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107


Forty-hertz light stimulation does not entrain native gamma oscillations in Alzheimer's disease model mice

Soula, Marisol; Martín-Ávila, Alejandro; Zhang, Yiyao; Dhingra, Annika; Nitzan, Noam; Sadowski, Martin J; Gan, Wen-Biao; Buzsáki, György
There is a demand for noninvasive methods to ameliorate disease. We investigated whether 40-Hz flickering light entrains gamma oscillations and suppresses amyloid-β in the brains of APP/PS1 and 5xFAD mouse models of Alzheimer's disease. We used multisite silicon probe recording in the visual cortex, entorhinal cortex or the hippocampus and found that 40-Hz flickering simulation did not engage native gamma oscillations in these regions. Additionally, spike responses in the hippocampus were weak, suggesting 40-Hz light does not effectively entrain deep structures. Mice avoided 40-Hz flickering light, associated with elevated cholinergic activity in the hippocampus. We found no reliable changes in plaque count or microglia morphology by either immunohistochemistry or in vivo two-photon imaging following 40-Hz stimulation, nor reduced levels of amyloid-β 40/42. Thus, visual flicker stimulation may not be a viable mechanism for modulating activity in deep structures.
PMID: 36879142
ISSN: 1546-1726
CID: 5432632

Synchronized activity of sensory neurons initiates cortical synchrony in a model of neuropathic pain

Chen, Chao; Sun, Linlin; Adler, Avital; Zhou, Hang; Zhang, Licheng; Zhang, Lihai; Deng, Junhao; Bai, Yang; Zhang, Jinhui; Yang, Guang; Gan, Wen-Biao; Tang, Peifu
Increased low frequency cortical oscillations are observed in people with neuropathic pain, but the cause of such elevated cortical oscillations and their impact on pain development remain unclear. By imaging neuronal activity in a spared nerve injury (SNI) mouse model of neuropathic pain, we show that neurons in dorsal root ganglia (DRG) and somatosensory cortex (S1) exhibit synchronized activity after peripheral nerve injury. Notably, synchronized activity of DRG neurons occurs within hours after injury and 1-2 days before increased cortical oscillations. This DRG synchrony is initiated by axotomized neurons and mediated by local purinergic signaling at the site of nerve injury. We further show that synchronized DRG activity after SNI is responsible for increasing low frequency cortical oscillations and synaptic remodeling in S1, as well as for inducing animals' pain-like behaviors. In naive mice, enhancing the synchrony, not the level, of DRG neuronal activity causes synaptic changes in S1 and pain-like behaviors similar to SNI mice. Taken together, these results reveal the critical role of synchronized DRG neuronal activity in increasing cortical plasticity and oscillations in a neuropathic pain model. These findings also suggest the potential importance of detection and suppression of elevated cortical oscillations in neuropathic pain states.
PMCID:9908980
PMID: 36755026
ISSN: 2041-1723
CID: 5420902

Generalized extinction of fear memory depends on co-allocation of synaptic plasticity in dendrites

Xu, Zhiwei; Geron, Erez; Pérez-Cuesta, Luis M; Bai, Yang; Gan, Wen-Biao
Memories can be modified by new experience in a specific or generalized manner. Changes in synaptic connections are crucial for memory storage, but it remains unknown how synaptic changes associated with different memories are distributed within neuronal circuits and how such distributions affect specific or generalized modification by novel experience. Here we show that fear conditioning with two different auditory stimuli (CS) and footshocks (US) induces dendritic spine elimination mainly on different dendritic branches of layer 5 pyramidal neurons in the mouse motor cortex. Subsequent fear extinction causes CS-specific spine formation and extinction of freezing behavior. In contrast, spine elimination induced by fear conditioning with >2 different CS-USs often co-exists on the same dendritic branches. Fear extinction induces CS-nonspecific spine formation and generalized fear extinction. Moreover, activation of somatostatin-expressing interneurons increases the occurrence of spine elimination induced by different CS-USs on the same dendritic branches and facilitates the generalization of fear extinction. These findings suggest that specific or generalized modification of existing memories by new experience depends on whether synaptic changes induced by previous experiences are segregated or co-exist at the level of individual dendritic branches.
PMCID:9889816
PMID: 36720872
ISSN: 2041-1723
CID: 5467412

Reduced levels of NGF shift astrocytes toward a neurotoxic phenotype

Tiberi, Alexia; Carucci, Nicola Maria; Testa, Giovanna; Rizzi, Caterina; Pacifico, Paola; Borgonovo, Giulia; Arisi, Ivan; D'Onofrio, Mara; Brandi, Rossella; Gan, Wen-Biao; Capsoni, Simona; Cattaneo, Antonino
Nerve growth factor (NGF) is critical for neuronal physiology during development and adulthood. Despite the well-recognized effect of NGF on neurons, less is known about whether NGF can actually affect other cell types in the central nervous system (CNS). In this work, we show that astrocytes are susceptible to changes in ambient levels of NGF. First, we observe that interfering with NGF signaling in vivo via the constitutive expression of an antiNGF antibody induces astrocytic atrophy. A similar asthenic phenotype is encountered in an uncleavable proNGF transgenic mouse model (TgproNGF#72), effectively increasing the brain proNGF levels. To examine whether this effect on astrocytes is cell-autonomous, we cultured wild-type primary astrocytes in the presence of antiNGF antibodies, uncovering that a short incubation period is sufficient to potently and rapidly trigger calcium oscillations. Acute induction of calcium oscillations by antiNGF antibodies is followed by progressive morphological changes similar to those observed in antiNGF AD11 mice. Conversely, incubation with mature NGF has no effect on either calcium activity nor on astrocytic morphology. At longer timescales, transcriptomic analysis revealed that NGF-deprived astrocytes acquire a proinflammatory profile. In particular, antiNGF-treated astrocytes show upregulation of neurotoxic transcripts and downregulation of neuroprotective mRNAs. Consistent with that data, culturing wild-type neurons in the presence of NGF-deprived astrocytes leads to neuronal cell death. Finally, we report that in both awake and anesthetized mice, astrocytes in layer I of the motor cortex respond with an increase in calcium activity to acute NGF inhibition using either NGF-neutralizing antibodies or a TrkA-Fc NGF scavenger. Moreover, in vivo calcium imaging in the cortex of the 5xFAD neurodegeneration mouse model shows an increased level of spontaneous calcium activity in astrocytes, which is significantly reduced after acute administration of NGF. In conclusion, we unveil a novel neurotoxic mechanism driven by astrocytes, triggered by their sensing and reacting to changes in the levels of ambient NGF.
PMCID:10151754
PMID: 37143894
ISSN: 2296-634x
CID: 5544962

High resolution ultrasonic neural modulation observed via in vivo two-photon calcium imaging

Cheng, Zongyue; Wang, Chenmao; Wei, Bowen; Gan, Wenbiao; Zhou, Qifa; Cui, Meng
Neural modulation plays a major role in delineating the circuit mechanisms and serves as the cornerstone of neural interface technologies. Among the various modulation mechanisms, ultrasound enables noninvasive label-free deep access to mammalian brain tissue. To date, most if not all ultrasonic neural modulation implementations are based on ∼1 MHz carrier frequency. The long acoustic wavelength results in a spatially coarse modulation zone, often spanning over multiple function regions. The modulation of one function region is inevitably linked with the modulation of its neighboring regions. Moreover, the lack of in vivo cellular resolution cell-type-specific recording capabilities in most studies prevents the revealing of the genuine cellular response to ultrasound. To significantly increase the spatial resolution, we explored the application of high-frequency ultrasound. To investigate the neuronal response at cellular resolutions, we developed a dual-modality system combining in vivo two-photon calcium imaging and focused ultrasound modulation. The studies show that the ∼30 MHz ultrasound can suppress the neuronal activity in awake mice at 100-μm scale spatial resolutions, paving the way for high-resolution ultrasonic neural modulation. The dual-modality in vivo system validated through this study will serve as a general platform for studying the dynamics of various cell types in response to ultrasound.
PMID: 34952226
ISSN: 1876-4754
CID: 5099632

Sleep promotes the formation of dendritic filopodia and spines near learning-inactive existing spines

Adler, Avital; Lai, Cora Sau Wan; Yang, Guang; Geron, Erez; Bai, Yang; Gan, Wen-Biao
Changes in synaptic connections are believed to underlie long-term memory storage. Previous studies have suggested that sleep is important for synapse formation after learning, but how sleep is involved in the process of synapse formation remains unclear. To address this question, we used transcranial two-photon microscopy to investigate the effect of postlearning sleep on the location of newly formed dendritic filopodia and spines of layer 5 pyramidal neurons in the primary motor cortex of adolescent mice. We found that newly formed filopodia and spines were partially clustered with existing spines along individual dendritic segments 24 h after motor training. Notably, posttraining sleep was critical for promoting the formation of dendritic filopodia and spines clustered with existing spines within 8 h. A fraction of these filopodia was converted into new spines and contributed to clustered spine formation 24 h after motor training. This sleep-dependent spine formation via filopodia was different from retraining-induced new spine formation, which emerged from dendritic shafts without prior presence of filopodia. Furthermore, sleep-dependent new filopodia and spines tended to be formed away from existing spines that were active at the time of motor training. Taken together, these findings reveal a role of postlearning sleep in regulating the number and location of new synapses via promoting filopodial formation.
PMCID:8685900
PMID: 34873044
ISSN: 1091-6490
CID: 5110152

Clear optically matched panoramic access channel technique (COMPACT) for large-volume deep brain imaging

Wei, Bowen; Wang, Chenmao; Cheng, Zongyue; Lai, Baoling; Gan, Wen-Biao; Cui, Meng
To understand neural circuit mechanisms underlying behavior, it is crucial to observe the dynamics of neuronal structure and function in different regions of the brain. Since current noninvasive imaging technologies allow cellular-resolution imaging of neurons only within ~1 mm below the cortical surface, the majority of mouse brain tissue remains inaccessible. While miniature optical imaging probes allow access to deep brain regions, cellular-resolution imaging is typically restricted to a small tissue volume. To increase the tissue access volume, we developed a clear optically matched panoramic access channel technique (COMPACT). With probe dimensions comparable to those of common gradient-index lenses, COMPACT enables a two to three orders of magnitude greater tissue access volume. We demonstrated the capabilities of COMPACT by multiregional calcium imaging in mice during sleep. We believe that large-volume in vivo imaging with COMPACT will be valuable to a variety of deep tissue imaging applications.
PMID: 34354291
ISSN: 1548-7105
CID: 4988722

BDNF produced by cerebral microglia promotes cortical plasticity and pain hypersensitivity after peripheral nerve injury

Huang, Lianyan; Jin, Jianhua; Chen, Kai; You, Sikun; Zhang, Hongyang; Sideris, Alexandra; Norcini, Monica; Recio-Pinto, Esperanza; Wang, Jing; Gan, Wen-Biao; Yang, Guang
Peripheral nerve injury-induced mechanical allodynia is often accompanied by abnormalities in the higher cortical regions, yet the mechanisms underlying such maladaptive cortical plasticity remain unclear. Here, we show that in male mice, structural and functional changes in the primary somatosensory cortex (S1) caused by peripheral nerve injury require neuron-microglial signaling within the local circuit. Following peripheral nerve injury, microglia in the S1 maintain ramified morphology and normal density but up-regulate the mRNA expression of brain-derived neurotrophic factor (BDNF). Using in vivo two-photon imaging and Cx3cr1CreER;Bdnfflox mice, we show that conditional knockout of BDNF from microglia prevents nerve injury-induced synaptic remodeling and pyramidal neuron hyperactivity in the S1, as well as pain hypersensitivity in mice. Importantly, S1-targeted removal of microglial BDNF largely recapitulates the beneficial effects of systemic BDNF depletion on cortical plasticity and allodynia. Together, these findings reveal a pivotal role of cerebral microglial BDNF in somatosensory cortical plasticity and pain hypersensitivity.
PMID: 34292944
ISSN: 1545-7885
CID: 4948532

Specific depletion of resident microglia in the early stage of stroke reduces cerebral ischemic damage

Li, Ting; Zhao, Jin; Xie, Wenguang; Yuan, Wanru; Guo, Jing; Pang, Shengru; Gan, Wen-Biao; Gómez-Nicola, Diego; Zhang, Shengxiang
BACKGROUND:Ischemia can induce rapid activation of microglia in the brain. As key immunocompetent cells, reactive microglia play an important role in pathological development of ischemic stroke. However, the role of activated microglia during the development of ischemia remains controversial. Thus, we aimed to investigate the function of reactive microglia in the early stage of ischemic stroke. METHODS:mice were used to specifically deplete resident microglia through intragastric administration of tamoxifen (Ta) and intraperitoneal injection of diphtheria toxin (DT). At day 3 after ischemic stroke, behavioral tests were performed. After that, mouse brains were collected for further histological analysis and detection of mRNA expression of inflammatory factors. RESULTS:) cells. Importantly, depleting microglia induced a significant increase in the mRNA expression level of anti-inflammatory factors TGF-β1, Arg1, IL-10, IL-4, and Ym1 as well as a significant decline of pro-inflammatory factors TNF-α, iNOS, and IL-1β 3 days after stroke. CONCLUSIONS:These results suggest that activated microglia is an important modulator of the brain's inflammatory response in stroke, contributing to neurological deficit and infarct expansion. Modulation of the inflammatory response through the elimination of microglia at a precise time point may be a promising therapeutic approach for the treatment of cerebral ischemia.
PMCID:7986495
PMID: 33757565
ISSN: 1742-2094
CID: 4836692

Bioinspired Cavity Regulation on Superhydrophobic Spheres for Drag Reduction in an Aqueous Medium

Yao, Changzhuang; Zhang, Jingjing; Xue, Zihan; Yu, Kang; Yu, Xinping; Yang, Xiaoxiao; Qu, Qiulin; Gan, Wenbiao; Wang, Jingming; Jiang, Lei
Hydrodynamic drag not only results in high-energy consumption for water vehicles but also impedes the increase of vehicle speed. The introduction of a low-viscosity gas lubricating film is assumed to be an effective and promising method to reduce hydrodynamic drag. However, the poor stability of the gas film and massive extra energy consumption restricts the practical application of the gas lubricating method. Herein, inspired by the microhairs with low surface energy wax covering the abdomen of water spiders, superhydrophobic sphere surfaces were designed. Attributed to numerous neighboring nanoneedle branches with low surface energy chemicals, an air-entrained cavity with a large surface area was captured and stabilized by the superhydrophobic sphere, changing its shape from a sphere to a streamlined body. The cavity continued attaching to the superhydrophobic sphere without bursting at a depth of 70.0-90.0 cm underwater and reduced the hydrodynamic drag by more than 90%. This work provides a simple, cost-effective, and energy-efficient way to stabilize the underwater gas-liquid interface to achieve a reduction in the hydrodynamic drag.
PMID: 33448779
ISSN: 1944-8252
CID: 4747332