gaolixia

Selective corticofugal modulation on sound processing in auditory thalamus of awake marmosets

Cortical feedback has long been considered crucial for the modulation of sensory perception and recognition. However, previous studies have shown varying modulatory effects of the primary auditory cortex (A1) on the auditory response of subcortical neurons, which complicate interpretations regarding the function of A1 in sound perception and recognition. This has been further complicated by studies conducted under different brainstates. In the current study, we used cryo-inactivation in A1 to examine the role of corticothalamic feedback on medial geniculate body (MGB) neurons in awake marmosets. The primary effects of A1 inactivation were a frequency-specific decrease in the auditory response of most MGB neurons coupled with ani ncreased spontaneous firingrate, which together resulted in a decrease in the signal-to-noise ratio. In addition, we report for the first time that A1 robustly modulated the long-lasting sustained response of MGB neurons, which changed the frequency tuning after A1 inactivation, e.g. some neurons are sharper with corticofugal feedback and some get broader. Takentogether, our results demonstrate that corticothalamic modulation in awake marmosets serves to enhance sensory processing in a manner similar to center-surround models proposed in visual and somatosensory systems, a finding which supports common principles of corticothalamic processing across sensory systems.

Xiaohui-Wang†, Yuanqing-Zhang†, Lin Zhu, Siyi-Bai, Rui Li, Hao Sun, Runze-Qi, Ruolan-Cai, Min Li, Guoqiang-Jia, Xinyuan-Cao, Kenneth E. Schriver, Xinjian-Li*, Lixia-Gao* (IF=4.8,

corresponding author)

bhac278.pdf

Distinct Subthreshold Mechanisms Underlying Rate-Coding Principles in Primate Auditory Cortex

A key computational principle for encoding timevarying signals in auditory and somatosensory cortices of monkeys is the opponent model of rate coding by two distinct populations of neurons. However, the subthreshold mechanisms that give rise to this computation have not been revealed. Because the rate-coding neurons are only observed in awake conditions, it is especially challenging to probe their underlying cellular mechanisms. Using a novel intracellular recording technique that we developed in awake marmosets, we found that the two types of rate-coding neurons in auditory cortex exhibited distinct subthreshold responses. While the positive-monotonic neurons (monotonically increasing firing rate with increasing stimulus repetition frequency) displayed sustained depolarization at high repetition frequency, the negative-monotonic neurons (opposite trend) instead exhibited hyperpolarization at high repetition frequency but sustained depolarization at low repetition frequency. The combination of excitatory and inhibitory subthreshold events allows the cortex to represent time-varying signals through these two opponent neuronal populations.

Lixia Gao, Kevin Kostlan, Yunyan Wang, and Xiaoqin Wang* (IF=18.7, first author)

Gao 2016.pdf

Restoring nuclear entry of Sirtuin 2 in oligodendrocyte progenitor cells promotes remyelination duri

Xiao-Ru Ma, Xudong Zhu, Yujie Xiao, Hui-Min Gu, Shuang-Shuang Zheng, Liang Li, Fan Wang, Zhao-Jun Dong, Di-Xian Wang, Yang Wu, Chenyu Yang, Wenhong Jiang, Ke Yao, Yue Yin, Yang Zhang, Chao Peng, Lixia Gao, Zhuoxian Meng, Zeping Hu, Chong Liu, Li Li, Hou-Zao Chen✉, Yousheng Shu✉, Zhenyu Ju✉ & Jing-Wei Zhao✉ (2022, IF, 14.9)

The age-dependent decline in remyelination potential of the central nervous system during ageing is associated with a declined differentiation capacity of oligodendrocyte progenitor cells (OPCs). The molecular players that can enhance OPC differentiation or rejuvenate OPCs are unclear. Here we show that, in mouse OPCs, nuclear entry of SIRT2 is impaired and NAD+ levels are reduced during ageing. When we supplement β-nicotinamide mononucleotide (β-NMN), an NAD+ precursor, nuclear entry of SIRT2 in OPCs, OPC differentiation, and remyelination were rescued in aged animals. We show that the effects on myelination are mediated via the NAD+-SIRT2-H3K18Ac-ID4 axis, and SIRT2 is required for rejuvenating OPCs. Our results show that SIRT2 and NAD+ levels rescue the aged OPC differentiation potential to levels comparable to young age, providing potential targets to enhance remyelination during ageing.

Restoring nuclear entry of Sirtuin 2 in oligodendrocyte progenitor cells promotes remyelination during ageing.pdf

Mapping Organizational Changes of Fiber-Like Structures in Disease Progression by Multiparametric, Q

Qian, Shuhao; Meng, Jia; Feng, Zhe; Zhou, Lingxi; Jiang, Shenyi; Wang, Yalun; Ye, Zitong; Zhuo, Shuangmu; Chen, Jianxin; Li, Xinjian; Gao, Lixia; Ding, Zhihua*; Qian, Jun*; Liu, Zhiyi* (2022, IF, 13.1)

With the progression of diseases, modified cell-matrix interactions have major effects not only upon key cellular functions but also upon the structure of extracellular matrix and vasculature, which are two of the most prevalent fiber-like structures in biological tissues. Unfortunately, quantitative approaches to assessing these structural changes are lacking. Herein, a multiparametric imaging system is established to resolve subtle organizational changes of collagen fibers and vasculature in disease progression. The pixel-wise, automated waviness (paWav) is developed as a novel biomarker, and a multimodal analysis system combining paWav with orientation and alignment assessments is constructed. Aggregation-induced emission luminogens (AIEgens) with second near-infrared excitation or emission are developed for in vivo deep-penetration vasculature imaging. The organization remodeling of cortical blood vessels in stroke in marmosets is quantitatively characterized using biologically excretable AIE dots that highlight the clinical translation potential, and a distance dependence law in vessel morphological remodeling is identified. Finally, the multiparametric analysis relying completely on collagen fiber signatures successfully differentiates cancerous from normal pancreatic tissues using a predictive classification approach. Collectively, the combined use of these structural changes in fibrillar tissue components may enable a better understanding of cell-matrix interactions in pathogenesis and identification of new potential treatment targets.

DOI :

10.1002/lpor.202100576

Mapping physiological and pathological functions of cortical vasculature through aggregation-induced

Jia Meng, Zhe Feng, Shuhao Qian, Chuncheng Wang, Xinjian Li, Lixia Gao, Zhihua Ding*, Jun Qian*, Zhiyi Liu** (2022, IF, 7.3)

Cerebrovascular disease includes all disorders that affect cerebrovascular and cerebral circulation. Unfortunately, there is currently a lack of a systematic method to image blood vessels directly and achieve accurate quantification. Herein, we build a non-invasive, quantitative imaging and characterization system applicable to mapping physiological and pathological functions of cortical vasculature. Assisted by aggregation-induced emission (AIE) luminogens with either excitation or emission at near-infrared-II (NIR-II) region, large-depth and/or high signal-to-background ratio images of cerebral blood vessels from mice and marmosets are captured, based on which we develop an optical metric of vessel thickness in an automated, pixel-wise manner and both two-dimensional (2D) and three-dimensional (3D) contexts. By monitoring time-dependent cerebrovascular images in marmosets, periodic changes in the diameter of vibrating cerebral blood vessels are found to be regulated mainly by heartbeat. In mice photothrombosis model, vessel alterations throughout the whole process of thrombotic stroke are found to be stage-dependent. From a large field of view, the distance-dependent vessel thickness variation before and right after stroke is obtained away from the thrombus site. Importantly, a buffer zone exists right surrounding the lesion, indicating the inhomogeneity of vascular morphological changes. Biologically excretable AIE nanoparticles are used for assessing physiological and pathological functions, offering great potential for clinical translation.

Mapping physiological and pathological functions of cortical vasculature through affreagtion-induced emission nanobrobes.pdf

Corticofugal Modulation of Temporal and Rate Representations in the Inferior Colliculus of the Awake

Temporal processing is crucial for auditory perception and cognition, especially for communication sounds. Previous studies have shown that the auditory cortex and the thalamus use temporal and rate representations to encode slowly and rapidly changing time-varying sounds. However, how the primate inferior colliculus (IC) encodes time-varying sounds at the millisecond scale remains unclear. In this study, we investigated the temporal processing by IC neurons in awake marmosets to Gaussian click trains with varying inter click intervals (2–100ms). Strikingly, we found that 28% of IC neurons exhibited rate representation with nonsynchronized responses, which is in sharp contrast to the current view that the IC only uses a temporal representation to encode time-varying signals. Moreover, IC neurons with rate representation exhibited response properties distinct from those with temporal representation. We further demonstrated that reversible inactivation of the primary auditory cortex modulated 17% of the stimulus-synchronized responses and 21% of the nonsynchronized responses of IC neurons, revealing that cortico-colliculus projections play a role, but not a crucial one, in temporal processing in the IC. This study has significantly advanced our understanding of temporal processing in the IC of awake animals and provides new insights into temporal processing from the midbrain to the cortex.

Xiaohui Wang, Yuanqing Zhang, Siyi Bai, Runze Qi, Hao Sun, Rui Li, Lin Zhu, Xinyuan Cao, Guoqiang Jia, Xinjian Li and Lixia Gao*（IF=4.8, corresponding author)

bhab467.pdf

Stimulus-Specific Adaptation in Auditory Thalamus Is Modulated by the Thalamic Reticular Nucleus

A striking property of the auditory system is its capacity for the stimulus-specific adaptation (SSA), which is the reduction of neural response to repeated stimuli but a recuperative response to novel stimuli. SSA is found in both the medial geniculate body (MGB) and thalamic reticular nucleus (TRN). However, it remains unknown whether the SSA of MGB neurons is modulated by inhibitory inputs from the TRN, as it is difficult to investigate using the extracellular recording method. In the present study, we performed intracellular recordings in the MGB of anesthetized guinea pigs and examined whether and how the TRN modulates the SSA of MGB neurons with inhibitory inputs. This was accomplished by using microinjection of lidocaine to inactivate the neural activity of the TRN. We found that (1) MGB neurons with hyperpolarized membrane potentials exhibited SSA at both the spiking and subthreshold levels; (2) SSA of MGB neurons depends on the interstimulus interval (ISI), where a shorter ISI results in stronger SSA; and (3) the long-lasting hyperpolarization of MGB neurons decreased after the burst firing of the TRN was inactivated. As a result, SSA of these MGB neurons was diminished after inactivation of the TRN. Taken together, our results revealed that the SSA of the MGB is strongly modulated by the neural activity of the TRN, which suggests an alternative circuit mechanism underlying the SSA of the auditory thalamus.

Guoqiang Jia, Xinjian Li, Chunhua Liu, Jufang He,* and Lixia Gao* (IF=5.8, corresponding author)

acschemneuro.1c00137 .pdf

Biologically Excretable Aggregation-Induced Emission Dots for Visualizing Through the Marmosets Intr

Superb reliability and biocompatibility equip aggregation-induced emission (AIE) dots with tremendous potential for fluorescence bioimaging. However, there is still a chronic lack of design instructions of excretable and bright AIE emitters. Here, a kind of PEGylated AIE (OTPA-BBT) dots with strong absorption and extremely high second near-infrared region (NIR-II) PLQY of 13.6% is designed, and a long-aliphatic-chain design blueprint contributing to their excretion from an animal’s body is proposed. Assisted by the OTPA-BBT dots with bright fluorescence beyond 1100 nm and even 1500 nm (NIR-IIb), large-depth cerebral vasculature (beyond 600 μm) as well as real-time blood flow are monitored through a thinned skull, and noninvasive NIR-IIb imaging with rich high-spatial-frequency information gives a precise presentation of gastrointestinal tract in marmosets. Importantly, after intravenous or oral administration, the definite excretion of OTPA-BBT dots from the body is demonstrated, which provides influential evidence of biosafety.

Zhe Feng, Siyi Bai, Ji Qi, Chaowei Sun, Yuhuang Zhang, Xiaoming Yu, Huwei Ni, Di Wu, Xiaoxiao Fan, Dingwei Xue, Shunjie Liu, Ming Chen, Junyi Gong, Peifa Wei, Mubin He, Jacky W. Y. Lam, Xinjian Li, Benzhong Tang,* Lixia Gao,* and Jun Qian* (IF=32.1, corresponding author)

adma.202008123.pdf

Intracellular neuronal recording in awake nonhuman primates

Intracellular neuronal recordings from the brain of awake nonhuman primates have remained difficult to obtain because of several formidable technical challenges, such as poor recording stability and difficulties in maintaining long-term recording conditions. We have developed a technique to record neuronal activity by using a coaxial guide tube and sharp electrode assembly, which allows researchers to repeatedly and reliably perform intracellular recordings in the cortex of awake marmosets. Recordings from individual neurons last from several minutes to more than an hour. A key advantage of this approach is that it does not require dura removal, permitting recordings over weeks and months in a single animal. This protocol describes the step-by-step procedures for construction of a custom-made marmoset chair, head-cap implantation, preparation of the sharp electrode and guide tube, neuronal recording and data analysis. As the technique is practical and easy to adapt, we anticipate that it can also be applied to other mammalian models, including larger-size nonhuman primates.

Lixia Gao* and Xiaoqin Wang* (IF=17.0, corresponding author)

s41596-020-0388-3.pdf

Enhancement of Neuronal Activity in the Auditory Thalamus After Simulated Slow-Wave Oscillation

Sleep is essential for survival in mammals, and there are many examples of how the brain fails to function properly without sleep. These include the importance of sleep for plasticity during development, memory formation and consolidation, and the erasure of undesired memories as well as the improvement of memory, perceptual skills, and learning abilities after sleep. These studies suggest that sleep not only benefits individual memories formed before sleep but also enhances individual performance on sensory discrimination tasks and learning ability after sleep. However, whether and how sleep contributes to sensory signal processing remains largely unknown. Sleep has different phases, one of which is slow-wave sleep (SWS), characterized by low-frequency (＜1 Hz), high-amplitude slow-wave oscillation (SWO) in the thalamocortical circuity, which is prevalent in both anesthetized and naturally sleeping animals. Accumulating evidence indicates that the SWO originates from thalamocortical circuitry. During SWO, intracellular recordings have revealed that both cortical and thalamic neurons exhibit spontaneous membrane potential (MP) fluctuations—an alternation between a depolarized UP state and a hyperpolarized DOWN state. In the DOWN state, the MP of thalamic neurons is as low as -75 to -90 mV and the duration is in the range of 1 to 10 s (3.9 ± 2.2 s, mean ± SD). It has been reported that SWO plays a critical role in the induction of long-term synaptic plasticity, triggering the reactivation of associated memories and memory retention as well as homeostatic regulation. Moreover, previous studies have shown that visual and barrel cortical neurons exhibit distinct reponses to visual or tactile stimuli during the UP and DOWN states, suggesting that the SWO plays a critical role in visual and tactile processing during sleep. The question we address is whether the long-lasting, hyperpolarized DOWN state in auditory thalamic neurons affects sound processing during and after SWO. We performed sharp electrode recordings in the medial geniculate body (MGB) of anesthetized guinea pigs and injected hyperpolarizing current into the recorded neurons to simulate SWO, and thus investigated the function of SWO in sound processing in the MGB.

Lixia Gao*, Yuanqing Zhang, Xinjian Li, Jufang He* (IF=5.3, corresponding author)

Gao2020_Article_EnhancementOfNeuronalActivityI.pdf