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Light-Controlled Modulation and Analysis of Neuronal Functions

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 35144

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Prof. Dr. Piotr Bregestovski

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1. Institut de Neurosciences des Systèmes, Aix-Marseille University, INSERM, INS, 13005 Marseille, France
2. Institute of Neurosciences, Kazan State Medical University, 420111 Kazan, Russia
3. Department of Normal Physiology, Kazan State Medical University, 420111 Kazan, Russia
Interests: cys-loop receptors; ion channels; synaptic transmission; genetically encoded biosensors; optopharmacology
Special Issues, Collections and Topics in MDPI journals

Dr. Carlo Matera

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Department of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milan, Italy
Interests: medicinal chemistry; chemical biology; photopharmacology; translational chemistry; GPCRs; biased signaling; ion channels; acetylcholine; muscarinic receptors; nicotinic receptors; dopamine; dopamine receptors; multi-target ligands; bifunctional ligands; dual-acting agents; dualsteric ligands; bitopic ligands; photoswitches; cancer; antibiotics; neurodegeneration
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Dear Colleagues,

Contemporary research has been enriched by new directions in which light plays a key role as a tool for the modulation of cellular activity and the invasive monitoring of intracellular ions and other components. The progress in molecular biology, imaging techniques and other modern technologies has led to the emergence of three main areas in which light is the main tool: optogenetics, photopharmacology and optosensorics. The main advantages of these approaches are the possibilities to investigate the functions of cells; modulate the activity of ion channels, synaptic transmission and neuronal circuits; measure concentrations of ions and other cellular components; and even control the behaviour of organisms.

Due to the development of these powerful molecular and genetic tools, our understanding of the mechanisms underlying the functioning of the nervous system has greatly advanced. This Special Issue is intended to highlight the latest experimental and methodological advances in these areas, as well as to present review articles with a primary focus on light-based analysis and control of neuronal functions. A discussion of the difficulties and limitations of using light as a modulator of cellular activity is also planned.

Prof. Dr. Piotr Bregestovski
Dr. Carlo Matera
Guest Editors

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Keywords

light-controlled molecular switches
molecular engineering
photopharmacology
chemical optogenetics
azo compounds
optogenetics
photochromic ligands
biosensors
genetically encoded biosensors
synaptic transmission
receptors
ion channels
light-activated channels
light delivery
light therapy
transgenic mouse

Related Special Issue

Light-Controlled Modulation and Analysis of Neuronal Functions II in International Journal of Molecular Sciences (3 articles)

Published Papers (11 papers)

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Editorial

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6 pages, 247 KiB

Open AccessEditorial

Light-Controlled Modulation and Analysis of Neuronal Functions

by Carlo Matera and Piotr Bregestovski

Int. J. Mol. Sci. 2022, 23(21), 12921; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112921 - 26 Oct 2022

Cited by 1 | Viewed by 1021

Abstract

Light is an extraordinary tool allowing us to read out and control neuronal functions thanks to its unique properties: it has a great degree of bioorthogonality and is minimally invasive; it can be precisely delivered with high spatial and temporal precision; and it [...] Read more.

(This article belongs to the Special Issue Light-Controlled Modulation and Analysis of Neuronal Functions)

Research

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12 pages, 1593 KiB

Open AccessArticle

Optical Activation of TrkB (E281A) in Excitatory and Inhibitory Neurons of the Mouse Visual Cortex

by Antonia Lilja, Giuliano Didio, Jongryul Hong, Won Do Heo, Eero Castrén and Juzoh Umemori

Int. J. Mol. Sci. 2022, 23(18), 10249; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810249 - 06 Sep 2022

Cited by 1 | Viewed by 1624

Abstract

The activation of tropomyosin receptor kinase B (TrkB), the receptor of brain-derived neurotrophic factor (BDNF), plays a key role in induced juvenile-like plasticity (iPlasticity), which allows restructuring of neural networks in adulthood. Optically activatable TrkB (optoTrkB) can temporarily and spatially evoke iPlasticity, and recently, optoTrkB (E281A) was developed as a variant that is highly sensitive to light stimulation while having lower basal activity compared to the original optoTrkB. In this study, we validate optoTrkB (E281A) activated in alpha calcium/calmodulin-dependent protein kinase type II positive (CKII⁺) pyramidal neurons or parvalbumin-positive (PV⁺) interneurons in the mouse visual cortex by immunohistochemistry. OptoTrkB (E281A) was activated in PV⁺ interneurons and CKII⁺ pyramidal neurons with blue light (488 nm) through the intact skull and fur, and through a transparent skull, respectively. LED light stimulation significantly increased the intensity of phosphorylated ERK and CREB even through intact skull and fur. These findings indicate that the highly sensitive optoTrkB (E281A) can be used in iPlasticity studies of both inhibitory and excitatory neurons, with flexible stimulation protocols in behavioural studies. Full article

(This article belongs to the Special Issue Light-Controlled Modulation and Analysis of Neuronal Functions)

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18 pages, 2174 KiB

Open AccessArticle

Reversible Photocontrol of Dopaminergic Transmission in Wild-Type Animals

by Carlo Matera, Pablo Calvé, Verònica Casadó-Anguera, Rosalba Sortino, Alexandre M. J. Gomila, Estefanía Moreno, Thomas Gener, Cristina Delgado-Sallent, Pau Nebot, Davide Costazza, Sara Conde-Berriozabal, Mercè Masana, Jordi Hernando, Vicent Casadó, M. Victoria Puig and Pau Gorostiza

Int. J. Mol. Sci. 2022, 23(17), 10114; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231710114 - 04 Sep 2022

Cited by 4 | Viewed by 3908

Abstract

Understanding the dopaminergic system is a priority in neurobiology and neuropharmacology. Dopamine receptors are involved in the modulation of fundamental physiological functions, and dysregulation of dopaminergic transmission is associated with major neurological disorders. However, the available tools to dissect the endogenous dopaminergic circuits have limited specificity, reversibility, resolution, or require genetic manipulation. Here, we introduce azodopa, a novel photoswitchable ligand that enables reversible spatiotemporal control of dopaminergic transmission. We demonstrate that azodopa activates D₁-like receptors in vitro in a light-dependent manner. Moreover, it enables reversibly photocontrolling zebrafish motility on a timescale of seconds and allows separating the retinal component of dopaminergic neurotransmission. Azodopa increases the overall neural activity in the cortex of anesthetized mice and displays illumination-dependent activity in individual cells. Azodopa is the first photoswitchable dopamine agonist with demonstrated efficacy in wild-type animals and opens the way to remotely controlling dopaminergic neurotransmission for fundamental and therapeutic purposes. Full article

(This article belongs to the Special Issue Light-Controlled Modulation and Analysis of Neuronal Functions)

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14 pages, 4004 KiB

Open AccessArticle

Optogenetic Control of PIP2 Interactions Shaping ENaC Activity

by Tarek Mohamed Abd El-Aziz, Amanpreet Kaur, Mark S. Shapiro, James D. Stockand and Crystal R. Archer

Int. J. Mol. Sci. 2022, 23(7), 3884; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073884 - 31 Mar 2022

Cited by 4 | Viewed by 2013

Abstract

The activity of the epithelial Na⁺ Channel (ENaC) is strongly dependent on the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2). PIP2 binds two distinct cationic clusters within the N termini of β- and γ-ENaC subunits (βN1 and γN2). The affinities of these sites were previously determined using short synthetic peptides, yet their role in sensitizing ENaC to changes in PIP2 levels in the cellular system is not well established. We addressed this question by comparing the effects of PIP2 depletion and recovery on ENaC channel activity and intracellular Na⁺ levels [Na⁺]_i. We tested effects on ENaC activity with mutations to the PIP2 binding sites using the optogenetic system CIBN/CRY2-OCRL to selectively deplete PIP2. We monitored changes of [Na⁺]_i by measuring the fluorescent Na⁺ indicator, CoroNa Green AM, and changes in channel activity by performing patch clamp electrophysiology. Whole cell patch clamp measurements showed a complete lack of response to PIP2 depletion and recovery in ENaC with mutations to βN1 or γN2 or both sites, compared to wild type ENaC. Whereas mutant βN1 also had no change in CoroNa Green fluorescence in response to PIP2 depletion, γN2 did have reduced [Na⁺]_i, which was explained by having shorter CoroNa Green uptake and half-life. These results suggest that CoroNa Green measurements should be interpreted with caution. Importantly, the electrophysiology results show that the βN1 and γN2 sites on ENaC are each necessary to permit maximal ENaC activity in the presence of PIP2. Full article

(This article belongs to the Special Issue Light-Controlled Modulation and Analysis of Neuronal Functions)

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19 pages, 7254 KiB

Open AccessArticle

Calcium Imaging Reveals Fast Tuning Dynamics of Hippocampal Place Cells and CA1 Population Activity during Free Exploration Task in Mice

by Vladimir P. Sotskov, Nikita A. Pospelov, Viktor V. Plusnin and Konstantin V. Anokhin

Int. J. Mol. Sci. 2022, 23(2), 638; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020638 - 07 Jan 2022

Cited by 4 | Viewed by 3810

Abstract

Hippocampal place cells are a well-known object in neuroscience, but their place field formation in the first moments of navigating in a novel environment remains an ill-defined process. To address these dynamics, we performed in vivo imaging of neuronal activity in the CA1 field of the mouse hippocampus using genetically encoded green calcium indicators, including the novel NCaMP7 and FGCaMP7, designed specifically for in vivo calcium imaging. Mice were injected with a viral vector encoding calcium sensor, head-mounted with an NVista HD miniscope, and allowed to explore a completely novel environment (circular track surrounded by visual cues) without any reinforcement stimuli, in order to avoid potential interference from reward-related behavior. First, we calculated the average time required for each CA1 cell to acquire its place field. We found that 25% of CA1 place fields were formed at the first arrival in the corresponding place, while the average tuning latency for all place fields in a novel environment equaled 247 s. After 24 h, when the environment was familiar to the animals, place fields formed faster, independent of retention of cognitive maps during this session. No cumulation of selectivity score was observed between these two sessions. Using dimensionality reduction, we demonstrated that the population activity of rapidly tuned CA1 place cells allowed the reconstruction of the geometry of the navigated circular maze; the distribution of reconstruction error between the mice was consistent with the distribution of the average place field selectivity score in them. Our data thus show that neuronal activity recorded with genetically encoded calcium sensors revealed fast behavior-dependent plasticity in the mouse hippocampus, resulting in the rapid formation of place fields and population activity that allowed the reconstruction of the geometry of the navigated maze. Full article

(This article belongs to the Special Issue Light-Controlled Modulation and Analysis of Neuronal Functions)

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22 pages, 2981 KiB

Open AccessArticle

Simultaneous Monitoring of pH and Chloride (Cl⁻) in Brain Slices of Transgenic Mice

by Daria Ponomareva, Elena Petukhova and Piotr Bregestovski

Int. J. Mol. Sci. 2021, 22(24), 13601; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413601 - 18 Dec 2021

Cited by 6 | Viewed by 2664

Abstract

Optosensorics is the direction of research possessing the possibility of non-invasive monitoring of the concentration of intracellular ions or activity of intracellular components using specific biosensors. In recent years, genetically encoded proteins have been used as effective optosensory means. These probes possess fluorophore groups capable of changing fluorescence when interacting with certain ions or molecules. For monitoring of intracellular concentrations of chloride ([Cl⁻]_i) and hydrogen ([H⁺] _i) the construct, called ClopHensor, which consists of a H⁺- and Cl⁻-sensitive variant of the enhanced green fluorescent protein (E²GFP) fused with a monomeric red fluorescent protein (mDsRed) has been proposed. We recently developed a line of transgenic mice expressing ClopHensor in neurons and obtained the map of its expression in different areas of the brain. The purpose of this study was to examine the effectiveness of transgenic mice expressing ClopHensor for estimation of [H⁺]_i and [Cl⁻]_i concentrations in neurons of brain slices. We performed simultaneous monitoring of [H⁺]_i and [Cl⁻]_i under different experimental conditions including changing of external concentrations of ions (Ca²⁺, Cl⁻, K⁺, Na⁺) and synaptic stimulation of Shaffer’s collaterals of hippocampal slices. The results obtained illuminate different pathways of regulation of Cl⁻ and pH equilibrium in neurons and demonstrate that transgenic mice expressing ClopHensor represent a reliable tool for non-invasive simultaneous monitoring of intracellular Cl⁻ and pH. Full article

(This article belongs to the Special Issue Light-Controlled Modulation and Analysis of Neuronal Functions)

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11 pages, 2156 KiB

Open AccessArticle

Optogenetic Activation of Astrocytes—Effects on Neuronal Network Function

by Evgenii Gerasimov, Alexander Erofeev, Anastasia Borodinova, Anastasia Bolshakova, Pavel Balaban, Ilya Bezprozvanny and Olga L. Vlasova

Int. J. Mol. Sci. 2021, 22(17), 9613; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179613 - 04 Sep 2021

Cited by 15 | Viewed by 3690

Abstract

Optogenetics approach is used widely in neurobiology as it allows control of cellular activity with high spatial and temporal resolution. In most studies, optogenetics is used to control neuronal activity. In the present study optogenetics was used to stimulate astrocytes with the aim to modulate neuronal activity. To achieve this goal, light stimulation was applied to astrocytes expressing a version of ChR2 (ionotropic opsin) or Opto-α1AR (metabotropic opsin). Optimal optogenetic stimulation parameters were determined using patch-clamp recordings of hippocampal pyramidal neurons’ spontaneous activity in brain slices as a readout. It was determined that the greatest increase in the number of spontaneous synaptic currents was observed when astrocytes expressing ChR2(H134R) were activated by 5 s of continuous light. For the astrocytes expressing Opto-α1AR, the greatest response was observed in the pulse stimulation mode (T = 1 s, t = 100 ms). It was also observed that activation of the astrocytic Opto-a1AR but not ChR2 results in an increase of the fEPSP slope in hippocampal neurons. Based on these results, we concluded that Opto-a1AR expressed in hippocampal astrocytes provides an opportunity to modulate the long-term synaptic plasticity optogenetically, and may potentially be used to normalize the synaptic transmission and plasticity defects in a variety of neuropathological conditions, including models of Alzheimer’s disease and other neurodegenerative disorders. Full article

(This article belongs to the Special Issue Light-Controlled Modulation and Analysis of Neuronal Functions)

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18 pages, 4511 KiB

Open AccessArticle

Activation of Neuronal Nicotinic Receptors Inhibits Acetylcholine Release in the Neuromuscular Junction by Increasing Ca²⁺ Flux through Ca_v1 Channels

by Nikita Zhilyakov, Arsenii Arkhipov, Artem Malomouzh and Dmitry Samigullin

Int. J. Mol. Sci. 2021, 22(16), 9031; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22169031 - 21 Aug 2021

Cited by 10 | Viewed by 3652

Abstract

Cholinergic neurotransmission is a key signal pathway in the peripheral nervous system and in several branches of the central nervous system. Despite the fact that it has been studied extensively for a long period of time, some aspects of its regulation still have not yet been established. One is the relationship between the nicotine-induced autoregulation of acetylcholine (ACh) release with changes in the concentration of presynaptic calcium levels. The mouse neuromuscular junction of m. Levator Auris Longus was chosen as the model of the cholinergic synapse. ACh release was assessed by electrophysiological methods. Changes in calcium transients were recorded using a calcium-sensitive dye. Nicotine hydrogen tartrate salt application (10 μM) decreased the amount of evoked ACh release, while the calcium transient increased in the motor nerve terminal. Both of these effects of nicotine were abolished by the neuronal ACh receptor antagonist dihydro-beta-erythroidine and Ca_v1 blockers, verapamil, and nitrendipine. These data allow us to suggest that neuronal nicotinic ACh receptor activation decreases the number of ACh quanta released by boosting calcium influx through Ca_v1 channels. Full article

(This article belongs to the Special Issue Light-Controlled Modulation and Analysis of Neuronal Functions)

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14 pages, 3989 KiB

Open AccessArticle

Imaging of C-fos Activity in Neurons of the Mouse Parietal Association Cortex during Acquisition and Retrieval of Associative Fear Memory

by Olga I. Ivashkina, Anna M. Gruzdeva, Marina A. Roshchina, Ksenia A. Toropova and Konstantin V. Anokhin

Int. J. Mol. Sci. 2021, 22(15), 8244; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158244 - 31 Jul 2021

Cited by 7 | Viewed by 4260

Abstract

The parietal cortex of rodents participates in sensory and spatial processing, movement planning, and decision-making, but much less is known about its role in associative learning and memory formation. The present study aims to examine the involvement of the parietal association cortex (PtA) in associative fear memory acquisition and retrieval in mice. Using ex vivo c-Fos immunohistochemical mapping and in vivo Fos-EGFP two-photon imaging, we show that PtA neurons were specifically activated both during acquisition and retrieval of cued fear memory. Fos immunohistochemistry revealed specific activation of the PtA neurons during retrieval of the 1-day-old fear memory. In vivo two-photon Fos-EGFP imaging confirmed this result and in addition detected specific c-Fos responses of the PtA neurons during acquisition of cued fear memory. To allow a more detailed study of the long-term activity of such PtA engram neurons, we generated a Fos-Cre-GCaMP transgenic mouse line that employs the Targeted Recombination in Active Populations (TRAP) technique to detect calcium events specifically in cells that were Fos-active during conditioning. We show that gradual accumulation of GCaMP3 in the PtA neurons of Fos-Cre-GCaMP mice peaks at the 4th day after fear learning. We also describe calcium transients in the cell bodies and dendrites of the TRAPed neurons. This provides a proof-of-principle for TRAP-based calcium imaging of PtA functions during memory processes as well as in experimental models of fear- and anxiety-related psychiatric disorders and their specific therapies. Full article

(This article belongs to the Special Issue Light-Controlled Modulation and Analysis of Neuronal Functions)

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Review

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26 pages, 8492 KiB

Open AccessReview

Photopharmacology of Ion Channels through the Light of the Computational Microscope

by Alba Nin-Hill, Nicolas Pierre Friedrich Mueller, Carla Molteni, Carme Rovira and Mercedes Alfonso-Prieto

Int. J. Mol. Sci. 2021, 22(21), 12072; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222112072 - 08 Nov 2021

Cited by 6 | Viewed by 3137

Abstract

The optical control and investigation of neuronal activity can be achieved and carried out with photoswitchable ligands. Such compounds are designed in a modular fashion, combining a known ligand of the target protein and a photochromic group, as well as an additional electrophilic group for tethered ligands. Such a design strategy can be optimized by including structural data. In addition to experimental structures, computational methods (such as homology modeling, molecular docking, molecular dynamics and enhanced sampling techniques) can provide structural insights to guide photoswitch design and to understand the observed light-regulated effects. This review discusses the application of such structure-based computational methods to photoswitchable ligands targeting voltage- and ligand-gated ion channels. Structural mapping may help identify residues near the ligand binding pocket amenable for mutagenesis and covalent attachment. Modeling of the target protein in a complex with the photoswitchable ligand can shed light on the different activities of the two photoswitch isomers and the effect of site-directed mutations on photoswitch binding, as well as ion channel subtype selectivity. The examples presented here show how the integration of computational modeling with experimental data can greatly facilitate photoswitchable ligand design and optimization. Recent advances in structural biology, both experimental and computational, are expected to further strengthen this rational photopharmacology approach. Full article

(This article belongs to the Special Issue Light-Controlled Modulation and Analysis of Neuronal Functions)

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29 pages, 1609 KiB

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Novel Approaches Used to Examine and Control Neurogenesis in Parkinson′s Disease

by Alla B. Salmina, Marina R. Kapkaeva, Anna S. Vetchinova and Sergey N. Illarioshkin

Int. J. Mol. Sci. 2021, 22(17), 9608; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179608 - 04 Sep 2021

Cited by 12 | Viewed by 3894

Abstract

Neurogenesis is a key mechanism of brain development and plasticity, which is impaired in chronic neurodegeneration, including Parkinson’s disease. The accumulation of aberrant α-synuclein is one of the features of PD. Being secreted, this protein produces a prominent neurotoxic effect, alters synaptic plasticity, deregulates intercellular communication, and supports the development of neuroinflammation, thereby providing propagation of pathological events leading to the establishment of a PD-specific phenotype. Multidirectional and ambiguous effects of α-synuclein on adult neurogenesis suggest that impaired neurogenesis should be considered as a target for the prevention of cell loss and restoration of neurological functions. Thus, stimulation of endogenous neurogenesis or cell-replacement therapy with stem cell-derived differentiated neurons raises new hopes for the development of effective and safe technologies for treating PD neurodegeneration. Given the rapid development of optogenetics, it is not surprising that this method has already been repeatedly tested in manipulating neurogenesis in vivo and in vitro via targeting stem or progenitor cells. However, niche astrocytes could also serve as promising candidates for controlling neuronal differentiation and improving the functional integration of newly formed neurons within the brain tissue. In this review, we mainly focus on current approaches to assess neurogenesis and prospects in the application of optogenetic protocols to restore the neurogenesis in Parkinson’s disease. Full article

(This article belongs to the Special Issue Light-Controlled Modulation and Analysis of Neuronal Functions)

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