Soma-Targeted Imaging of Neural Circuits by Ribosome Tethering

Chen, Yiming; Jang, Heeun; Spratt, Perry W.E.; Kosar, Seher; Taylor, David E.; Essner, Rachel; Bai, Lijun; Leib, David E.; Kuo, Tzu-Wei; Lin, Yen‐Chu; Patel, Mili B.; Subkhangulova, Aygul; Kato, Saul; Feinberg, Evan H.; Bender, Kevin J.; Knight, Zachary A.; Garrison, Jennifer L.

doi:10.1016/j.neuron.2020.05.005

Cited by 65 publications

(69 citation statements)

References 73 publications

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“…In particular, the human brain transcriptome correlates closely with advanced human cognition 17 . As expected, there is little concordance between brain transcriptomic data from human AD brain and AD animal models 18 , 19 .…”

Section: Introductionmentioning

confidence: 63%

Defining early changes in Alzheimer’s disease from RNA sequencing of brain regions differentially affected by pathology

Guennewig

Lim

Marshall

et al. 2021

Sci Rep

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Tau pathology in Alzheimer’s disease (AD) spreads in a predictable pattern that corresponds with disease symptoms and severity. At post-mortem there are cortical regions that range from mildly to severely affected by tau pathology and neuronal loss. A comparison of the molecular signatures of these differentially affected areas within cases and between cases and controls may allow the temporal modelling of disease progression. Here we used RNA sequencing to explore differential gene expression in the mildly affected primary visual cortex and moderately affected precuneus of ten age-, gender- and RNA quality-matched post-mortem brains from AD patients and healthy controls. The two regions in AD cases had similar transcriptomic signatures but there were broader abnormalities in the precuneus consistent with the greater tau load. Both regions were characterised by upregulation of immune-related genes such as those encoding triggering receptor expressed on myeloid cells 2 and membrane spanning 4-domains A6A and milder changes in insulin/IGF1 signalling. The precuneus in AD was also characterised by changes in vesicle secretion and downregulation of the interneuronal subtype marker, somatostatin. The ‘early’ AD transcriptome is characterised by perturbations in synaptic vesicle secretion on a background of neuroimmune dysfunction. In particular, the synaptic deficits that characterise AD may begin with the somatostatin division of inhibitory neurotransmission.

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Section: Introductionmentioning

confidence: 63%

Defining early changes in Alzheimer’s disease from RNA sequencing of brain regions differentially affected by pathology

Guennewig

Lim

Marshall

et al. 2021

Sci Rep

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“…Second, our recordings were performed with GCaMP6s, a variant of GCaMP that has slow dynamics. Different relationships may be observed with GCaMP variants with faster kinetics, or those that target GCaMP to specific cellular compartments (11,12). Despite these limitations, we believe our results speak to the utility of fiber photometry, and the interpretation of findings with this technique.…”

Section: Discussionmentioning

confidence: 78%

“…Our finding is also not surprising, as neuropil calcium is known to influence calcium signals in microscope-based imaging (1-4). Recently, new approaches have limited the expression of GCaMP to the soma to mitigate the contribution of neuropil in calcium imaging (11,12). Despite knowledge of this issue and the widespread use of fiber photometry, there have been few attempts to quantify the relative contribution of neuropil vs. spiking to the fiber photometry signal.…”

Section: Discussionmentioning

confidence: 99%

Striatal fiber photometry reflects primarily non-somatic activity

Kravitz¹,

Macal

2021

Preprint

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Fiber photometry recordings are commonly used as a proxy for neuronal activity, based on the assumption that increases in bulk calcium fluorescence reflect increases in spiking of the underlying neural population. However, this assumption has not been adequately tested. Here, using endoscopic calcium imaging in the striatum we report that the bulk fluorescence signal correlates weakly with somatic calcium signals, suggesting that this signal does not reflect spiking activity, but may instead reflect subthreshold changes in neuropil calcium. Consistent with this suggestion, the bulk fluorescence photometry signal correlated strongly with neuropil calcium signals extracted from these same endoscopic recordings. We further confirmed that photometry did not reflect striatal spiking activity with simultaneous in vivo extracellular electrophysiology and fiber photometry recordings in awake behaving mice. We conclude that the fiber photometry signal should not be considered a proxy for spiking activity in neural populations in the striatum.Significance statementFiber photometry is a technique for recording brain activity that has gained popularity in recent years due to it being an efficient and robust way to record the activity of genetically defined populations of neurons. However, it remains unclear what cellular events are reflected in the photometry signal. While it is often assumed that the photometry signal reflects changes in spiking of the underlying cell population, this has not been adequately tested. Here, we processed calcium imaging recordings to extract both somatic and non-somatic components of the imaging field, as well as a photometry signal from the whole field. Surprisingly, we found that the photometry signal correlated much more strongly with the non-somatic than the somatic signals. This suggests that the photometry signal most strongly reflects subthreshold changes in calcium, and not spiking. We confirmed this point with simultaneous fiber photometry and extracellular spiking recordings, again finding that photometry signals relate poorly to spiking in the striatum. Our results may change interpretations of studies that use fiber photometry as an index of spiking output of neural populations.

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“…The approach of choosing the appropriate promoter and tagging sequence for the desired location for GECI expression aligns itself extraordinarily well with the aims of synthetic biology to develop standardized sets of biological parts. Considering the targeting sequences as modular parts, the schemata of modular design are not just limited to the ER but to the tagging of GECIs to other locations with distinctive spatiotemporal Ca 2+ behavior [156,157]. Replacing the ER targeting sequence of CEPIA3 with a mitochondrial target sequence generated a CEPIA variant which has enabled study of mitochondrial dynamics in diverse cell types [117].…”

Section: Subcellular Localization Of Gecismentioning

confidence: 99%

Optimizing Calcium Detection Methods in Animal Systems: A Sandbox for Synthetic Biology

Saha

2021

Biomolecules

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Since the 1970s, the emergence and expansion of novel methods for calcium ion (Ca2+) detection have found diverse applications in vitro and in vivo across a series of model animal systems. Matched with advances in fluorescence imaging techniques, the improvements in the functional range and stability of various calcium indicators have significantly enhanced more accurate study of intracellular Ca2+ dynamics and its effects on cell signaling, growth, differentiation, and regulation. Nonetheless, the current limitations broadly presented by organic calcium dyes, genetically encoded calcium indicators, and calcium-responsive nanoparticles suggest a potential path toward more rapid optimization by taking advantage of a synthetic biology approach. This engineering-oriented discipline applies principles of modularity and standardization to redesign and interrogate endogenous biological systems. This review will elucidate how novel synthetic biology technologies constructed for eukaryotic systems can offer a promising toolkit for interfacing with calcium signaling and overcoming barriers in order to accelerate the process of Ca2+ detection optimization.

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Soma-Targeted Imaging of Neural Circuits by Ribosome Tethering

Cited by 65 publications

References 73 publications

Defining early changes in Alzheimer’s disease from RNA sequencing of brain regions differentially affected by pathology

Defining early changes in Alzheimer’s disease from RNA sequencing of brain regions differentially affected by pathology

Striatal fiber photometry reflects primarily non-somatic activity

Optimizing Calcium Detection Methods in Animal Systems: A Sandbox for Synthetic Biology

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