L-DOPA has been the gold standard for symptomatic treatment of Parkinson’s disease. However, its efficacy wanes over time as motor complications develop. Very little is known about how L-DOPA therapy affects the dynamics of fluctuating dopamine concentrations in the striatum on a rapid timescale (seconds). Electrochemical studies investigating the effects of L-DOPA treatment on electrically evoked dopamine release have reported conflicting results with significant variability. We hypothesize that the uncertainty in the electrochemical data is largely due to electrode fouling caused by polymerization of L-DOPA and endogenous catecholamines on the electrode surface. Thus, we have systematically optimized the procedure for fabricating cylindrical, Nafion-coated, carbon-fiber microelectrodes. This has enabled rapid and reliable detection of L-DOPA’s effects on striatal dopamine signaling in intact rat brain using fast-scan cyclic voltammetry. An acute dose of 5 mg/kg L-DOPA had no significant effect on dopamine dynamics, demonstrating the highly efficient regulatory mechanisms at work in the intact brain. In contrast, administration of 200 mg/kg L-DOPA significantly increased the amplitude of evoked dopamine release by ~200%. Overall, this work describes a reliable tool that allows a better measure of L-DOPA augmented dopamine release in vivo, measured using fast-scan cyclic voltammetry. It provides a methodology that improves the stability and performance of the carbon fiber microelectrode when studying the molecular mechanisms underlying L-DOPA therapy, and also promises to benefit a wide variety of studies because Nafion is so commonly used in electroanalytical chemistry.
Recent data demonstrate that noradrenergic neurons of the locus coeruleus (LC-NE) are required for fear-induced suppression of feeding, but the role of endogenous LC-NE activity in natural, homeostatic feeding remains unclear. Here, we found that LC-NE activity was suppressed during food consumption, and the magnitude of this neural response was attenuated as mice consumed more pellets throughout the session, suggesting that LC responses to food are modulated by satiety state. Visual-evoked LC-NE activity was also attenuated in sated mice, suggesting that satiety state modulates LC-NE encoding of multiple behavioral states. We also found that food intake could be attenuated by brief or longer durations of LC-NE activation. Last, we found that activation of the LC to the lateral hypothalamus pathway suppresses feeding and enhances avoidance and anxiety-like responding. Our findings suggest that LC-NE neurons modulate feeding by integrating both external cues (e.g., anxiogenic environmental cues) and internal drives (e.g., satiety).
Hydrogen peroxide (HO) is an endogenous molecule that plays several important roles in brain function: it is generated in cellular respiration, serves as a modulator of dopaminergic signaling, and its presence can indicate the upstream production of more aggressive reactive oxygen species (ROS). HO has been implicated in several neurodegenerative diseases, including Parkinson's disease (PD), creating a critical need to identify mechanisms by which HO modulates cellular processes in general and how it affects the dopaminergic nigrostriatal pathway, in particular. Furthermore, there is broad interest in selective electrochemical quantification of HO, because it is often enzymatically generated at biosensors as a reporter for the presence of nonelectroactive target molecules. HO fluctuations can be monitored in real time using fast-scan cyclic voltammetry (FSCV) coupled with carbon-fiber microelectrodes. However, selective identification is a critical issue when working in the presence of other molecules that generate similar voltammograms, such as adenosine and histamine. We have addressed this problem by fabricating a robust, HO-selective electrode. 1,3-Phenylenediamine (mPD) was electrodeposited on a carbon-fiber microelectrode to create a size-exclusion membrane, rendering the electrode sensitive to HO fluctuations and pH shifts but not to other commonly studied neurochemicals. The electrodes are described and characterized herein. The data demonstrate that this technology can be used to ensure the selective detection of HO, enabling confident characterization of the role this molecule plays in normal physiological function as well as in the progression of PD and other neuropathies involving oxidative stress.
Noradrenergic neurons of the locus coeruleus (LC-NE) are known to play an important role in arousal, emotion, memory and cognition. In the present study, we use fiber photometry combined with chemogenetic and optogenetic approaches to demonstrate a previously unrecognized role for LC-NE neurons in the modulation of feeding. We show that endogenous activity of LC-NE neurons is enhanced while approaching food and suppressed during feeding. These changes in LC activity during feeding behavior are attenuated as mice approach satiety, demonstrating that nutritional state modulates LC responses to food. Direct activation of LC-NE neurons results in the suppression of feeding. Further, activation of an LC projection to the lateral hypothalamus also suppresses feeding. Together, these findings demonstrate a direct causal role for LC-NE activity in the modulation of feeding.
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