Optogenetic stimulation of the brainstem dorsal motor nucleus ameliorates acute pancreatitis
Dane ThompsonTéa TsaavaArvind RishiSandeep NadellaLopa MishraDavid A. TuvesonValentin A. PavlovMichael BrinesKevin J. TraceySangeeta S. Chavan
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Introduction Inflammation is an inherently self-amplifying process, resulting in progressive tissue damage when unresolved. A brake on this positive feedback system is provided by the nervous system which has evolved to detect inflammatory signals and respond by activating anti-inflammatory processes, including the cholinergic anti-inflammatory pathway mediated by the vagus nerve. Acute pancreatitis, a common and serious condition without effective therapy, develops when acinar cell injury activates intrapancreatic inflammation. Prior study has shown that electrical stimulation of the carotid sheath, which contains the vagus nerve, boosts the endogenous anti-inflammatory response and ameliorates acute pancreatitis, but it remains unknown whether these anti-inflammatory signals originate in the brain. Methods Here, we used optogenetics to selectively activate efferent vagus nerve fibers originating in the brainstem dorsal motor nucleus of the vagus (DMN) and evaluated the effects on caerulein-induced pancreatitis. Results Stimulation of the cholinergic neurons in the DMN significantly attenuates the severity of pancreatitis as indicated by reduced serum amylase, pancreatic cytokines, tissue damage, and edema. Either vagotomy or silencing cholinergic nicotinic receptor signaling by pre-administration of the antagonist mecamylamine abolishes the beneficial effects. Discussion These results provide the first evidence that efferent vagus cholinergic neurons residing in the brainstem DMN can inhibit pancreatic inflammation and implicate the cholinergic anti-inflammatory pathway as a potential therapeutic target for acute pancreatitis.Keywords:
Dorsal motor nucleus
Vagus Nerve Stimulation
Halorhodopsin
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Optogenetics combines the biological techniques of optics and genetics and uses light to control the activities of living tissues such as neurons and heart. Optogenetic actuators including channelrhodopsin (ChR), halorhodopsin (NpHR), and archaerhodopsin specifically provide for neuronal or cardiac controls. The clinical translation of cardiac optogenetics will include human and larger mammalian animal model applications and ultimately optogenetics may have the power to restore normal heart rhythm
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Abstract Optogenetics has revolutionized neurosciences by allowing fine control of neuronal activity. An important aspect for this control is assessing the activation and/or adjusting the stimulation, which requires imaging the entire volume of optogenetically-induced neuronal activity. An ideal technique for this aim is fUS imaging, which allows one to generate brain-wide activation maps with submesoscopic spatial resolution. However, optical stimulation of the brain with blue light might lead to non-specific activations at high irradiances. fUS imaging of optogenetic activations can be obtained at these wavelengths using lower light power (< 2mW) but it limits the depth of directly activatable neurons from the cortical surface. Our main goal was to report that we can detect specific optogenetic activations in V1 even in deep layers following stimulation at the cortical surface. Here, we show the possibility to detect deep optogenetic activations in anesthetized rats expressing the red-shifted opsin ChrimsonR in V1 using fUS imaging. We demonstrate the optogenetic specificity of these activations and their neuronal origin with electrophysiological recordings. Finally, we show that the optogenetic response initiated in V1 spreads to downstream (LGN) and upstream (V2) visual areas.
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Abstract Patients diagnosed with heart failure have high rates of mortality and morbidity. Based on promising preclinical studies, vagal nerve stimulation has been trialled in these patients using whole nerve electrical stimulation, but the results have been mixed. This is, at least in part, due to an inability to selectively recruit the activity of specific fibres within the vagus with whole nerve electrical stimulation, as well as not knowing which the ‘therapeutic’ fibres are. This symposium review focuses on a population of cardiac‐projecting efferent vagal fibres with cell bodies located within the dorsal motor nucleus of the vagus nerve and a new method of selectively targeting these projections as a potential treatment in heart failure.
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Abstract The method of optogenetics has spread widely in neurobiology over the past 10 years and has found extensive application in various fields of this sciences. It allows to control and regulate cellular activity with high spatial and temporal resolution. In this study, optogenetic activation was applied to astrocytes expressing ChR2. Optogenetic stimulation parameters were determined, in which the frequency of spontaneous currents of hippocampal pyramidal neurons significantly changed. In the future, it is planned to use the obtained data on the modes of optogenetic stimulation of astrocytes to normalize the functions of the hippocampus in mice-models of Alzheimer’s disease.
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Optogenetics combines the biological techniques of optics and genetics and uses light to control
the activities of living tissues such as neurons and heart. Optogenetic actuators including
channelrhodopsin (ChR), halorhodopsin (NpHR), and archaerhodopsin specifically provide for
neuronal or cardiac controls. The clinical translation of cardiac optogenetics will include human
and larger mammalian animal model applications and ultimately optogenetics may have the
power to restore normal heart rhythm.
Halorhodopsin
Channelrhodopsin
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