Patterned Neuronal Activities Dictate Cell Type-specific Axon Regeneration

AbstractInjured neurons exhibit cell type-specific axon regeneration, but the underlying mechanisms remain elusive. Two subtypes of Drosophila sensory neurons show distinct regenerative competence. Here, we show that axotomy induces long-lasting burst firing and Ca2+ spikes specifically in the regenerative subtype. Genetic silencing of firing in the regenerative subtype inhibits regeneration. Optogenetic stimulation of the non-regenerative subtype reveals that activity patterns critically determine regeneration; burst firing triggers Ca2+ spikes and suffices to induce regeneration, while tonic firing fails to induce Ca2+ spikes and regeneration. We further show the L-type Ca2+ channel, Dmca1D, regulates Ca2+ spikes and regeneration. Intriguingly, the regenerative neuronal subtype expresses higher levels of Dmca1D, and overexpression of Dmca1D in the non-regenerative subtype facilitates regeneration. Our studies indicate that injury induces cell type-specific neuronal activities, which act through Ca2+ spikes to govern regeneration, and suggest that precise control of neuronal activity patterns is an effective way to promote regeneration.

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Downregulation of renal TonEBP in hypokalemic rats

AJP Renal Physiology ◽

10.1152/ajprenal.00502.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. F408-F415 ◽

Cited By ~ 22

Author(s):

Un Sil Jeon ◽

Ki-Hwan Han ◽

Soo-Hyun Park ◽

Sang Do Lee ◽

Mee Rie Sheen ◽

...

Keyword(s):

Cultured Cells ◽

Renal Medulla ◽

Distal Tubule ◽

Cell Type ◽

Outer Medulla ◽

Sodium Transporters ◽

Enhancer Binding Protein ◽

Collecting Ducts ◽

Cell Type Specific ◽

Underlying Mechanisms

Hypokalemia causes a significant decrease in the tonicity of the renal medullary interstitium in association with reduced expression of sodium transporters in the distal tubule. We asked whether hypokalemia caused downregulation of the tonicity-responsive enhancer binding protein (TonEBP) transcriptional activator in the renal medulla due to the reduced tonicity. We found that the abundance of TonEBP decreased significantly in the outer and inner medullas of hypokalemic rats. Underlying mechanisms appeared different in the two regions because the abundance of TonEBP mRNA was lower in the outer medulla but unchanged in the inner medulla. Immunohistochemical examination of TonEBP revealed cell type-specific differences. TonEBP expression decreased dramatically in the outer and inner medullary collecting ducts, thick ascending limbs, and interstitial cells. In the descending and ascending thin limbs, TonEBP abundance decreased modestly. In the outer medulla, TonEBP shifted to the cytoplasm in the descending thin limbs. As expected, transcription of aldose reductase, a target of TonEBP, was decreased since the abundance of mRNA and protein was reduced. Downregulation of TonEBP appeared to have also contributed to reduced expression of aquaporin-2 and UT-A urea transporters in the renal medulla. In cultured cells, expression and activity of TonEBP were not affected by reduced potassium concentrations in the medium. These data support the view that medullary tonicity regulates expression and nuclear distribution of TonEBP in the renal medulla in cell type-specific manners.

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The Cell Type–Specific Functions of miR-21 in Cardiovascular Diseases

Frontiers in Genetics ◽

10.3389/fgene.2020.563166 ◽

2020 ◽

Vol 11 ◽

Author(s):

Beibei Dai ◽

Feng Wang ◽

Xiang Nie ◽

Hengzhi Du ◽

Yanru Zhao ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Vascular System ◽

Cardiac Fibroblasts ◽

Pressure Overload ◽

Cell Type ◽

Physiological Processes ◽

A Cell ◽

Cell Type Specific ◽

Underlying Mechanisms ◽

Endothelial Nitric Oxide

Cardiovascular diseases are one of the prime reasons for disability and death worldwide. Diseases and conditions, such as hypoxia, pressure overload, infection, and hyperglycemia, might initiate cardiac remodeling and dysfunction by inducing hypertrophy or apoptosis in cardiomyocytes and by promoting proliferation in cardiac fibroblasts. In the vascular system, injuries decrease the endothelial nitric oxide levels and affect the phenotype of vascular smooth muscle cells. Understanding the underlying mechanisms will be helpful for the development of a precise therapeutic approach. Various microRNAs are involved in mediating multiple pathological and physiological processes in the heart. A cardiac enriched microRNA, miR-21, which is essential for cardiac homeostasis, has been demonstrated to act as a cell–cell messenger with diverse functions. This review describes the cell type–specific functions of miR-21 in different cardiovascular diseases and its prospects in clinical therapy.

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Cell-Type Specific Burst Firing Interacts with Theta and Beta Activity in Prefrontal Cortex During Attention States

Cerebral Cortex ◽

10.1093/cercor/bhx287 ◽

2017 ◽

Vol 28 (12) ◽

pp. 4348-4364 ◽

Cited By ~ 9

Author(s):

B Voloh ◽

T Womelsdorf

Keyword(s):

Prefrontal Cortex ◽

Burst Firing ◽

Beta Activity ◽

Cell Type ◽

Cell Type Specific

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Two distinct auto-regulatory loops operate at the PU.1 locus in B cells and myeloid cells

Blood ◽

10.1182/blood-2010-08-302976 ◽

2011 ◽

Vol 117 (10) ◽

pp. 2827-2838 ◽

Cited By ~ 81

Author(s):

Mathias Leddin ◽

Chiara Perrod ◽

Maarten Hoogenkamp ◽

Saeed Ghani ◽

Salam Assi ◽

...

Keyword(s):

B Cells ◽

Activity Patterns ◽

Regulatory Elements ◽

Specific Pattern ◽

Cell Type ◽

Hematopoietic Progenitors ◽

Specific Expression ◽

Targeted Deletion ◽

Cis Element ◽

Cell Type Specific

Abstract The transcription factor PU.1 occupies a central role in controlling myeloid and early B-cell development, and its correct lineage-specific expression is critical for the differentiation choice of hematopoietic progenitors. However, little is known of how this tissue-specific pattern is established. We previously identified an upstream regulatory cis element whose targeted deletion in mice decreases PU.1 expression and causes leukemia. We show here that the upstream regulatory cis element alone is insufficient to confer physiologic PU.1 expression in mice but requires the cooperation with other, previously unidentified elements. Using a combination of transgenic studies, global chromatin assays, and detailed molecular analyses we present evidence that PU.1 is regulated by a novel mechanism involving cross talk between different cis elements together with lineage-restricted autoregulation. In this model, PU.1 regulates its expression in B cells and macrophages by differentially associating with cell type–specific transcription factors at one of its cis-regulatory elements to establish differential activity patterns at other elements.

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Optogenetic stimulation of long-range inputs and functional characterization of connectivity in patch-clamp recordings in mouse brain slices

10.1101/491563 ◽

2018 ◽

Author(s):

Louis Richevaux ◽

Louise Schenberg ◽

Mathieu Beraneck ◽

Desdemona Fricker

Keyword(s):

Patch Clamp ◽

Long Range ◽

Brain Slices ◽

Cell Type ◽

Patch Clamp Recording ◽

Axon Terminals ◽

Optogenetic Stimulation ◽

Cell Type Specific ◽

The Brain ◽

Stimulation Of

Knowledge of cell type specific synaptic connectivity is a crucial prerequisite for understanding brain wide neuronal circuits. The functional investigation of long-range connections requires targeted recordings of single neurons combined with the specific stimulation of identified distant inputs. This is often difficult to achieve with conventional, electrical stimulation techniques, because axons from converging upstream brain areas may intermingle in the target region. The stereotaxic targeting of a specific brain region for virus-mediated expression of light sensitive ion channels allows to selectively stimulate axons coming from that region with light. Intracerebral stereotaxic injections can be used in well-delimited structures, such as the anterodorsal thalamic nuclei, and also in other subcortical or cortical areas throughout the brain. Here we describe a set of techniques for precise stereotaxic injection of viral vectors expressing channelrhodopsin in the anterodorsal thalamus, followed by photostimulation of their axon terminals in hippocampal slices. In combination with whole-cell patch clamp recording from a postsynaptically connected presubicular neuron, photostimulation of thalamic axons allows the detection of functional synaptic connections, their pharmacological characterization, and the evaluation of their strength in the brain slice preparation. We demonstrate that axons originating in the anterodorsal thalamus ramify densely in presubicular layers 1 and 3. The photostimulation of Chronos expressing thalamic axon terminals in presubiculum initiates short latency postsynaptic responses in a presubicular layer3 neuron, indicating a monosynaptic connection. In addition, biocytin filling of the recorded neuron and posthoc revelation confirms the layer localization and pyramidal morphology of the postsynaptic neuron. Taken together, the optogenetic stimulation of long-range inputs in ex vivo brain slices is a useful method to determine the cell-type specific functional connectivity from distant brain regions.

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Cell-type specific burst firing interacts with theta and beta activity in prefrontal cortex during attention states

10.1101/127811 ◽

2017 ◽

Cited By ~ 5

Author(s):

B. Voloh ◽

T. Womelsdorf

Keyword(s):

Prefrontal Cortex ◽

Population Level ◽

Burst Firing ◽

Anterior Cingulate ◽

Beta Activity ◽

Cell Type ◽

Beta Band ◽

Beta Power ◽

A Cell ◽

Cell Type Specific

AbstractPopulation-level theta and beta band activity in anterior cingulate and prefrontal cortex (ACC/PFC) are prominent signatures of endogenously controlled, adaptive behaviors. But how these rhythmic activities are linked to cell-type specific activity has remained unclear. Here, we suggest such a cell-to-systems level linkage. We found that the rate of burst spiking events is enhanced particularly during attention states and that attention-specific burst spikes have a unique temporal relationship to local theta and beta band population level activities. For the 5-10Hz theta frequency range, bursts coincided with transient increases of local theta power relative to non-bursts, particularly for bursts of putative interneurons. For the 16-30Hz beta frequency, bursts of putative interneurons phase synchronized stronger than nonbursts, and were associated with larger beta power modulation. In contrast, burst of putative pyramidal cells were overall similarly beta-synchronized than nonbursts, but were linked with stronger beta power only when they occurred early in the beta cycle. These findings suggests that in the ACC/PFC during attention states, mechanisms underlying burst firing are intimately linked to narrow band population level activities, providing a cell-type specific window into the emergence, resetting, or termination of oscillatory activities.

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Gap Junctions Between Striatal D1 Neurons and Cholinergic Interneurons

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.674399 ◽

2021 ◽

Vol 15 ◽

Author(s):

Yuqi Ren ◽

Yang Liu ◽

Minmin Luo

Keyword(s):

Gap Junctions ◽

Electrical Coupling ◽

Cell Types ◽

Projection Neurons ◽

Chemical Synapse ◽

Cell Type ◽

Cholinergic Interneurons ◽

Optogenetic Stimulation ◽

Electrophysiological Recordings ◽

Cell Type Specific

The striatum participates in numerous important behaviors. Its principal projection neurons use GABA and peptides as neurotransmitters and interact extensively with interneurons, including cholinergic interneurons (ChIs) that are tonically active. Dissecting the interactions between projection neurons and ChIs is important for uncovering the role and mechanisms of the striatal microcircuits. Here, by combining several optogenetic tools with cell type-specific electrophysiological recordings, we uncovered direct electrical coupling between D1-type projection neurons and ChIs, in addition to the chemical transmission between these two major cell types. Optogenetic stimulation or inhibition led to bilateral current exchanges between D1 neurons and ChIs, which can be abolished by gap junction blockers. We further confirmed the presence of gap junctions through paired electrophysiological recordings and dye microinjections. Finally, we found that activating D1 neurons promotes basal activity of ChIs via gap junctions. Collectively, these results reveal the coexistence of the chemical synapse and gap junctions between D1 neurons and ChIs, which contributes to maintaining the tonically active firing patterns of ChIs.

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Fast and reversible neural inactivation in macaque cortex by optogenetic stimulation of GABAergic neurons

eLife ◽

10.7554/elife.52658 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 2

Author(s):

Abhishek De ◽

Yasmine El-Shamayleh ◽

Gregory D Horwitz

Keyword(s):

Neural Activity ◽

Neural Circuits ◽

Gabaergic Neurons ◽

Visual Sensitivity ◽

Cell Type ◽

Behavioral Deficits ◽

Inhibitory Cell ◽

Optogenetic Stimulation ◽

Cell Type Specific ◽

Stimulation Of

Optogenetic techniques for neural inactivation are valuable for linking neural activity to behavior but they have serious limitations in macaques. To achieve powerful and temporally precise neural inactivation, we used an adeno-associated viral (AAV) vector carrying the channelrhodopsin-2 gene under the control of a Dlx5/6 enhancer, which restricts expression to GABAergic neurons. We tested this approach in the primary visual cortex, an area where neural inactivation leads to interpretable behavioral deficits. Optical stimulation modulated spiking activity and reduced visual sensitivity profoundly in the region of space represented by the stimulated neurons. Rebound firing, which can have unwanted effects on neural circuits following inactivation, was not observed, and the efficacy of the optogenetic manipulation on behavior was maintained across >1000 trials. We conclude that this inhibitory cell-type-specific optogenetic approach is a powerful and spatiotemporally precise neural inactivation tool with broad utility for probing the functional contributions of cortical activity in macaques.

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Alternative mechanisms for trafficking of lysosomal enzymes in mannose 6-phosphate receptor-deficient mice are cell type-specific

Journal of Cell Science ◽

10.1242/jcs.112.10.1591 ◽

1999 ◽

Vol 112 (10) ◽

pp. 1591-1597 ◽

Cited By ~ 8

Author(s):

F. Dittmer ◽

E.J. Ulbrich ◽

A. Hafner ◽

W. Schmahl ◽

T. Meister ◽

...

Keyword(s):

Cathepsin D ◽

Lysosomal Enzymes ◽

Lysosomal Storage ◽

Cell Type ◽

Genes Encoding ◽

Cell Type Specific ◽

Mannose 6 Phosphate ◽

Underlying Mechanisms

Viable mice nullizygous in genes encoding the 300 kDa and the 46 kDa mannose 6-phosphate receptors (MPR 300 and MPR 46) and the insulin like growth factor II (IGF II) were generated to study the trafficking of lysosomal enzymes in the absence of MPRs. The mice have an I-cell disease-like phenotype, with increase of lysosomal enzymes in serum and normal activities in tissues. Surprisingly, the ability of MPR-deficient cells to transport newly synthesized lysosomal enzymes to lysosomes and the underlying mechanisms were found to depend on the cell type. MPR-deficient thymocytes target newly synthesized cathepsin D to lysosomes via an intracellular route. In contrast, hepatocytes and fibroblasts secrete newly synthesized cathepsin D. In fibroblasts recapture of secreted lysosomal enzymes, including that of cathepsin D, is limited and results in lysosomal storage, both in vivo and in vitro, whereas recapture by hepatocytes is remarkably effective in vivo and can result in lysosomal enzyme levels even above normal.

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