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Application of In Vivo Ca2+ Imaging in the Pathological Study of Autism Spectrum Disorders
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Through transgenic or viral labeling, GECIs can be expressed in neurons, and are now widely used in the research of brain functions with several advantages. First, the activity of dozens, hundreds, or even thousands of neurons can be simultaneously imaged with sub-cellular resolution. Second, it could be combined with cell-type-specific genetic manipulations, fulfilling to record from specific cell populations. Third, it allows chronic imaging in freely moving animals over a period of weeks or months using photon based-microscope. Fourth, it makes neural activity imaging less invasive than traditional methods (e.g., tetrodes, silicon probes). Fifth, it could be used to manipulate network activity, by combining with other approaches, such as optogenetics, chemogenetics (Packer et al., 2013).
Untangling Appetite Circuits with Optogenetics and Chemogenetics
Published in Ruth B.S. Harris, Appetite and Food Intake, 2017
Chemogenetics is a system to control neuronal activity noninvasively in the mammalian brain by regulating signaling through a G-protein-coupled receptor (GPCR) (Armbruster et al. 2007, Luo, Callaway, and Svoboda 2008) or recently using ligand-activated ion channels (Atasoy et al. 2012, Magnus et al. 2011, Stachniak, Ghosh, and Sternson 2014). These pharmacological approaches to manipulate neuronal activity through GPCR signaling pathways in neurons both in vitro and in vivo include ectopic expression of either GPCRs with engineered binding sites such as receptors activated solely by synthetic ligands (RASSLs) (Redfern et al. 1999, Zhao et al. 2003) or nonnative GPCRs such as the Drosophila allatostatin receptor (AlstR) (Lechner, Lein, and Callaway 2002, Tan et al. 2006).
From leptin to lasers: the past and present of mouse models of obesity
Published in Expert Opinion on Drug Discovery, 2021
Joshua R. Barton, Adam E. Snook, Scott A. Waldman
Chemogenetic study of the DRN has extended our knowledge of this circuit. In addition to optogenetic stimulation and inhibition of DRNVgat+ neurons, chemogenetic neuromodulation has revealed the role of these neurons in the regulation of appetite and obesity. Crossing Vgat-IRES-Cre mice to ob/ob mice permitted evaluation of this circuit in an obese mouse model. Expression of the DREADD hM4D in the DVN revealed weight loss and feeding reduction over 24 days of CNO injection that was reversed after CNO was withdrawn [132]. In a follow-up study, the DRN of Vgat-IRES-Cre mice was injected with AAV5-hSyn-DIO-hM3D(Gq)-mCherry, a virus that induced expression of the excitatory hM3D DREADD in DRNVgat+ neurons of these mice [139]. Activation of DRNVgat+ neurons with CNO decreased thermogenesis in mice, indicating that DRNVgat+ neurons both increase appetite and decrease energy expenditure. Further, these neurons were shown to exert their effect on feeding through projections to the Bed Nucleus of the Stria Terminalis (BNST), and the Dorsomedial Hypothalamus (DMH), while regulating temperature chiefly through descending projections to the raphe palladius (RPa).
Potassium channels as prominent targets and tools for the treatment of epilepsy
Published in Expert Opinion on Therapeutic Targets, 2021
To the best of our knowledge, there have been no direct attempts to apply gene therapy to treat epilepsy in the clinic so far. However, there is a growing body of published studies on rodent models of epilepsy. Most of them describe the employment of genetic expression of anionic (chloride) or potassium channels or ion exchangers in principal glutamatergic neurons [164–167], thus attempting to decrease the excitability of central networks. An alternative approach involves opioid expression and activity-dependent release, which is assumed, in its turn, to activate endogenous potassium channels on demand [168]. Moreover, a chemogenetic approach is thought to be very promising for potential epilepsy treatment [169] which may employ modern so-called Designer Receptors Exclusively Activated by Designer Drugs (DREADDs [170]). It supposes the creation of new pharmacological targets in the CNS using genetically expressed modified muscarinic receptors or kappa-opioid receptors, which are activated by exogenous ligands specifically designed to interact with the receptor part. Activation of the DREADD receptor triggers a G-protein cascade that opens inward-rectifying potassium channels (see review by Walker & Kullmann [171]).
The role of cells and their products in respiratory drug delivery: the past, present, and future
Published in Expert Opinion on Drug Delivery, 2020
Claire H. Masterson, Sean D. McCarthy, Daniel O’Toole, John G. Laffey
There are many innovative approaches being taken toward engineering cells to optimize their delivery invivo. For example, researchers have developed methods for guiding cells by loading them with nanoparticles and using ultrasound and MRI imaging to track the cell delivery [166]. This study also reported the use of the same nanoparticles which were engineered to slow release insulin like growth factor, prolonged the survival of the delivered cells to myocardial infarcts. The use of antibody coating of nanoparticles for targeting the lung microvasculature in ARDS has also been employed [111,116] which has the potential to be further optimized. Optogenetics uses specific wavelengths of light (such as the tissue-penetrating far red wavelength) to activate signaling cascades or initiate gene editing in cells [167]. Cells can also be gene edited to express receptors only activated by ‘designer drugs’ thereby enabling activation invivo [168] in a method known as ‘chemogenetics’. Thus far there are only a handful of modified MSCs which have been brought forward to clinical trial and the majority of these harbor therapeutics to target cancer [169].