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- Bimpisidis, Zisis, et al.
(författare)
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Differential effects of gaseous versus injectable anesthetics on changes in regional cerebral blood flow and metabolism induced by l-DOPA in a rat model of Parkinson's disease
- 2017
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 292, s. 113-124
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Tidskriftsartikel (refereegranskat)abstract
- Preclinical imaging of brain activity requires the use of anesthesia. In this study, we have compared the effects of two widely used anesthetics, inhaled isoflurane and ketamine/xylazine cocktail, on cerebral blood flow and metabolism in a rat model of Parkinson's disease and l-DOPA-induced dyskinesia. Specific tracers were used to estimate regional cerebral blood flow (rCBF - [(14)C]-iodoantipyrine) and regional cerebral metabolic rate (rCMR - [(14)C]-2-deoxyglucose) with a highly sensitive autoradiographic method. The two types of anesthetics had quite distinct effects on l-DOPA-induced changes in rCBF and rCMR. Isoflurane did not affect either the absolute rCBF values or the increases in rCBF in the basal ganglia after l-DOPA administration. On the contrary, rats anesthetized with ketamine/xylazine showed lower absolute rCBF values, and the rCBF increases induced by l-DOPA were masked. We developed a novel improved model to calculate rCMR, and found lower metabolic activities in rats anesthetized with isoflurane compared to animals anesthetized with ketamine/xylazine. Both anesthetics prevented changes in rCMR upon l-DOPA administration. Pharmacological challenges in isoflurane-anesthetized rats indicated that drugs mimicking the actions of ketamine/xylazine on adrenergic or glutamate receptors reproduced distinct effects of the injectable anesthetics on rCBF and rCMR. Our results highlight the importance of anesthesia in studies of cerebral flow and metabolism, and provide novel insights into mechanisms mediating abnormal neurovascular responses to l-DOPA in Parkinson's disease.
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| 2. |
- Bimpisidis, Zisis, et al.
(författare)
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Increased sucrose consumption in mice gene-targeted for Vmat2 selectively in NeuroD6-positive neurons of the ventral tegmental area
- 2023
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Ingår i: Frontiers in Molecular Neuroscience. - : Frontiers Media S.A.. - 1662-5099. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Ventral tegmental area (VTA) dopamine (DA) neurons are implicated in reward processing, motivation, reward prediction error, and in substance use disorder. Recent studies have identified distinct neuronal subpopulations within the VTA that can be clustered based on their molecular identity, neurotransmitter profile, physiology, projections and behavioral role. One such subpopulation is characterized by expression of the NeuroD6 gene, and projects primarily to the nucleus accumbens medial shell. We recently showed that optogenetic stimulation of these neurons induces real-time place preference while their targeted deletion of the Vmat2 gene caused altered response to rewarding substances, including ethanol and psychostimulants. Based on these recent findings, we wanted to further investigate the involvement of the NeuroD6-positive VTA subpopulation in reward processing. Using the same NeuroD6(Cre+/wt);Vmat2(flox/flox) mice as in our prior study, we now addressed the ability of the mice to process sucrose reward. In order to assess appetitive behavior and motivation to obtain sucrose reward, we tested conditional knockout (cKO) and control littermate mice in an operant sucrose self-administration paradigm. We observed that cKO mice demonstrate higher response rates to the operant task and consume more sucrose rewards than control mice. However, their motivation to obtain sucrose is identical to that of control mice. Our results highlight previous observations that appetitive behavior and motivation to obtain rewards can be served by distinct neuronal circuits, and demonstrate that the NeuroD6 VTA subpopulation is involved in mediating the former, but not the latter. Together with previous studies on the NeuroD6 subpopulation, our findings pinpoint the importance of unraveling the molecular and functional role of VTA subpopulations in order to better understand normal behavior and psychiatric disease.
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| 3. |
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| 4. |
- Bimpisidis, Zisis, et al.
(författare)
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Neurocircuitry of Reward and Addiction : Potential Impact of Dopamine-Glutamate Co-release as Future Target in Substance Use Disorder
- 2019
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Ingår i: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 8:11
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Forskningsöversikt (refereegranskat)abstract
- Dopamine-glutamate co-release is a unique property of midbrain neurons primarily located in the ventral tegmental area (VTA). Dopamine neurons of the VTA are important for behavioral regulation in response to rewarding substances, including natural rewards and addictive drugs. The impact of glutamate co-release on behaviors regulated by VTA dopamine neurons has been challenging to probe due to lack of selective methodology. However, several studies implementing conditional knockout and optogenetics technologies in transgenic mice have during the past decade pointed towards a role for glutamate co-release in multiple physiological and behavioral processes of importance to substance use and abuse. In this review, we discuss these studies to highlight findings that may be critical when considering mechanisms of importance for prevention and treatment of substance abuse.
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| 5. |
- Bimpisidis, Zisis, et al.
(författare)
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The NeuroD6 Subtype of VTA Neurons Contributes to Psychostimulant Sensitization and Behavioral Reinforcement
- 2019
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Ingår i: eNeuro. - : SOC NEUROSCIENCE. - 2373-2822. ; 6:3
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Tidskriftsartikel (refereegranskat)abstract
- Reward-related behavior is complex and its dysfunction correlated with neuropsychiatric illness. Dopamine (DA) neurons of the ventral tegmental area (VTA) have long been associated with different aspects of reward function, but it remains to be disentangled how distinct VTA DA neurons contribute to the full range of behaviors ascribed to the VTA. Here, a recently identified subtype of VTA neurons molecularly defined by NeuroD6 (NEX1M) was addressed. Among all VTA DA neurons, less than 15% were identified as positive for NeuroD6. In addition to dopaminergic markers, sparse NeuroD6 neurons expressed the vesicular glutamate transporter 2 (Vglut2) gene. To achieve manipulation of NeuroD6 VTA neurons, NeuroD6(NEX)-Cre-driven mouse genetics and optogenetics were implemented. First, expression of vesicular monoamine transporter 2 (VMAT2) was ablated to disrupt dopaminergic function in NeuroD6 VTA neurons. Comparing Vmat2(Cre)(lox/lox;NEX-) conditional knock-out (cKO) mice with littermate controls, it was evident that baseline locomotion, preference for sugar and ethanol, and place preference upon amphetamine-induced and cocaine-induced conditioning were similar between genotypes. However, locomotion upon repeated psychostimulant administration was significantly elevated above control levels in cKO mice. Second, optogenetic activation of NEX-Cre VTA neurons was shown to induce DA release and glutamatergic postsynaptic currents within the nucleus accumbens. Third, optogenetic stimulation of NEX-Cre VTA neurons in vivo induced significant place preference behavior, while stimulation of VTA neurons defined by Calretinin failed to cause a similar response. The results show that NeuroD6 VTA neurons exert distinct regulation over specific aspects of reward-related behavior, findings that contribute to the current understanding of VTA neurocircuitry.
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| 6. |
- Bimpisidis, Zisis, et al.
(författare)
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Two Different Real-Time Place Preference Paradigms Using Optogenetics within the Ventral Tegmental Area of the Mouse
- 2020
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Ingår i: Journal of Visualized Experiments. - : JOURNAL OF VISUALIZED EXPERIMENTS. - 1940-087X. ; :156
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Tidskriftsartikel (refereegranskat)abstract
- Understanding how neuronal activation leads to specific behavioral output is fundamental for modern neuroscience. Combining optogenetics in rodents with behavioral testing in validated paradigms allows the measurement of behavioral consequences upon stimulation of distinct neurons in real-time with high spatial and temporal selectivity, and thus the establishment of causal relationships between neuronal activation and behavior. Here, we describe a step-by-step protocol fora real-time place preference (RT-PP) paradigm, a modified version of the classical conditioned place preference (CPP) test. The RT-PP is performed in a three-compartment apparatus and can be utilized to answer if optogenetic stimulation of a specific neuronal population is rewarding or aversive. We also describe an alternative version of the RT-PP protocol, the socalled neutral compartment preference (NCP) protocol, which can be used to confirm aversion. The two approaches are based on extensions of classical methodology originating from behavioral pharmacology and recent implementation of optogenetics within the neuroscience field. Apart from measuring place preference in real time, these setups can also give information regarding conditioned behavior. We provide easyto-follow step-by-step protocols alongside examples of our own data and discuss important aspects to consider when applying these types of experiments.
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