scholarly journals Cellular Circuits in the Brain and Their Modulation in Acute and Chronic Pain

2021 ◽  
Vol 101 (1) ◽  
pp. 213-258 ◽  
Author(s):  
Rohini Kuner ◽  
Thomas Kuner
Keyword(s):  
Chronic Pain ◽  
Neural Circuits ◽  
Cell Types ◽  
Mammalian Brain ◽  
Specific Cell ◽  
Dynamic Regulation ◽  
Maladaptive Plasticity ◽  
Pathological Pain ◽  
Dimensions Of Pain ◽  
Cellular Circuits

Chronic, pathological pain remains a global health problem and a challenge to basic and clinical sciences. A major obstacle to preventing, treating, or reverting chronic pain has been that the nature of neural circuits underlying the diverse components of the complex, multidimensional experience of pain is not well understood. Moreover, chronic pain involves diverse maladaptive plasticity processes, which have not been decoded mechanistically in terms of involvement of specific circuits and cause-effect relationships. This review aims to discuss recent advances in our understanding of circuit connectivity in the mammalian brain at the level of regional contributions and specific cell types in acute and chronic pain. A major focus is placed on functional dissection of sub-neocortical brain circuits using optogenetics, chemogenetics, and imaging technological tools in rodent models with a view towards decoding sensory, affective, and motivational-cognitive dimensions of pain. The review summarizes recent breakthroughs and insights on structure-function properties in nociceptive circuits and higher order sub-neocortical modulatory circuits involved in aversion, learning, reward, and mood and their modulation by endogenous GABAergic inhibition, noradrenergic, cholinergic, dopaminergic, serotonergic, and peptidergic pathways. The knowledge of neural circuits and their dynamic regulation via functional and structural plasticity will be beneficial towards designing and improving targeted therapies.

scholarly journals Transgenic Silencing of Neurons in the Mammalian Brain by Expression of the Allatostatin Receptor (AlstR)

2009 ◽  
Vol 102 (4) ◽  
pp. 2554-2562 ◽  
Author(s):  
M. Wehr ◽  
U. Hostick ◽  
M. Kyweriga ◽  
A. Tan ◽  
A. P. Weible ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cortical Neurons ◽  
Action Potentials ◽  
Neural Circuits ◽  
Hippocampal Slices ◽  
Neuronal Cell ◽  
Cell Types ◽  
Mammalian Brain ◽  
Specific Cell ◽  
Membrane Hyperpolarization

The mammalian brain is an enormously complex set of circuits composed of interconnected neuronal cell types. The analysis of central neural circuits will be greatly served by the ability to turn off specific neuronal cell types while recording from others in intact brains. Because drug delivery cannot be restricted to specific cell types, this can only be achieved by putting “silencer” transgenes under the control of neuron-specific promoters. Towards this end we have created a line of transgenic mice putting the Drosophila allatostatin (AL) neuropeptide receptor (AlstR) under the control of the tetO element, thus enabling its inducible expression when crossed to tet-transactivator lines. Mammals have no endogenous AL or AlstR, but activation of exogenously expressed AlstR in mammalian neurons leads to membrane hyperpolarization via endogenous G-protein-coupled inward rectifier K+ channels, making the neurons much less likely to fire action potentials. Here we show that this tetO/AlstR line is capable of broadly expressing AlstR mRNA in principal neurons throughout the forebrain when crossed to a commercially-available transactivator line. We electrophysiologically characterize this cross in hippocampal slices, demonstrating that bath application of AL leads to hyperpolarization of CA1 pyramidal neurons, making them refractory to the induction of action potentials by injected current. Finally, we demonstrate the ability of AL application to silence the sound-evoked spiking responses of auditory cortical neurons in intact brains of AlstR/tetO transgenic mice. When crossed to other transactivator lines expressing in defined neuronal cell types, this AlstR/tetO line should prove a very useful tool for the analysis of intact central neural circuits.

scholarly journals Development of Viral Vectors for Gene Therapy for Chronic Pain

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Yu Huang ◽  
Xin Liu ◽  
Lanlan Dong ◽  
Zhongchun Liu ◽  
Xiaohua He ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Chronic Pain ◽  
Viral Vectors ◽  
Treatment Strategies ◽  
Opioid Analgesics ◽  
Cell Types ◽  
Health Concern ◽  
Specific Cell ◽  
New Treatment ◽  
The Individual

Chronic pain is a major health concern that affects millions of people. There are no adequate long-term therapies for chronic pain sufferers, leading to significant cost for both society and the individual. The most commonly used therapy for chronic pain is the application of opioid analgesics and nonsteroidal anti-inflammatory drugs, but these drugs can lead to addiction and may cause side effects. Further studies of the mechanisms of chronic pain have opened the way for development of new treatment strategies, one of which is gene therapy. The key to gene therapy is selecting safe and highly efficient gene delivery systems that can deliver therapeutic genes to overexpress or suppress relevant targets in specific cell types. Here we review several promising viral vectors that could be applied in gene transfer for the treatment of chronic pain and further discuss the possible mechanisms of genes of interest that could be delivered with viral vectors for the treatment of chronic pain.

scholarly journals Comprehensive Assessment of Sequence and Expression of Circular-RNAs in Progenitor Cell Types of the Developing Mammalian Cortex

2019 ◽  
Author(s):  
Martina Dori ◽  
Leila Haj Abdullah Alieh ◽  
Daniel Cavalli ◽  
Simone Massalini ◽  
Mathias Lesche ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Expression Patterns ◽  
Biological Significance ◽  
Cell Types ◽  
Mammalian Brain ◽  
Circular Rnas ◽  
Sequence Information ◽  
Specific Cell ◽  
Newborn Neurons ◽  
And Function

ABSRTRACTCircular (circ) RNAs have recently emerged as a novel class of non coding transcripts whose identification and function remain elusive. Among many tissues and species, the mammalian brain is the organ in which circRNAs are more abundant and first evidence of their functional significance started to emerge. Yet, even within this well studied organ, annotation of circRNAs remains fragmentary, their sequence is unknown and their expression in specific cell types was never investigated. Overcoming these limitations, here we provide the fist comprehensive identification of circRNAs and their expression patterns in proliferating neural stem cells, neurogenic progenitors and newborn neurons of the developing mouse cortex. Extending the current knowledge about the diversity of this class of transcripts by the identification of nearly 4,000 new circRNAs, our study is the first to provide the full sequence information and expression patterns of circRNAs in cell types representing the lineage of neurogenic commitment. We further exploited our data by evaluating the coding potential, evolutionary conservation and biogenesis of circRNAs that we found to arise from a specific sub-class of linear mRNAs. Our study provides the arising field of circRNA biology with a powerful new resource to address the complexity and potential biological significance of this new class of transcripts.

scholarly journals A pharmacological interactome platform for discovery of pain mechanisms and targets

2020 ◽  
Author(s):  
Andi Wangzhou ◽  
Candler Paige ◽  
Sanjay V Neerukonda ◽  
Gregory Dussor ◽  
Pradipta R Ray ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Sensory Neurons ◽  
Cell Types ◽  
Specific Cell ◽  
Interaction Point ◽  
Pain Mechanisms ◽  
Peripheral Cell ◽  
Disease States ◽  
Enteric Glial Cells ◽  
Receptor Interactions

AbstractCells communicate with each other through ligand and receptor interactions. In the case of the peripheral nervous system, these ligand-receptor interactions shape sensory experience. In disease states, such as chronic pain, these ligand-receptor interactions can change the excitability of target neurons augmenting nociceptive input to the CNS. While the importance of these cell to neuron interactions are widely acknowledged, they have not been thoroughly characterized. We sought to address this by cataloging how peripheral cell types interact with sensory neurons in the dorsal root ganglion (DRG) using RNA sequencing datasets. Using single cell sequencing datasets from mouse we created a comprehensive interactome map for how mammalian sensory neurons interact with 42 peripheral cell types. We used this knowledge base to understand how specific cell types and sensory neurons interact in disease states. In mouse datasets, we created an interactome of colonic enteric glial cells in the naïve and inflamed state with sensory neurons that specifically innervate this tissue. In human datasets, we created interactomes of knee joint macrophages from rheumatoid arthritis patients and pancreatic cancer samples with human DRG. Collectively, these interactomes highlight ligand-receptor interactions in mouse models and human disease states that reflect the complexity of cell to neuron signaling in chronic pain states. These interactomes also highlight therapeutic targets, such as the epidermal growth factor receptor (EGFR), which was a common interaction point emerging from our studies.

scholarly journals Control of synaptic specificity by limiting promiscuous synapse formation

2018 ◽  
Author(s):  
Chundi Xu ◽  
Emma Theisen ◽  
Elijah Rumbaut ◽  
Bryan Shum ◽  
Jing Peng ◽  
...  
Keyword(s):  
Visual System ◽  
Synapse Formation ◽  
Neural Circuits ◽  
Local Environment ◽  
Cell Types ◽  
Partner Choice ◽  
Synaptic Connectivity ◽  
Specific Cell ◽  
Synaptic Specificity ◽  
And Function

SUMMARYThe ability of neurons to distinguish appropriate from inappropriate synaptic partners in their local environment is fundamental to the proper assembly and function of neural circuits. How synaptic partner selection is regulated is a longstanding question in Neurobiology. A prevailing hypothesis is that appropriate partners express complementary molecules that match them together and promote synaptogenesis. Dpr and DIP IgSF proteins bind heterophilically and are expressed in a complementary manner between synaptic partners in the Drosophila visual system. Here, we show that in the lamina, DIP mis-expression is sufficient to promote synapse formation with Dpr-expressing neurons, and that DIP proteins are not necessary for synaptogenesis but rather function to prevent ectopic synapse formation. These findings indicate that Dpr-DIP interactions regulate synaptic specificity by biasing synapse formation towards specific cell-types. We propose that synaptogenesis occurs independent of synaptic partner choice, and that precise synaptic connectivity is established by limiting promiscuous synapse formation.

scholarly journals Sequence and expression levels of circular RNAs in progenitor cell types during mouse corticogenesis

2019 ◽  
Vol 2 (2) ◽  
pp. e201900354 ◽  
Author(s):  
Martina Dori ◽  
Leila Haj Abdullah Alieh ◽  
Daniel Cavalli ◽  
Simone Massalini ◽  
Mathias Lesche ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Expression Patterns ◽  
Biological Significance ◽  
Cell Types ◽  
Mammalian Brain ◽  
Circular Rnas ◽  
Sequence Information ◽  
Specific Cell ◽  
Newborn Neurons ◽  
And Function

Circular (circ) RNAs have recently emerged as a novel class of transcripts whose identification and function remain elusive. Among many tissues and species, the mammalian brain is the organ in which circRNAs are more abundant and first evidence of their functional significance started to emerge. Yet, even within this well-studied organ, annotation of circRNAs remains fragmentary, their sequence is unknown, and their expression in specific cell types was never investigated. Overcoming these limitations, here we provide the first comprehensive identification of circRNAs and assessment of their expression patterns in proliferating neural stem cells, neurogenic progenitors, and newborn neurons of the developing mouse cortex. Extending the current knowledge about the diversity of this class of transcripts by the identification of nearly 4,000 new circRNAs, our study is the first to provide the full sequence information and expression patterns of circRNAs in cell types representing the lineage of neurogenic commitment. We further exploited our data by evaluating the coding potential, evolutionary conservation, and biogenesis of circRNAs that we found to arise from a specific subclass of linear mRNAs. Our study provides the arising field of circRNA biology with a powerful new resource to address the complexity and potential biological significance of this new class of transcripts.

Correlative transmission and high-resolution scanning electron microscopic studies on pituitary cells

1990 ◽  
Vol 48 (3) ◽  
pp. 20-21
Author(s):  
S. Tai
Keyword(s):  
Cell Types ◽  
Depth Of Field ◽  
Secretory Cells ◽  
Specific Cell ◽  
Pituitary Cells ◽  
Electron Microscopic ◽  
3 Dimensional ◽  
Microscopic Studies ◽  
Structure And Activity ◽  
Intracellular Structure

Extensive cytological and histological research, correlated with physiological experimental analysis, have been done on the anterior pituitaries of many different vertebrates which have provided the knowledge to create the concept that specific cell types synthesize, store and release their specific hormones. These hormones are stored in or associated with granules. Nevertheless, there are still many doubts - that need further studies, specially on the ultrastructure and physiology of these endocrine cells during the process of synthesis, transport and secretion, whereas some new methods may provide the information about the intracellular structure and activity in detail.In the present work, ultrastructural study of the hormone-secretory cells of chicken pituitaries have been done by using TEM as well as HR-SEM, to correlate the informations obtained from 2-dimensional TEM micrography with the 3-dimensional SEM topographic images, which have a continous surface with larger depth of field that - offers the adventage to interpretate some intracellular structures which were not possible to see using TEM.

Nanotheranostic agents for neurodegenerative diseases

2020 ◽  
Vol 4 (6) ◽  
pp. 645-675
Author(s):  
Parasuraman Padmanabhan ◽  
Mathangi Palanivel ◽  
Ajay Kumar ◽  
Domokos Máthé ◽  
George K. Radda ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Neurodegenerative Diseases ◽  
Cell Types ◽  
Specific Cell ◽  
Ageing Population ◽  
Target Tissue ◽  
Therapeutic Approaches ◽  
Surface Receptors ◽  
Theranostic Agents ◽  
Preclinical Animal Models

Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), affect the ageing population worldwide and while severely impairing the quality of life of millions, they also cause a massive economic burden to countries with progressively ageing populations. Parallel with the search for biomarkers for early detection and prediction, the pursuit for therapeutic approaches has become growingly intensive in recent years. Various prospective therapeutic approaches have been explored with an emphasis on early prevention and protection, including, but not limited to, gene therapy, stem cell therapy, immunotherapy and radiotherapy. Many pharmacological interventions have proved to be promising novel avenues, but successful applications are often hampered by the poor delivery of the therapeutics across the blood-brain-barrier (BBB). To overcome this challenge, nanoparticle (NP)-mediated drug delivery has been considered as a promising option, as NP-based drug delivery systems can be functionalized to target specific cell surface receptors and to achieve controlled and long-term release of therapeutics to the target tissue. The usefulness of NPs for loading and delivering of drugs has been extensively studied in the context of NDDs, and their biological efficacy has been demonstrated in numerous preclinical animal models. Efforts have also been made towards the development of NPs which can be used for targeting the BBB and various cell types in the brain. The main focus of this review is to briefly discuss the advantages of functionalized NPs as promising theranostic agents for the diagnosis and therapy of NDDs. We also summarize the results of diverse studies that specifically investigated the usage of different NPs for the treatment of NDDs, with a specific emphasis on AD and PD, and the associated pathophysiological changes. Finally, we offer perspectives on the existing challenges of using NPs as theranostic agents and possible futuristic approaches to improve them.

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