Fiber photometry

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Fiber photometry is a calcium imaging technique that captures 'bulk' or population-level calcium (Ca2+) activity [1] from specific cell-types within a brain region or functional network in order to study neural circuits [2] [3] [4] [5] [6] Population-level calcium activity can be correlated with behavioral tasks, such as spatial learning, memory recall and goal-directed behaviors. [7] The technique involves the surgical implantation of fiber optics into the brains of living animals. The benefits to researchers are that optical fibers are simpler to implant, less invasive and less expensive than other calcium methods, and there is less weight and stress on the animal, as compared to miniscopes. It also allows for imaging of multiple interacting brain regions and integration with other neuroscience techniques. The limitations of fiber photometry are low cellular and spatial resolution, and the fact that animals must be securely tethered to a rigid fiber bundle, which may impact the naturalistic behavior of smaller mammals such as mice.

Contents

Technical description

Fiber photometry relies on the expression of genetically encoded calcium indicators (GECIs), like GCaMP or RCaMP, which can be targeted to specific cells using cell-specific promoters like Ca2+/calmodulin-dependent protein kinase II (CaMKII) and human synapsin (hSyn) that confer excitatory neuronal and pan-neuronal expression, respectively. [1] These promoters can be used to target various neuronal subtypes as well as non-neuronal cells that exhibit calcium dynamics, such as astrocytes, using the glial fibrillary acidic protein (GFAP) promoter. [8] [9] [10] [11] In both neurons and astrocytes, cellular activity in the form of action potentials, exocytosis of neurotransmitters, changes in synaptic plasticity and gene transcription is coupled to an influx of Ca2+ ions. [5]

These activity-dependent changes in intracellular calcium levels can be monitored by introducing GECIs to the cell. Following this influx of ions, GECIs fluoresce upon Ca2+ binding and the change in fluorescence corresponds proportionally to intracellular calcium changes. [12] The most commonly used calcium indicator for fiber photometry (and other in vivo imaging method) is GCaMP6, although additional GECIs continue to be developed with unique fluorescence spectra, kinetics, signal-to-noise ratios and calcium-sensitivities. [13] [14] These indicators can be expressed in the brain in two main ways: viral expression [15] and transgenic mouse lines. [16] Recently, there has been a growing list of indicators that have become available to measure different chemical signals, like dLight to record dopamine signaling, or OxLight to record orexin, for example. [15] [17] [18] GCaMP, RCaMP, dLight and other indicators are excited by a light source at an optimal wavelength and emit their own light in return, allowing for recording of calcium or neurotransmitter dynamics across time. [15] [19] [13] [3] [20] [21]

Fiber photometry systems are designed to deliver precise excitation wavelengths of light that are specific to a calcium (e.g. GCaMP) or neurotransmitter indicator (e.g. dLight). [3] This light travels down an optical fiber to a fiber optic that is implanted in the brain region or regions of interest. The calcium indicator is that is expressed in a cell-type specific manner is excited by this light and in turn, emits its own signal that travels back through the same fiber. [3] [4] [22] These collected emission signals are spectrally-separated by a dichroic mirror, passed through a filter and focused onto a photodetector, scientific camera, or PMT. [3] The collected signal represents a change in fluorescence (ΔF) relative to an initial baseline (F). In turn, researchers can observe a signal that corresponds to calcium transients (ΔF/F). This time series data can be analyzed using a variety of open-source pipelines, such as pMAT, [23] pyPhotometry [24] and GuPPy. [25]

Importantly, isosbestic signals are calcium-independent signals (i.e. approximately 405-415 nm) that are in contrast to the calcium-dependent wavelength (i.e. 470 nm for GCaMP). Because GCaMP has two states, Ca2+ bound and un-bound, the two protein conformations have unique excitation and emission spectra. The wavelength of excitation at which GCaMP has the same absorbance with and without Ca2+ is the isosbestic and determines the calcium-independent fluorescence baseline. Animal motion and tissue autofluorescence are reflected in this calcium-independent signal and can be subtracted or regressed to reveal the true change in fluorescence. [26]

Structure of GCaMP, a genetically encoded calcium indicator commonly used in calcium imaging methods, such as fiber photometry, one- and two-photon microscopy. Gcamp.jpg
Structure of GCaMP, a genetically encoded calcium indicator commonly used in calcium imaging methods, such as fiber photometry, one- and two-photon microscopy.

Genetically-encoded calcium indicators (GECIs)

What are genetically encoded calcium indicators?

Optimal expression of genetically encoded calcium indicators (GECIs) can be accomplished in two ways: adeno-associated viral vectors and transgenic rodent lines. [15] [16] Viral injection requires GECI infusion into the brain region of interest. [15] This virus can be targeted to infect unique cell-types through the use of cell-specific promoters like CaMKII and GFAP to target excitatory neurons and astrocytes, respectively. This allows for neural activity to be recorded from a genetically defined subpopulation of neurons or glial cells through an implanted optical fiber. [1] Viral expression requires titration of dilutions to obtain optimal expression in the brain, which may be necessary instead of using transgenic rodent lines for certain experiments. Expression of GECIs can also be accomplished through the use of transgenic lines that allow for ubiquitous expression throughout the entire brain. Depending on the strain of mouse or rat, the expression can vary across brain regions, posing potential challenges during recording. [16]

What is GCaMP?

GCaMP is a genetically encoded calcium indicator (GECI) that is commonly used in multiple imaging methods. [19] GCaMP emits fluorescence when the indicator is bound to a calcium ion (Ca2+). This calcium signal is directly tied to neural response patterns, neurotransmitter release, and membrane excitability. [27] The excitation wavelengths for GCaMP and its isosbestic signal are approximately 470 nm and 415 nm (blue), respectively. The goal is to photo-excite the maximum absorption and isosbestic points of the indicator. The isosbestic point of GCaMP is the calcium-independent signal, approximately 405-415 nm. This is determined based on GCaMP having two functional states, bound and unbound to calcium ions. These two states have unique protein excitation and emission spectra. The wavelength of excitation where these two protein states have the same absorbance is the isosbestic point and determines the baseline fluorescence. Motion and autofluorescence are reflected in this calcium-independent signal and can be subtracted or regressed to reveal the true change in cellular fluorescence during a behavioral task or experimental manipulation. [26]

The emission wavelength of GCaMP is approximately 525 nm (green), which can be analyzed and correlated across time during behavioral tasks.

Multiple-color fiber photometry

To observe simultaneous calcium dynamics in multiple cell types, researchers have combined two or more GECIs in a single brain region. [3] [28] For example, a research group recorded fluorescence from the green and red GECIs, GCaMP6f and jRGECO1a, that were differentially expressed in striatal direct- and indirect-pathway spiny projection neurons in freely behaving mice. [29] The expression of multiple GECIs in the same brain region can not only be performed in two sets of neurons, as shown in the previous study. These simultaneous recordings of bulk calcium can also be performed with multiple cell types, such as neurons and astrocytes. These cell types express unique promoters, such as GFAP and hSyn, and the GECIs can be targeted specifically in this way. Another research group performed successful dual-color fiber photometry using astrocyte- and neuron-specific promoters while mice freely performed a working memory task (T-maze). [30]

Example of genetically encoded calcium indicator (GECI), Lck-GCaMP3 expressed in acute brain slice astrocytes during a calcium imaging session.

Equipment

The goal of fiber photometry is to precisely deliver, extract and record bulk calcium signal from specific populations of cells within a brain region of interest. To access the signal, an optical cannula/fiber must be surgically implanted at the site of GECI expression. This optical fiber can only collect population-level calcium signal, not individual cell activity. [1] Additionally, optical fibers allow recording from both deep and shallow brain structures, and minimize tissue damage unlike GRIN lenses or cortical windows.

GCaMP has specific excitation and emission spectra at approximately 470 nm and 530 nm, respectively. [27] LED light sources are amongst the most commonly selected, due to the low optical power necessary to excite GECIs. Proper transmission of the excitation and emission signals bidirectionally from the brain to the imaging device is coordinated by dichroic mirrors and excitation/emission filters. There are three different types of imaging devices: photodetectors, photomultiplier tubes (PMTs) and scientific cameras. When collecting signal from a single brain region, it is typical to use a photodetector or PMT due to their fast acquisition and low signal-to-noise ratio (SNR). Alternatively, when collecting from multiple brain regions, scientific cameras or multiple photodetectors or PMTs must be used.

Overall, this system allows for coupling between the optical cannula, light source and imaging device. Precise light delivery to the GECI is enabled by the optical cannula/fiber and the emission signal is collected by the imaging device during recording.

Some examples of commercially available fiber photometry systems include Neurophotometrics, Inscopix and MightexBio.

Benefits and limitations

All scientific methods have considerations that must be taken into account before use. Fiber photometry has many benefits over other techniques for calcium imaging, but it comes with limitations.

Benefits

For individuals in labs that want to integrate calcium imaging into their experiments but may not have the financial or technical circumstances to do so yet, fiber photometry is a low barrier of entry. Optical fibers are simpler to implant, less invasive and are more inexpensive than other calcium methods such as one- or two-photon imaging. [14] It is good for longitudinal [31] behavioral paradigms because there is less weight and stress on the animal, as compared to miniscopes. It limits mobility of the animal significantly less than other methods, allowing for more freely-moving, naturalistic behaviors in larger rodent models. It is a versatile technique, allowing for imaging of multiple interacting brain regions and integration with optogenetics, [32] electrophysiology [33] and more systems-level neuroscience techniques. More recently, this technique can be coupled with other fluorescent indicators for neurotransmitter activity or pH changes. [15] [21]

Limitations

It is important when planning experiments to consider the major limitation of fiber photometry: low cellular and spatial resolution. This lack of optical resolution can be attributed to the collection of an aggregation of activity within a field of view, only allowing for 'bulk' changes in fluorescent signal. [5] Although the size of an optical cannula is much smaller than technology used in other calcium imaging methods, such as one- and two-photon microscopy, animals must be securely tethered to a rigid fiber bundle. [1] This may limit the naturalistic behavior and of smaller mammals, such as mice.

Integration with other methods

Rat receiving optogenetic stimulation via a fiber optic implant. This method can be combined with fiber photometry to manipulate and measure population calcium dynamics within a neural circuit. Ontogenetics-mousehead-ImbededWithLightTransmitter.jpg
Rat receiving optogenetic stimulation via a fiber optic implant. This method can be combined with fiber photometry to manipulate and measure population calcium dynamics within a neural circuit.

Optogenetics and DREADDs

Fiber photometry can be integrated with cellular manipulation to draw a causal link between neural activity and behavior. Targeted modulation of defined cell types and projections in the brain can be accomplished using optogenetics or Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). [14] The method is chosen based on the temporal precision necessary for the experimental design, amongst other factors. Optogenetics allows for manipulation of a specific cell-type with high temporal precision. DREADDs have a much lower temporal precision due to the pharmacokinetics of the ligand, such as clozapine-N-oxide (CNO) [34] or deschloroclozapine (DCZ). [35] It is important to note that simultaneous optical readout and optogenetic manipulation comes with several potential issues that are discussed below. [32]

In vivo electrophysiology

Additionally, fiber photometry can be coupled with in vivo electrophysiology within the same animal. [33] When combined, this combination of electrophysiological recording and calcium imaging can be used to observe cell-type specific activity with higher temporal precision read-outs of neuronal action potentials in freely-behaving animal models.

Potential problems and solutions

Delivery and expression of optogenetic probes and calcium indicators to the same neurons can pose problems. Calcium indicators and manipulation channels can have overlapping excitation spectrums, such as GCaMP and channelrhodopsin (ChR2), which both have a peak wavelength of excitation at approximately 470 nm. Excitation of the calcium indicator can potentially activate the optogenetic light-sensitive ion channel. The measured change in calcium signal cannot be easily attributed to actual changes in calcium or optogenetic-induced signal. Solutions to this issue include the combination of indicators that have non-overlapping excitation spectrum with your optogenetic probe or calcium indicator. Calcium indicators (GCaMP, RCaMP) and optogenetic probes for excitation (ChR2, Crimson) and inhibition (eNpHR, Arch, Jaws) are options for this.

Other calcium imaging methods

Multi-photon calcium imaging of mouse cerebellar neurons during a tail pinch. The change in fluorescence over baseline fluorescence (dF/F) and raw data are shown above.

Miniscopes and single-photon imaging

Miniscopes [36] [37] [38] [39] are head-mounted, miniature microscopes that allow imaging of large populations of neural activity in freely-behaving mice and rats. This is possible due to their small size, as they are light enough for a mouse or rat to easily carry without interfering greatly with behavior. Researchers couple miniscopes with implanted gradient-refractive-index (GRIN) lenses or cortical windows that enable deep and superficial brain imaging. [38] [5] [40] This method is ideal for monitoring the activity of hundreds of genetically- and spatially-defined cells within a single animal. [37] As compared to fiber photometry, miniscopes allow imaging with high cellular resolution, detecting changes in calcium within individual neurons and non-neuronal cells. [36] Additionally, this method enables repeated imaging over time to analyze the transition from 'healthy' to pathological states or changes over the course of behavior. [37] However, this method of imaging has low sensitivity and high noise, producing lower resolution imaging compared to other multi-photon methods like two-photon. [7] These miniature microscopes are limited in their ability to detect far-red-shifted indicators that would be necessary for combination of optogenetics and calcium imaging here, as is discussed above.

Two-photon imaging

Two-photon imaging [41] [5] is another calcium imaging method that records fluctuations in cellular GECI dynamics. It provides a way to penetrate highly light-scattering brain tissue up to 600-700 microns below the surface of the brain. [36] [42] As compared to other techniques, two-photon offers higher cellular and sub-cellular spatial resolution, such as within dendrites and axonal boutons, within a well-defined focal plane. [36] [41] However, without the assistance of an optical cannula or micro-endoscope, this method is limited to more superficial brain areas. [36] [43] [44] This type of imaging also requires that the animals remain head-fixed, limiting naturalistic behaviors necessary for some complex behavioral tasks. [41] [36]

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The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field of neural development draws on both neuroscience and developmental biology to describe and provide insight into the cellular and molecular mechanisms by which complex nervous systems develop, from nematodes and fruit flies to mammals.

<span class="mw-page-title-main">Behavioral neuroscience</span> Field of study

Behavioral neuroscience, also known as biological psychology, biopsychology, or psychobiology, is the application of the principles of biology to the study of physiological, genetic, and developmental mechanisms of behavior in humans and other animals.

<span class="mw-page-title-main">Melanopsin</span> Mammalian protein found in Homo sapiens

Melanopsin is a type of photopigment belonging to a larger family of light-sensitive retinal proteins called opsins and encoded by the gene Opn4. In the mammalian retina, there are two additional categories of opsins, both involved in the formation of visual images: rhodopsin and photopsin in the rod and cone photoreceptor cells, respectively.

Channelrhodopsins are a subfamily of retinylidene proteins (rhodopsins) that function as light-gated ion channels. They serve as sensory photoreceptors in unicellular green algae, controlling phototaxis: movement in response to light. Expressed in cells of other organisms, they enable light to control electrical excitability, intracellular acidity, calcium influx, and other cellular processes. Channelrhodopsin-1 (ChR1) and Channelrhodopsin-2 (ChR2) from the model organism Chlamydomonas reinhardtii are the first discovered channelrhodopsins. Variants that are sensitive to different colors of light or selective for specific ions have been cloned from other species of algae and protists.

<span class="mw-page-title-main">Photostimulation</span>

Photostimulation is the use of light to artificially activate biological compounds, cells, tissues, or even whole organisms. Photostimulation can be used to noninvasively probe various relationships between different biological processes, using only light. In the long run, photostimulation has the potential for use in different types of therapy, such as migraine headache. Additionally, photostimulation may be used for the mapping of neuronal connections between different areas of the brain by “uncaging” signaling biomolecules with light. Therapy with photostimulation has been called light therapy, phototherapy, or photobiomodulation.

<span class="mw-page-title-main">Purkinje cell</span> Specialized neuron in the cerebellum

Purkinje cells, or Purkinje neurons, are a class of GABAergic inhibitory neurons located in the cerebellum. They are named after their discoverer, Czech anatomist Jan Evangelista Purkyně, who characterized the cells in 1839.

<span class="mw-page-title-main">Medium spiny neuron</span> Type of GABAergic neuron in the striatum

Medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), are a special type of GABAergic inhibitory cell representing 95% of neurons within the human striatum, a basal ganglia structure. Medium spiny neurons have two primary phenotypes : D1-type MSNs of the direct pathway and D2-type MSNs of the indirect pathway. Most striatal MSNs contain only D1-type or D2-type dopamine receptors, but a subpopulation of MSNs exhibit both phenotypes.

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<span class="mw-page-title-main">Brainbow</span> Neuroimaging technique to differentiate neurons

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Optogenetics is a biological technique to control the activity of neurons or other cell types with light. This is achieved by expression of light-sensitive ion channels, pumps or enzymes specifically in the target cells. On the level of individual cells, light-activated enzymes and transcription factors allow precise control of biochemical signaling pathways. In systems neuroscience, the ability to control the activity of a genetically defined set of neurons has been used to understand their contribution to decision making, learning, fear memory, mating, addiction, feeding, and locomotion. In a first medical application of optogenetic technology, vision was partially restored in a blind patient.

<span class="mw-page-title-main">GCaMP</span> Genetically encoded calcium indicator

GCaMP is a genetically encoded calcium indicator (GECI) initially developed in 2001 by Junichi Nakai. It is a synthetic fusion of green fluorescent protein (GFP), calmodulin (CaM), and M13, a peptide sequence from myosin light-chain kinase. When bound to Ca2+, GCaMP fluoresces green with a peak excitation wavelength of 480 nm and a peak emission wavelength of 510 nm. It is used in biological research to measure intracellular Ca2+ levels both in vitro and in vivo using virally transfected or transgenic cell and animal lines. The genetic sequence encoding GCaMP can be inserted under the control of promoters exclusive to certain cell types, allowing for cell-type specific expression of GCaMP. Since Ca2+ is a second messenger that contributes to many cellular mechanisms and signaling pathways, GCaMP allows researchers to quantify the activity of Ca2+-based mechanisms and study the role of Ca2+ ions in biological processes of interest.

Calcium imaging is a microscopy technique to optically measure the calcium (Ca2+) status of an isolated cell, tissue or medium. Calcium imaging takes advantage of calcium indicators, fluorescent molecules that respond to the binding of Ca2+ ions by fluorescence properties. Two main classes of calcium indicators exist: chemical indicators and genetically encoded calcium indicators (GECI). This technique has allowed studies of calcium signalling in a wide variety of cell types. In neurons, electrical activity is always accompanied by an influx of Ca2+ ions. Thus, calcium imaging can be used to monitor the electrical activity in hundreds of neurons in cell culture or in living animals, which has made it possible to dissect the function of neuronal circuits.

Magnetogenetics refers to a biological technique that involves the use of magnetic fields to remotely control cell activity.

Attila Losonczy is a Hungarian neuroscientist, Professor of Neuroscience at Columbia University Medical Center. Losonczy's main area of research is on the relationship between neural networks and behavior, specifically with regard to learning in the hippocampus.

<span class="mw-page-title-main">Anion-conducting channelrhodopsin</span> Class of light-gated ion channels

Anion-conducting channelrhodopsins are light-gated ion channels that open in response to light and let negatively charged ions enter a cell. All channelrhodopsins use retinal as light-sensitive pigment, but they differ in their ion selectivity. Anion-conducting channelrhodopsins are used as tools to manipulate brain activity in mice, fruit flies and other model organisms (Optogenetics). Neurons expressing anion-conducting channelrhodopsins are silenced when illuminated with light, an effect that has been used to investigate information processing in the brain. For example, suppressing dendritic calcium spikes in specific neurons with light reduced the ability of mice to perceive a light touch to a whisker. Studying how the behavior of an animal changes when specific neurons are silenced allows scientists to determine the role of these neurons in the complex circuits controlling behavior.

Genetically encoded voltage indicator is a protein that can sense membrane potential in a cell and relate the change in voltage to a form of output, often fluorescent level. It is a promising optogenetic recording tool that enables exporting electrophysiological signals from cultured cells, live animals, and ultimately human brain. Examples of notable GEVIs include ArcLight, ASAP1, ASAP3, Archons, SomArchon, and Ace2N-mNeon.

<span class="mw-page-title-main">William Schafer</span> American geneticist

William Ronald Schafer is a neuroscientist and geneticist who has made important contributions to understanding the molecular and neural basis of behaviour. His work, principally in the nematode C. elegans, has used an interdisciplinary approach to investigate how small groups of neurons generate behavior, and he has pioneered methodological approaches, including optogenetic neuroimaging and automated behavioural phenotyping, that have been widely influential in the broader neuroscience field. He has made significant discoveries on the functional properties of ionotropic receptors in sensory transduction and on the roles of gap junctions and extrasynaptic modulation in neuronal microcircuits. More recently, he has applied theoretical ideas from network science and control theory to investigate the structure and function of simple neuronal connectomes, with the goal of understanding conserved computational principles in larger brains. He is an EMBO member, Welcome Investigator and Fellow of the Academy of Medical Sciences.

<span class="mw-page-title-main">George J. Augustine</span> American neuroscientist

George James Augustine is an American neuroscientist known for his work on presynaptic mechanisms of neurotransmitter release and his contributions to the development of optogenetics, a tool to control neural activity using light. He is best known as the author of the popular neuroscience textbook published by Oxford University Press along with lead author Dale Purves.

Nadine Gogolla is a Research Group Leader at the Max Planck Institute of Neurobiology in Martinsried, Germany as well as an Associate Faculty of the Graduate School for Systemic Neuroscience. Gogolla investigates the neural circuits underlying emotion to understand how the brain integrates external cues, feeling states, and emotions to make calculated behavioral decisions. Gogolla is known for her discovery using machine learning and two-photon microscopy to classify mouse facial expressions into emotion-like categories and correlate these facial expressions with neural activity in the insular cortex.

Optogenetics began with methods to alter neuronal activity with light, using e.g. channelrhodopsins. In a broader sense, optogenetic approaches also include the use of genetically encoded biosensors to monitor the activity of neurons or other cell types by measuring fluorescence or bioluminescence. Genetically encoded calcium indicators (GECIs) are used frequently to monitor neuronal activity, but other cellular parameters such as membrane voltage or second messenger activity can also be recorded optically. The use of optogenetic sensors is not restricted to neuroscience, but plays increasingly important roles in immunology, cardiology and cancer research.

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