scholarly journals In vivo photopharmacology enabled by multifunctional fibers

2020 ◽  
Author(s):  
James A. Frank ◽  
Marc-Joseph Antonini ◽  
Po-Han Chiang ◽  
Andres Canales ◽  
David B. Konrad ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Optical Switch ◽  
Brain Regions ◽  
Behavioral Experiments ◽  
Mesolimbic Pathway ◽  
Molecular Neuroscience ◽  
Freely Moving ◽  
Thermal Drawing ◽  
Deep Brain

ABSTRACTTo reversibly manipulate neural circuits with increased spatial and temporal control, photoswitchable ligands can add an optical switch to a target receptor or signaling cascade. This approach, termed photopharmacology, has been enabling to molecular neuroscience, however, its application to behavioral experiments has been impeded by a lack of integrated hardware capable of delivering both light and compounds to deep brain regions in moving subjects. Here, we devise a hybrid photochemical genetic approach to target neurons using a photoswitchable agonist of capsaicin receptor (TRPV1), red-AzCA-4. Using the thermal drawing process we created multifunctional fibers that can deliver viruses, photoswitchable ligands, and light to deep brain regions in awake, freely moving mice. We implanted our fibers into the ventral tegmental area (VTA), a midbrain hub of the mesolimbic pathway, and used them to deliver a transgene coding for TRPV1. This sensitized excitatory VTA neurons to red-AzCA-4, and allowed us to optically control conditioned place preference using a mammalian ion-channel, thus extending applications of photopharmacology to behavioral experiments. Applied to endogenous receptors, our approach may accelerate studies of molecular mechanisms underlying animal behavior.

scholarly journals MAPSSIC, a communicating MAPS-based intracerebral positrons probe for deep brain imaging in awake and freely-moving rats

2020 ◽  
Vol 225 ◽  
pp. 09002
Author(s):  
F. Gensolen ◽  
L. Ammour ◽  
M. Bautista ◽  
J. Heymes ◽  
S. Fieux ◽  
...  
Keyword(s):  
Human Brain ◽  
Neural Mechanisms ◽  
Small Animals ◽  
Biological Mechanisms ◽  
Behavioral Experiments ◽  
Freely Moving ◽  
The Brain ◽  
Significant Model ◽  
Deep Brain

Radioisotope imaging is a powerful tool to understand the biological mechanisms in-vivo, especially in the brain of small animals, providing a significant model to study the human brain. In this context, we have developed and built a pixelated intracerebral positron probe to be embedded on awake and freely moving small animals, typically rats. This pixelated probe will represent a key instrument for neuroscientists to study neural mechanisms and correlate them to behavioral experiments. We describe in this paper the simulations carried out to design the intracerebral sensor, its architecture, and the detection of positrons in a volume with a couple of sensors assembled back-to-back. We also depict the architecture of the wireless acquisition system. Finally, we present the first measurements performed in real-time by this miniaturized probe with sealed radioactive sources and a 18F solution.

scholarly journals Understanding the Effects of General Anesthetics on Cortical Network Activity Using Ex Vivo Preparations

2019 ◽  
Vol 130 (6) ◽  
pp. 1049-1063 ◽  
Author(s):  
Logan J. Voss ◽  
Paul S. García ◽  
Harald Hentschke ◽  
Matthew I. Banks
Keyword(s):  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Brain Slices ◽  
Brain Regions ◽  
Cortical Network ◽  
Network Activity ◽  
Common Mechanism ◽  
General Anesthetics ◽  
Neural Basis

Abstract General anesthetics have been used to ablate consciousness during surgery for more than 150 yr. Despite significant advances in our understanding of their molecular-level pharmacologic effects, comparatively little is known about how anesthetics alter brain dynamics to cause unconsciousness. Consequently, while anesthesia practice is now routine and safe, there are many vagaries that remain unexplained. In this paper, the authors review the evidence that cortical network activity is particularly sensitive to general anesthetics, and suggest that disruption to communication in, and/or among, cortical brain regions is a common mechanism of anesthesia that ultimately produces loss of consciousness. The authors review data from acute brain slices and organotypic cultures showing that anesthetics with differing molecular mechanisms of action share in common the ability to impair neurophysiologic communication. While many questions remain, together, ex vivo and in vivo investigations suggest that a unified understanding of both clinical anesthesia and the neural basis of consciousness is attainable.

scholarly journals Longitudinal noninvasive monitoring of transcription factor activation in cardiovascular regulatory nuclei using bioluminescence imaging

2008 ◽  
Vol 33 (2) ◽  
pp. 292-299 ◽  
Author(s):  
Jeffrey R. Peterson ◽  
David W. Infanger ◽  
Valdir A. Braga ◽  
Yulong Zhang ◽  
Ram V. Sharma ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Gene Transfer ◽  
Molecular Mechanisms ◽  
Bioluminescence Imaging ◽  
Brain Regions ◽  
Luciferase Reporter ◽  
Viral Gene ◽  
Adenoviral Delivery ◽  
Wide Range

The ability to monitor transcription factor (TF) activation in the central nervous system (CNS) has the potential to provide novel information regarding the molecular mechanisms underlying a wide range of neurobiological processes. However, traditional biochemical assays limit the mapping of TF activity to select time points. In vivo bioluminescence imaging (BLI) has emerged as an attractive technology for visualizing internal molecular events in the same animal over time. Here, we evaluated the utility of BLI, in combination with virally mediated delivery of reporter constructs to cardiovascular nuclei, for monitoring of TF activity in these discrete brain regions. Following viral gene transfer of NF-κB-driven luciferase reporter to the subfornical organ (SFO), BLI enabled daily measurements of baseline TF activity in the same animal for 1 mo. Importantly, systemic endotoxin, a stimulator of NF-κB activity, induced dramatic and dose-dependent increases in NF-κB-dependent bioluminescence in the SFO up to 30 days after gene transfer. Cotreatment with a dominant-negative IκBα mutant significantly prevented endotoxin-dependent NF-κB activation, confirming the specificity of the bioluminescence signal. NF-κB-dependent luminescence signals were also stable and inducible 1 mo following delivery of luciferase reporter construct to the paraventricular nucleus or rostral ventrolateral medulla. Lastly, using targeted adenoviral delivery of an AP-1 responsive luciferase reporter, we showed similar baseline and endotoxin-induced AP-1 activity in these same brain regions as with NF-κB reporters. These results demonstrate that BLI, in combination with virally mediated gene transfer, is a powerful method for longitudinal monitoring and quantification of TF activity in targeted CNS nuclei in vivo.

scholarly journals In vivo electroporation to physiologically identified deep brain regions in postnatal mammals

2014 ◽  
Vol 220 (3) ◽  
pp. 1307-1316 ◽  
Author(s):  
Nami Ohmura ◽  
Kazuha Kawasaki ◽  
Takemasa Satoh ◽  
Yoshio Hata
Keyword(s):  
Brain Regions ◽  
In Vivo Electroporation ◽  
Deep Brain

scholarly journals Scaling up to meet new challenges of brain and behaviour: Deep brain electrophysiology in freely moving sheep

2021 ◽  
Author(s):  
Nikolas Perentos ◽  
Marino Krstulovic ◽  
A Jennifer Morton
Keyword(s):  
Brain Function ◽  
Large Scale ◽  
Electrophysiological Recording ◽  
Large Animal ◽  
Freely Moving ◽  
Hippocampal Theta ◽  
Exceptional Stability ◽  
Oscillatory Rhythms ◽  
Deep Brain

While rodents are arguably the easiest animals to use for studying brain function, relying on them as model species for translational research comes with its own sets of limitations. Here, we propose sheep as a practical large animal species for in vivo brain function studies performed in naturalistic settings. To demonstrate their experimental usefulness, we performed proof-of-principle deep brain electrophysiological recording experiments from unrestrained sheep. Recordings were made from cortex and hippocampus both whilst sheep performed goal-directed behaviours (two-choice discrimination tasks), and across states of vigilance that included natural sleep. Hippocampal and cortical oscillatory rhythms were consistent with those seen in rodents and non-human primates, and included cortical alpha oscillations during immobility, hippocampal theta oscillations (5-6Hz) during locomotion and hippocampal sharp wave ripple oscillations (~150 Hz) during immobility. Moreover, we found clear examples of neurons whose activity was modulated by task, speed of locomotion, spatial position, reward and vigilance states. Recordings were conducted over a period of many months. Due to the exceptional stability of individual electrodes we were able to record from some neurons continuously for more than 1 month. Together these experiments demonstrate that sheep are an excellent experimental animal model to use in longitudinal electrophysiological and imaging studies, particularly those requiring a large brained mammal, large scale recordings across distributed neuronal networks, experimentation outside the confounds of the traditional laboratory, or all the above concomitantly.

scholarly journals Injectable Nanoelectrodes Enable Wireless Deep Brain Stimulation of Native Tissue in Freely Moving Mice

2020 ◽  
Author(s):  
Kristen L. Kozielski ◽  
Ali Jahanshahi ◽  
Hunter B. Gilbert ◽  
Yan Yu ◽  
Önder Erin ◽  
...  
Keyword(s):  
Behavioral Changes ◽  
Less Invasive ◽  
Magnetoelectric Materials ◽  
The Central Nervous System ◽  
Freely Moving ◽  
The Brain ◽  
Deep Brain ◽  
Stimulation Of

AbstractDevices that electrically modulate the central nervous system have enabled important breakthroughs in the management of neurological and psychiatric disorders. Such devices typically have centimeter-scale dimensions, requiring surgical implantation and wired-in powering. Using smaller, remotely powered materials could lead to less invasive neuromodulation. Herein, we present injectable magnetoelectric nanoelectrodes that wirelessly transmit electrical signals to the brain in response to an external magnetic field. Importantly, this mechanism of modulation requires no genetic modification of the brain, and allows animals to freely move during stimulation. Using these nanoelectrodes, we demonstrate neuronal modulation in vitro and in deep brain targets in vivo. We also show that local thalamic modulation promotes modulation in other regions connected via basal ganglia circuitry, leading to behavioral changes in mice. Magnetoelectric materials present a versatile platform technology for less invasive, deep brain neuromodulation.

The preclinical pharmacologic profile of tiapride

2001 ◽  
Vol 16 (S1) ◽  
pp. 29s-34S ◽  
Author(s):  
B. Scatton ◽  
C. Cohen ◽  
G. Perrault ◽  
A. Oblin ◽  
Y. Claustre ◽  
...  
Keyword(s):  
Dopamine Receptors ◽  
Learning Task ◽  
Brain Regions ◽  
Clinical Activity ◽  
Behavioral Experiments ◽  
Impaired Performance ◽  
Selective Blockade ◽  
Interoceptive Stimulus

SummaryTiapride is a benzamide derivative that has been used successfully in the clinic for a number of years for the treatment of agitation and aggressiveness in elderly patients. Like many substituted benzamides, tiapride specifically blocks dopamine receptors in the brain. It has affinity for dopamine D2 (IC50 = 110–320 nM) and D3 (IC50 = 180 nM) receptors in vitro but lacks affinity for dopamine D1 and D4 receptors and for non-dopaminergic receptors including H1, α1, α2-adrenergic and serotonergic receptors. Tiapride also shows dose-related inhibition of [3H]-raclopride binding in limbic areas and in the striatum of the rat in vivo (ED50 ∼ 20 mg/kg, ip). In microdialysis experiments, tiapride (over the range 10–30 mg/kg, ip) increased extracellular levels of dopamine in the nucleus accumbens and striatum, a reflection of its blockade of postsynaptic dopamine receptors in these brain areas.In behavioral experiments in rats, lower doses of tiapride (ED50 = 10 mg/kg, ip) antagonised dopamine agonist-induced hyperactivity while higher doses (ED50 = 60 mg/kg, ip) were required to block stereotyped movements.In addition, doses of tiapride up to 200 mg/kg, ip failed to induce catalepsy, an effect observed with many other drugs which block dopamine receptors. In tests of conditioned behavior in rats, tiapride was found to give rise to an interoceptive stimulus associated with dopamine receptor blockade at doses (ED50 = 2.2 mg/kg, ip) much lower than those producing motor disturbances or sedation (ED50 = 40 mg/kg, ip), in striking contrast to a range of conventional or atypical neuroleptics that produced interoceptive stimulus and sedation at similar doses. Furthermore, the acquisition by rats of a place-learning task in a water maze was not affected by tiapride (over the range 3–30 mg/kg, ip), whereas haloperidol (MED = 0.25 mg/kg, ip) and risperidone (MED = 0.03 mg/kg, ip) impaired performance.The preclinical pharmacologic and behavioral profile of tiapride suggests that its clinical activity may be due to a selective blockade of dopamine D2 and D3 receptors in limbic brain regions. The results are also consistent with a lack of motor or cognitive side effects.

scholarly journals Wireless optoelectronic photometers for monitoring neuronal dynamics in the deep brain

2018 ◽  
Vol 115 (7) ◽  
pp. E1374-E1383 ◽  
Author(s):  
Luyao Lu ◽  
Philipp Gutruf ◽  
Li Xia ◽  
Dionnet L. Bhatti ◽  
Xinying Wang ◽  
...  
Keyword(s):  
In Vivo Studies ◽  
Polymer Support ◽  
Neuronal Dynamics ◽  
Physical Constraints ◽  
Neuroscience Research ◽  
Calcium Indicators ◽  
Freely Moving ◽  
Complex Features ◽  
Deep Brain

Capabilities for recording neural activity in behaving mammals have greatly expanded our understanding of brain function. Some of the most sophisticated approaches use light delivered by an implanted fiber-optic cable to optically excite genetically encoded calcium indicators and to record the resulting changes in fluorescence. Physical constraints induced by the cables and the bulk, size, and weight of the associated fixtures complicate studies on natural behaviors, including social interactions and movements in environments that include obstacles, housings, and other complex features. Here, we introduce a wireless, injectable fluorescence photometer that integrates a miniaturized light source and a photodetector on a flexible, needle-shaped polymer support, suitable for injection into the deep brain at sites of interest. The ultrathin geometry and compliant mechanics of these probes allow minimally invasive implantation and stable chronic operation. In vivo studies in freely moving animals demonstrate that this technology allows high-fidelity recording of calcium fluorescence in the deep brain, with measurement characteristics that match or exceed those associated with fiber photometry systems. The resulting capabilities in optical recordings of neuronal dynamics in untethered, freely moving animals have potential for widespread applications in neuroscience research.

scholarly journals Minimally invasive deep-brain imaging through a 50 μm-core multimode fibre

2018 ◽  
Author(s):  
Sebastian A. Vasquez-Lopez ◽  
Vadim Koren ◽  
Martin Plöschner ◽  
Zahid Padamsey ◽  
Tomáš Čižmár ◽  
...  
Keyword(s):  
High Resolution ◽  
Brain Imaging ◽  
Light Propagation ◽  
Neural Circuit ◽  
Complex Refractive Index ◽  
Brain Structures ◽  
Brain Regions ◽  
Long Distance ◽  
Deep Brain

AbstractAchieving optical access to deep-brain structures represents an important step towards the goal of understanding the mammalian central nervous system. The complex refractive index distribution within brain tissue introduces severe aberrations to long-distance light propagation thereby prohibiting image reconstruction using currently available non-invasive techniques. In an attempt to overcome this challenge endoscopic approaches have been adopted, principally in the form of fibre bundles or GRIN-lens based endoscopes. Unfortunately, these approaches create substantial mechanical lesions of the tissue precipitating neuropathological responses that include inflammation and gliosis. Together, lesions and the associated neuropathology may compromise neural circuit performance. By replacing Fourier-based image relay with a holographic approach, we have been able to reduce the volume of tissue lesion by more than 100-fold, while preserving diffraction-limited imaging performance. Here we demonstrate high-resolution fluorescence imaging of neuronal structures, dendrites and synaptic specialisations, in deep-brain regions of living mice. These results represent a major breakthrough in the compromise between high-resolution imaging and tissue damage, heralding new possibilities for deep-brain imaging in vivo.

scholarly journals Optogenetic silencing of neurotransmitter release with a naturally occurring invertebrate rhodopsin

2021 ◽  
Author(s):  
Mathias Mahn ◽  
Inbar Saraf-Sinik ◽  
Pritish Patil ◽  
Mauro Pulin ◽  
Eyal Bitton ◽  
...  
Keyword(s):  
Neurotransmitter Release ◽  
Brain Regions ◽  
Presynaptic Terminals ◽  
Functional Roles ◽  
Naturally Occurring ◽  
Neuronal Projection ◽  
Freely Moving ◽  
Target Effects

AbstractInformation is carried between brain regions through neurotransmitter release from axonal presynaptic terminals. Understanding the functional roles of defined neuronal projection pathways in cognitive and behavioral processes requires temporally precise manipulation of their activity in vivo. However, existing optogenetic tools have low efficacy and off-target effects when applied to presynaptic terminals, while chemogenetic tools are difficult to control in space and time. Here, we show that a targeting-enhanced mosquito homologue of the vertebrate encephalopsin (eOPN3) can effectively suppress synaptic transmission through the Gi/o signaling pathway. Brief illumination of presynaptic terminals expressing eOPN3 triggers a lasting suppression of synaptic output that recovers spontaneously within minutes in vitro as well as in vivo. In freely moving mice, eOPN3-mediated suppression of dopaminergic nigrostriatal afferents leads to an ipsiversive rotational bias. We conclude that eOPN3 can be used to selectively suppress neurotransmitter release at synaptic terminals with high spatiotemporal precision, opening new avenues for functional interrogation of long-range neuronal circuits in vivo.

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