A diencephalic pathway for movement initiation and rescue of Parkinsonian symptoms

SummaryThe parafascicular nucleus (Pf) of the thalamus projects to the subthalamic nucleus (STN), a major target for deep brain stimulation (DBS) in Parkinson’s disease (PD), but the function of this projection remains unknown. Here, we used optogenetics, 3D motion capture, in vivo electrophysiology and 1-photon calcium imaging, unsupervised behavioral classification, and viral-based neuroanatomical tracing to examine the contribution of Pf efferents to movement generation in mice. We discovered that Pf neurons are highly correlated with movement velocity and excitation of Pf neurons generates turning and orienting movements. Movement initiation was not due to Pf projections to the striatum, but rather its projections to the STN. Optogenetic excitation of the Pf-STN pathway restores movement in a common mouse model of PD with complete akinesia. Collectively, our results reveal a thalamo-subthalamic pathway regulating movement initiation, and demonstrate a circuit mechanism that could potentially explain the clinical efficacy of DBS for relief of PD motor symptoms.

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Stereotaxic Viral Injection and Gradient-Index Lens Implantation for Deep Brain In Vivo Calcium Imaging

Journal of Visualized Experiments ◽

10.3791/63049 ◽

2021 ◽

Author(s):

Rashmi Thapa ◽

Bo Liang ◽

Rongsong Liu ◽

Yun Li

Keyword(s):

Calcium Imaging ◽

Gradient Index ◽

Lens Implantation ◽

Gradient Index Lens ◽

Deep Brain

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Thalamic projections to the subthalamic nucleus contribute to movement initiation and rescue of parkinsonian symptoms

Science Advances ◽

10.1126/sciadv.abe9192 ◽

2021 ◽

Vol 7 (6) ◽

pp. eabe9192

Author(s):

Glenn D. R. Watson ◽

Ryan N. Hughes ◽

Elijah A. Petter ◽

Isabella P. Fallon ◽

Namsoo Kim ◽

...

Keyword(s):

Subthalamic Nucleus ◽

Dopamine Depletion ◽

Movement Initiation ◽

Thalamic Projections ◽

Subcortical Nuclei ◽

Stn Dbs ◽

Shed Light ◽

Major Target ◽

Deep Brain ◽

Action Initiation

The parafascicular nucleus (Pf) of the thalamus provides major projections to the basal ganglia, a set of subcortical nuclei involved in action initiation. Here, we show that Pf projections to the subthalamic nucleus (STN), but not to the striatum, are responsible for movement initiation. Because the STN is a major target of deep brain stimulation treatments for Parkinson’s disease, we tested the effect of selective stimulation of Pf-STN projections in a mouse model of PD. Bilateral dopamine depletion with 6-OHDA created complete akinesia in mice, but Pf-STN stimulation immediately and markedly restored a variety of natural behaviors. Our results therefore revealed a functionally novel neural pathway for the initiation of movements that can be recruited to rescue movement deficits after dopamine depletion. They not only shed light on the clinical efficacy of conventional STN DBS but also suggest more selective and improved stimulation strategies for the treatment of parkinsonian symptoms.

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Differential cell-type dependent brain state modulations of sensory representations in the non-lemniscal mouse inferior colliculus

Communications Biology ◽

10.1038/s42003-019-0602-4 ◽

2019 ◽

Vol 2 (1) ◽

Cited By ~ 1

Author(s):

Chenggang Chen ◽

Sen Song

Keyword(s):

Inferior Colliculus ◽

Calcium Imaging ◽

Inhibitory Neurons ◽

Brain State ◽

Spectral Tuning ◽

State Dependent ◽

Excitatory Neurons ◽

Sensory Responses ◽

Highly Correlated

Abstract Sensory responses of the neocortex are strongly influenced by brain state changes. However, it remains unclear whether and how the sensory responses of the midbrain are affected. Here we addressed this issue by using in vivo two-photon calcium imaging to monitor the spontaneous and sound-evoked activities in the mouse inferior colliculus (IC). We developed a method enabling us to image the first layer of non-lemniscal IC (IC shell L1) in awake behaving mice. Compared with the awake state, spectral tuning selectivity of excitatory neurons was decreased during isoflurane anesthesia. Calcium imaging in behaving animals revealed that activities of inhibitory neurons were highly correlated with locomotion. Compared with stationary periods, spectral tuning selectivity of excitatory neurons was increased during locomotion. Taken together, our studies reveal that neuronal activities in the IC shell L1 are brain state dependent, whereas the brain state modulates the excitatory and inhibitory neurons differentially.

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A Modified Miniscope System for Simultaneous Electrophysiology and Calcium Imaging in vivo

Frontiers in Integrative Neuroscience ◽

10.3389/fnint.2021.682019 ◽

2021 ◽

Vol 15 ◽

Author(s):

Xiaoting Wu ◽

Xiangyu Yang ◽

Lulu Song ◽

Yang Wang ◽

Yamin Li ◽

...

Keyword(s):

Calcium Imaging ◽

Adult Mouse ◽

Field Potential ◽

Simultaneous Recording ◽

Ca1 Region ◽

Volume Weight ◽

The Brain ◽

Local Field Potential Lfp ◽

Deep Brain

The miniscope system is one of the calcium (Ca2+) imaging tools with small size and lightweight and can realize the deep-brain Ca2+ imaging not confined to the cerebral cortex. Combining Ca2+ imaging and electrophysiology recording has been an efficient method for extracting high temporal-spatial resolution signals in the brain. In this study, a particular electrode probe was developed and assembled on the imaging lens to modify the miniscope system. The electrode probe can be tightly integrated into the lens of the miniscope without increasing the volume, weight, and implantation complexity. In vivo tests verified that the proposed modified system has realized the simultaneous recording of Ca2+ signals and local field potential (LFP) signal in the hippocampus CA1 region of an adult mouse.

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Benchmarking miniaturized microscopy against two-photon calcium imaging using single-cell orientation tuning in mouse visual cortex

10.1101/494641 ◽

2018 ◽

Cited By ~ 1

Author(s):

Annet Glas ◽

Mark Huebener ◽

Tobias Bonhoeffer ◽

Pieter M Goltstein

Keyword(s):

Visual Cortex ◽

Calcium Imaging ◽

Visual Stimulation ◽

Signal To Noise Ratio ◽

Imaging Techniques ◽

Orientation Tuning ◽

Cell Orientation ◽

Two Photon ◽

Highly Correlated

Miniaturized microscopes are lightweight imaging devices that allow optical recordings from neurons in freely moving animals over the course of weeks. Despite their ubiquitous use, individual neuronal responses measured with these microscopes have not been directly compared to those obtained with established in vivo imaging techniques such as bench-top two-photon microscopes. To achieve this, we performed calcium imaging in mouse primary visual cortex while presenting animals with drifting gratings. We identified the same neurons in image stacks acquired with both microscopy methods and quantified orientation tuning of individual neurons. The response amplitude and signal-to-noise ratio of calcium transients recorded upon visual stimulation were highly correlated between both microscopy methods, although influenced by neuropil contamination in miniaturized microscopy. Tuning properties, calculated for individual orientation tuned neurons, were strongly correlated between imaging techniques. Thus, neuronal tuning features measured with a miniaturized microscope are quantitatively similar to those obtained with a two-photon microscope.

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Do Extra-Platelet Sources Contribute to the Plasma Level of Thrombospondin?

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642769 ◽

1988 ◽

Vol 59 (02) ◽

pp. 273-276 ◽

Cited By ~ 8

Author(s):

J Dawes ◽

D A Pratt ◽

M S Dewar ◽

F E Preston

Keyword(s):

Platelet Count ◽

Background Concentration ◽

Serum Concentrations ◽

Bone Marrow Depression ◽

Serial Sampling ◽

Control Serum ◽

Platelet Release ◽

Highly Correlated ◽

The Relationship

SummaryThrombospondin, a trimeric glycoprotein contained in the platelet α-granules, has been proposed as a marker of in vivo platelet activation. However, it is also synthesised by a range of other cells. The extraplatelet contribution to plasma levels of thrombospondin was therefore estimated by investigating the relationship between plasma thrombospondin levels and platelet count in samples from profoundly thrombocytopenic patients with marrow hypoplasia, using the platelet-specific α-granule protein β-thromboglobulin as control. Serum concentrations of both proteins were highly correlated with platelet count, but while plasma β-thromboglobulin levels and platelet count also correlated, there was no relationship between the number of platelets and thrombospondin concentrations in plasma. Serial sampling of patients recovering from bone marrow depression indicated that the plasma thrombospondin contributed by platelets is superimposed on a background concentration of at least 50 ng/ml probably derived from a non-platelet source, and plasma thrombospondin levels do not simply reflect platelet release.

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In Vivo Deep-Brain Structural and Hemodynamic Multiphoton Microscopy Enabled by Quantum Dots

Nano Letters ◽

10.1021/acs.nanolett.9b01708 ◽

2019 ◽

Vol 19 (8) ◽

pp. 5260-5265 ◽

Cited By ~ 14

Author(s):

Hongji Liu ◽

Xiangquan Deng ◽

Shen Tong ◽

Chen He ◽

Hui Cheng ◽

...

Keyword(s):

Quantum Dots ◽

Multiphoton Microscopy ◽

Deep Brain

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PPM1G promotes the progression of hepatocellular carcinoma via phosphorylation regulation of alternative splicing protein SRSF3

Cell Death and Disease ◽

10.1038/s41419-021-04013-y ◽

2021 ◽

Vol 12 (8) ◽

Author(s):

Dawei Chen ◽

Zhenguo Zhao ◽

Lu Chen ◽

Qinghua Li ◽

Jixue Zou ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Alternative Splicing ◽

Protein Function ◽

Vital Role ◽

Normal Tissues ◽

Mechanistic Analysis ◽

Highly Correlated ◽

Splicing Patterns

AbstractEmerging evidence has demonstrated that alternative splicing has a vital role in regulating protein function, but how alternative splicing factors can be regulated remains unclear. We showed that the PPM1G, a protein phosphatase, regulated the phosphorylation of SRSF3 in hepatocellular carcinoma (HCC) and contributed to the proliferation, invasion, and metastasis of HCC. PPM1G was highly expressed in HCC tissues compared to adjacent normal tissues, and higher levels of PPM1G were observed in adverse staged HCCs. The higher levels of PPM1G were highly correlated with poor prognosis, which was further validated in the TCGA cohort. The knockdown of PPM1G inhibited the cell growth and invasion of HCC cell lines. Further studies showed that the knockdown of PPM1G inhibited tumor growth in vivo. The mechanistic analysis showed that the PPM1G interacted with proteins related to alternative splicing, including SRSF3. Overexpression of PPM1G promoted the dephosphorylation of SRSF3 and changed the alternative splicing patterns of genes related to the cell cycle, the transcriptional regulation in HCC cells. In addition, we also demonstrated that the promoter of PPM1G was activated by multiple transcription factors and co-activators, including MYC/MAX and EP300, MED1, and ELF1. Our study highlighted the essential role of PPM1G in HCC and shed new light on unveiling the regulation of alternative splicing in malignant transformation.

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Predicting in Vivo Soft Tissue Masses of the Lower Extremity Using Segment Anthropometric Measures and DXA

Journal of Applied Biomechanics ◽

10.1123/jab.21.4.371 ◽

2005 ◽

Vol 21 (4) ◽

pp. 371-382 ◽

Cited By ~ 22

Author(s):

Jeffrey D. Holmes ◽

David M. Andrews ◽

Jennifer L. Durkin ◽

James J. Dowling

Keyword(s):

Soft Tissue ◽

Lower Extremity ◽

Prediction Equation ◽

Regression Equations ◽

Anthropometric Measures ◽

Soft Tissue Masses ◽

Highly Correlated ◽

Relative Errors ◽

Dxa Scans

The purpose of this study was to derive and validate regression equations for the prediction of fat mass (FM), lean mass (LM), wobbling mass (WM), and bone mineral content (BMC) of the thigh, leg, and leg + foot segments of living people from easily measured segmental anthropometric measures. The segment masses of 68 university-age participants (26 M, 42 F) were obtained from full-body dual photon x-ray absorptiometry (DXA) scans, and were used as the criterion values against which predicted masses were compared. Comprehensive anthropometric measures (6 lengths, 6 circumferences, 8 breadths, 4 skinfolds) were taken bilaterally for the thigh and leg for each person. Stepwise multiple linear regression was used to derive a prediction equation for each mass type and segment. Prediction equations exhibited high adjustedR2values in general (0.673 to 0.925), with higher correlations evident for the LM and WM equations than for FM and BMC. Predicted (equations) and measured (DXA) segment LM and WM were also found to be highly correlated (R2= 0.85 to 0.96), and FM and BMC to a lesser extent (R2= 0.49 to 0.78). Relative errors between predicted and measured masses ranged between 0.7% and –11.3% for all those in the validation sample (n= 16). These results on university-age men and women are encouraging and suggest that in vivo estimates of the soft tissue masses of the lower extremity can be made fairly accurately from simple segmental anthropometric measures.

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