to severe reduction in SV exocytosis. Fluorescence recovery after photobleaching revealed a markedly increased mobile fraction of the otof-GFP-associated SV in Otof GFP/GFP IHCs. Correspondingly, 3D-electron tomographic of the ribbon synapses indicated a reduced density of SV attached to the ribbon active zone. Collectively, these results indicate that otoferlin requires a free intravesicular C-terminal end for normal SV docking and fusion.

我们对内毛细胞 (ihc) 突触传递中的主要钙传感器otoferlin如何促进突触小泡 (SV) 运输的整体动力学的理解仍然有限。为了解决这个问题，我们产生了表达otoferlin-gfp蛋白的敲入小鼠模型，其中GFP与其C末端跨膜结构域融合。与野生型蛋白相似，GFP标记的otoferlin显示正常表达并与ihcsv相关。令人惊讶的是，虽然杂合子Otof /GFP小鼠表现出正常的听力功能，但纯合子OtofGFP/GFP小鼠由于SV胞吐作用的严重减少而严重耳聋。光漂白后的荧光恢复显示otofgfp/GFP ihc中otof-gfp相关SV的移动部分显着增加。相应地，带状突触的3d电子断层扫描表明附着在带状活动区上的SV密度降低。总的来说，这些结果表明otoferlin需要一个游离的囊内C-末端来进行正常的SV对接和融合。

REF: Dulon D, de Monvel JB, Plion B, et al. A free intravesicular C-terminal of otoferlin is essential for synaptic vesicle docking and fusion at auditory inner hair cell ribbon synapses. Prog Neurobiol. 2024;240:102658. doi:10.1016/j.pneurobio.2024.102658 PMID: 39103114

Naturalistic movies and encoding analysis define areal borders in marmoset third-tier visual cortex

自然电影和编码分析定义了mor族第三层视觉皮层的区域边界

Accurate definition of the borders of cortical visual areas is essential for the study of neuronal processes leading to perception. However, data used for definition of areal boundaries have suffered from issues related to resolution, uniform coverage, or suitability for objective analysis, leading to ambiguity. Here, we present a novel approach that combines widefield optical imaging, presentation of naturalistic movies, and encoding model analysis, to objectively define borders in the primate extrastriate cortex. We applied this method to test conflicting hypotheses about the third-tier visual cortex, where areal boundaries have remained controversial. We demonstrate pronounced tuning preferences in the third-tier areas, and an organizational structure in which the dorsomedial area (DM) contains representations of both the upper and lower contralateral quadrants, and is located immediate anterior to V2. High-density electrophysiological recordings with a Neuropixels probe confirm these findings. Our encoding-model approach offers a powerful, objective way to disambiguate areal boundaries.

准确定义皮质视觉区域的边界对于研究导致感知的神经元过程至关重要。但是，用于定义区域边界的数据遇到了与分辨率，统一覆盖范围或客观分析的适用性有关的问题，导致歧义。在这里，我们提出了一种新颖的方法，该方法结合了宽场光学成像，自然电影的呈现和编码模型分析，以客观地定义灵长类动物的条纹皮层中的边界。我们应用此方法来测试有关第三层视觉皮层的相互矛盾的假设，其中区域边界仍然存在争议。我们展示了在第三层区域中明显的调谐偏好，以及一种组织结构，其中背内侧区域 (DM) 包含上部和下部对侧象限的表示，并且位于v2的紧前方。使用神经像素探针进行的高密度电生理记录证实了这些发现。我们的编码模型方法提供了一种强大的，客观的方法来消除区域边界的歧义。

REF: Shimaoka D, Wong YT, Rosa MGP, Price NSC. Naturalistic movies and encoding analysis define areal borders in marmoset third-tier visual cortex. Prog Neurobiol. 2024;240:102657. doi:10.1016/j.pneurobio.2024.102657 PMID: 39103115

Distinct 5-HT receptor subtypes regulate claustrum excitability by serotonin and the psychedelic, DOI

不同的5-HT受体亚型通过5-羟色胺和迷幻药DOI调节claustrum兴奋性

ecent evidence indicates that neuronal activity within the claustrum (CLA) may be central to cellular and behavioral responses to psychedelic hallucinogens. The CLA prominently innervates many cortical targets and displays exceptionally high levels of serotonin (5-HT) binding. However, the influence of serotonin receptors, prime targets of psychedelic drug action, on CLA activity remains unexplored. We characterize the CLA expression of all known 5-HT subtypes and contrast the effects of 5-HT and the psychedelic hallucinogen, 2,5-dimethoxy-4-iodoamphetamine (DOI), on excitability of cortical-projecting CLA neurons. We find that the CLA is particularly enriched with 5-HT2C receptors, expressed predominantly on glutamatergic neurons. Electrophysiological recordings from CLA neurons that project to the anterior cingulate cortex (ACC) indicate that application of 5-HT inhibits glutamate receptor-mediated excitatory postsynaptic currents (EPSCs). In contrast, application of DOI stimulates EPSCs. We find that the opposite effects of 5-HT and DOI on synaptic signaling can both be reversed by inhibition of the 5-HT2C, but not 5-HT2A, receptors. We identify specific 5-HT receptor subtypes as serotonergic regulators of the CLA excitability and argue against the canonical role of 5-HT2A in glutamatergic synapse response to psychedelics within the CLA-ACC circuit.

ecent证据表明，claustrum (CLA) 内的神经元活动可能是对迷幻致幻剂的细胞和行为反应的核心。CLA显着支配许多皮质靶标，并显示出异常高水平的5-羟色胺 (5-HT) 结合。然而，迷幻药物作用的主要靶标5-羟色胺受体对CLA活性的影响仍未得到探索。我们表征了所有已知的5-HT亚型的CLA表达，并比较了5-HT和迷幻剂2，5-二甲氧基-4-碘安非他明 (DOI) 对皮质投射CLA神经元兴奋性的影响。我们发现CLA特别富含5-HT2C受体，主要在谷氨酸能神经元上表达。投射到前扣带回皮层 (ACC) 的CLA神经元的电生理记录表明，5-HT的应用抑制了谷氨酸受体介导的兴奋性突触后电流 (epsc)。相反，DOI的应用刺激EPSCs。我们发现5-HT和DOI对突触信号传导的相反作用都可以通过抑制5-HT2C而不是5-HT2A受体来逆转。我们将特定的5-HT受体亚型确定为CLA兴奋性的血清素能调节剂，并反对5-HT2A在cla-acc回路中对迷幻剂的谷氨酸能突触反应中的典型作用。

REF: Anderson TL, Keady JV, Songrady J, et al. Distinct 5-HT receptor subtypes regulate claustrum excitability by serotonin and the psychedelic, DOI. Prog Neurobiol. 2024;240:102660. doi:10.1016/j.pneurobio.2024.102660 PMID: 39218140IF

TRPV1 channel in the pathophysiology of epilepsy and its potential as a molecular target for the development of new antiseizure drug candidates

癫痫病理生理学中的TRPV1通道及其作为开发新的抗癫痫药候选物的分子靶标的潜力

Identification of transient receptor potential cation channel, subfamily V member 1 (TRPV1), also known as capsaicin receptor, in 1997 was a milestone achievement in the research on temperature sensation and pain signalling. Very soon after it became evident that TRPV1 is implicated in a wide array of physiological processes in different peripheral tissues, as well as in the central nervous system, and thereby could be involved in the pathophysiology of numerous diseases. Increasing evidence suggests that modulation of TRPV1 may also affect seizure susceptibility and epilepsy. This channel is localized in brain regions associated with seizures and epilepsy, and its overexpression was found both in animal models of seizures and in brain samples from epileptic patients. Moreover, modulation of TRPV1 on non-neuronal cells (microglia, astrocytes, and/or peripheral immune cells) may have an impact on the neuroinflammatory processes that play a role in epilepsy and epileptogenesis. In this paper, we provide a comprehensive and critical overview of currently available data on TRPV1 as a possible molecular target for epilepsy management, trying to identify research gaps and future directions. Overall, several converging lines of evidence implicate TRPV1 channel as a potentially attractive target in epilepsy research but more studies are needed to exploit the possible role of TRPV1 in seizures/epilepsy and to evaluate the value of TRPV1 ligands as candidates for new antiseizure drugs.

1997年鉴定瞬时受体电位阳离子通道，亚家族V成员1 (TRPV1)，也称为辣椒素受体，是温度感觉和疼痛信号传导研究中的里程碑成就。很快就发现TRPV1参与了不同外周组织以及中枢神经系统的一系列生理过程，从而可能参与了许多疾病的病理生理学。越来越多的证据表明，TRPV1的调节也可能影响癫痫易感性和癫痫。该通道位于与癫痫发作和癫痫相关的大脑区域，并且在癫痫发作的动物模型和癫痫患者的大脑样本中均发现了其过表达。此外，TRPV1对非神经元细胞 (小胶质细胞、星形胶质细胞和/或外周免疫细胞) 的调节可能对在癫痫和癫痫发生中起作用的神经炎性过程具有影响。在本文中，我们提供了关于TRPV1作为癫痫管理的可能分子靶标的当前可用数据的全面和关键概述，试图确定研究空白和未来方向。总体而言，几个趋同的证据表明TRPV1通道是癫痫研究中潜在的有吸引力的靶标，但需要更多的研究来利用TRPV1在癫痫发作/癫痫中的可能作用，并评估TRPV1配体作为新抗癫痫药候选物的价值。

REF: Socała K, Jakubiec M, Abram M, et al. TRPV1 channel in the pathophysiology of epilepsy and its potential as a molecular target for the development of new antiseizure drug candidates. Prog Neurobiol. 2024;240:102634. doi:10.1016/j.pneurobio.2024.102634 PMID: 38834133