scholarly journals Forebrain NgR1 Overexpression Impairs DA Release Suggesting Synergy of Local and Global Synaptic Plasticity Mechanisms

2020 ◽  
Vol 12 ◽  
Author(s):  
Emma Arvidsson ◽  
Sarolta Gabulya ◽  
Alvin Tore Brodin ◽  
Tobias Erik Karlsson ◽  
Lars Olson
Keyword(s):  
Synaptic Plasticity ◽  
Potassium Chloride ◽  
Neural Activity ◽  
Dorsal Striatum ◽  
Inverse Correlation ◽  
Long Term Memory ◽  
The Status ◽  
Global Systems ◽  
Da Release

Structural synaptic reorganizations needed to permanently embed novel memories in the brain involve complex plasticity-enhancing and plasticity-inhibiting systems. Increased neural activity is linked to rapid downregulation of Nogo receptor 1 (NgR1), needed to allow local structural synaptic plasticity. This local regulation of plasticity is thought to be moderated by global systems, such as the ascending cholinergic and monoaminergic systems, adding significance to locally increased neural activity. Here we address the reverse possibility that the global systems may also be influenced by the status of local plasticity. Using NgR1-overexpressing mice, with impaired plasticity and long-term memory, we measured the ability to release dopamine (DA), implicated in regulating plasticity and memory. In vivo chronoamperometric recording with high temporal and spatial resolution revealed severe impairment of potassium chloride (KCl)-induced increase of extracellular DA in the dorsal striatum of mice overexpressing NgR1 in forebrain neurons. A similar, but lesser, impairment of DA release was seen following amphetamine delivery. In contrast, potassium chloride-evoked DA release in NgR1 knockout (KO) mice led to increased levels of extracellular DA. That NgR1 can impair DA signaling, thereby further dampening synaptic plasticity, suggests a new role for NgR1 signaling, acting in synergy with DA signaling to control synaptic plasticity.Significance Statement:The inverse correlation between local NgR1 levels and magnitude of KCl-inducible amounts of DA release in the striatum reinforces the rule of NgR1 as a regulator of structural synaptic plasticity and suggests synergy between local and global plasticity regulating systems.

scholarly journals Dopamine D2/3 Receptor Availabilities and Evoked Dopamine Release in Striatum Differentially Predict Impulsivity and Novelty Preference in Roman High- and Low-Avoidance Rats

2020 ◽  
Author(s):  
Lidia Bellés ◽  
Andrea Dimiziani ◽  
Stergios Tsartsalis ◽  
Philippe Millet ◽  
François R Herrmann ◽  
...  
Keyword(s):  
Ventral Striatum ◽  
Single Photon ◽  
Ex Vivo ◽  
Photon Emission ◽  
Dorsal Striatum ◽  
Reaction Time Task ◽  
Emission Computed Tomography ◽  
Novelty Preference ◽  
Da Release

Abstract Background Impulsivity and novelty preference are both associated with an increased propensity to develop addiction-like behaviors, but their relationship and respective underlying dopamine (DA) underpinnings are not fully elucidated. Methods We evaluated a large cohort (n = 49) of Roman high- and low-avoidance rats using single photon emission computed tomography to concurrently measure in vivo striatal D2/3 receptor (D2/3R) availability and amphetamine (AMPH)-induced DA release in relation to impulsivity and novelty preference using a within-subject design. To further examine the DA-dependent processes related to these traits, midbrain D2/3-autoreceptor levels were measured using ex vivo autoradiography in the same animals. Results We replicated a robust inverse relationship between impulsivity, as measured with the 5-choice serial reaction time task, and D2/3R availability in ventral striatum and extended this relationship to D2/3R levels measured in dorsal striatum. Novelty preference was positively related to impulsivity and showed inverse associations with D2/3R availability in dorsal striatum and ventral striatum. A high magnitude of AMPH-induced DA release in striatum predicted both impulsivity and novelty preference, perhaps owing to the diminished midbrain D2/3-autoreceptor availability measured in high-impulsive/novelty-preferring Roman high-avoidance animals that may amplify AMPH effect on DA transmission. Mediation analyses revealed that while D2/3R availability and AMPH-induced DA release in striatum are both significant predictors of impulsivity, the effect of striatal D2/3R availability on novelty preference is fully mediated by evoked striatal DA release. Conclusions Impulsivity and novelty preference are related but mediated by overlapping, yet dissociable, DA-dependent mechanisms in striatum that may interact to promote the emergence of an addiction-prone phenotype.

scholarly journals Effectiveness and relationship between biased and unbiased measures of dopamine release and clearance

2021 ◽  
Author(s):  
Anna C Everett ◽  
Benjamin E. Graul ◽  
Daniel B. Watts ◽  
James Kayden Robinson ◽  
Rodrigo A. Espana ◽  
...  
Keyword(s):  
Dopamine Release ◽  
Gabab Receptor ◽  
Dorsal Striatum ◽  
Peak Height ◽  
Maximal Velocity ◽  
Fast Scan Cyclic Voltammetry ◽  
Knock Out ◽  
Upward Velocity ◽  
Da Release

Fast-scan cyclic voltammetry (FSCV) is an effective tool for measuring dopamine (DA) release and clearance throughout the brain, including the ventral and dorsal striatum. Striatal DA terminals are abundant with signals heavily regulated by release machinery and the dopamine transporter (DAT). Peak height is a common method for measuring release but can be affected by changes in clearance. The Michaelis-Menten model has been a standard in measuring DA clearance, but requires experimenter fitted modeling subject to experimenter bias. The current study presents the use of the first derivative (velocity) of evoked DA signals as an alternative approach for measuring dopamine release and clearance and can be used to distinguish the two measures. Maximal upwards velocity predicts reductions in DA peak height due to D2 and GABAB receptor stimulation and by alterations in calcium concentrations. The Michaelis-Menten maximal velocity (Vmax) measure, an approximation for DAT numbers, predicted maximal downward velocity in slices and in vivo. Dopamine peak height and upward velocity were similar between wildtype C57 (WT) and DAT knock out (DATKO) mice. In contrast, downward velocity was considerably reduced and exponential decay (tau) was increased in DATKO mice, supporting use of both measures for changes in DAT activity. In slices, the competitive DAT inhibitors cocaine, PTT and WF23 increased peak height and upward velocity differentially across increasing concentrations, with PTT and cocaine reducing these measures at high concentrations. Downward velocity and tau values decreased and increased respectively across concentrations, with greater potency and efficacy observed with WF23 and PTT. In vivo recordings demonstrated similar effects of WF23 and PTT on measures of release and clearance. Tau was a more sensitive measure at low concentrations, supporting its use as a surrogate for the Michaelis-Menten measure of apparent affinity (Km). Together, these results inform on the use of these measures for DA release and clearance.

scholarly journals The pharmacological perturbation of brain zinc impairs BDNF-related signalling and the cognitive performances of young mice

2018 ◽  
Author(s):  
Valerio Frazzini ◽  
Alberto Granzotto ◽  
Manuela Bomba ◽  
Noemi Massetti ◽  
Vanessa Castelli ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Brain Activity ◽  
Long Term Memory ◽  
Spine Density ◽  
Short And Long Term ◽  
Copper Chelator ◽  
Related Proteins ◽  
Metalloproteinase Activity

AbstractZinc (Zn2+) is a pleiotropic modulator of the neuronal and brain activity. The disruption of intraneuronal Zn2+levels triggers neurotoxic processes and affects neuronal functioning. In this study, we investigated how the pharmacological modulation of brain Zn2+affects synaptic plasticity and cognition in wild-type mice. To manipulate brain Zn2+levels, we employed the Zn2+(and copper) chelator 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, CQ). CQ was administered for two weeks to 2.5-month-old (m.o.) mice, and effects studied on BDNF-related signalling, metalloproteinase activity as well as learning and memory performances. CQ treatment was found to negatively affect short- and long-term memory performances. The CQ-driven perturbation of brain Zn2+was found to reduce levels of BDNF, synaptic plasticity-related proteins and dendritic spine densityin vivo.Our study highlights the importance of choosing “when”, “where”, and “how much” in the modulation of brain Zn2+levels. Our findings confirm the importance of targeting Zn2+as a therapeutic approach against neurodegenerative conditions but, at the same time, underscore the potential drawbacks of reducing brain Zn2+availability upon the early stages of development.

scholarly journals In vivo assessment of mechanisms underlying the neurovascular basis of postictal amnesia

2020 ◽  
Author(s):  
Jordan S. Farrell ◽  
Roberto Colangeli ◽  
Barna Dudok ◽  
Marshal D. Wolff ◽  
Sarah L. Nguyen ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Synaptic Transmission ◽  
Neural Activity ◽  
Long Term Potentiation ◽  
Activity Network ◽  
Network Oscillations ◽  
Short Period ◽  
Cox 2

AbstractLong-lasting confusion and memory difficulties during the postictal state remain a major unmet problem in epilepsy that lacks pathophysiological explanation and treatment. We previously identified that long-lasting periods of severe postictal hypoperfusion/hypoxia, not seizures per se, are associated with memory impairment after temporal lobe seizures. While this observation suggests a key pathophysiological role for insufficient energy delivery, it is unclear how the networks that underlie episodic memory respond to vascular constraints that ultimately give rise to amnesia. Here, we focused on cellular/network level analyses in the CA1 of hippocampus in vivo to determine if neural activity, network oscillations, synaptic transmission, and/or synaptic plasticity are impaired following kindled seizures. Importantly, the induction of severe postictal hypoperfusion/hypoxia was prevented in animals treated by a COX-2 inhibitor, which experimentally separated seizures from their vascular consequences. We observed complete activation of CA1 pyramidal neurons during brief seizures, followed by a short period of reduced activity and flattening of the local field potential that resolved within minutes. During the postictal state, constituting tens of minutes to hours, we observed no changes in neural activity, network oscillations, and synaptic transmission. However, long-term potentiation of the temporoammonic pathway to CA1 was impaired in the postictal period, but only when severe local hypoxia occurred. Lastly, we tested the ability of rats to perform object-context discrimination, which has been proposed to require temporoammonic input to differentiate between sensory experience and the stored representation of the expected object-context pairing. Deficits in this task following seizures were reversed by COX-2 inhibition, which prevented severe postictal hypoxia. These results support a key role for hypoperfusion/hypoxia in postictal memory impairments and identify that many aspects of hippocampal network function are resilient during severe hypoxia except for long-term synaptic plasticity.

scholarly journals In vivo assessment of mechanisms underlying the neurovascular basis of postictal amnesia

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jordan S. Farrell ◽  
Roberto Colangeli ◽  
Barna Dudok ◽  
Marshal D. Wolff ◽  
Sarah L. Nguyen ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Synaptic Transmission ◽  
Neural Activity ◽  
Long Term Potentiation ◽  
Activity Network ◽  
Network Oscillations ◽  
Short Period ◽  
Cox 2

Abstract Long-lasting confusion and memory difficulties during the postictal state remain a major unmet problem in epilepsy that lacks pathophysiological explanation and treatment. We previously identified that long-lasting periods of severe postictal hypoperfusion/hypoxia, not seizures per se, are associated with memory impairment after temporal lobe seizures. While this observation suggests a key pathophysiological role for insufficient energy delivery, it is unclear how the networks that underlie episodic memory respond to vascular constraints that ultimately give rise to amnesia. Here, we focused on cellular/network level analyses in the CA1 of hippocampus in vivo to determine if neural activity, network oscillations, synaptic transmission, and/or synaptic plasticity are impaired following kindled seizures. Importantly, the induction of severe postictal hypoperfusion/hypoxia was prevented in animals treated by a COX-2 inhibitor, which experimentally separated seizures from their vascular consequences. We observed complete activation of CA1 pyramidal neurons during brief seizures, followed by a short period of reduced activity and flattening of the local field potential that resolved within minutes. During the postictal state, constituting tens of minutes to hours, we observed no changes in neural activity, network oscillations, and synaptic transmission. However, long-term potentiation of the temporoammonic pathway to CA1 was impaired in the postictal period, but only when severe local hypoxia occurred. Lastly, we tested the ability of rats to perform object-context discrimination, which has been proposed to require temporoammonic input to differentiate between sensory experience and the stored representation of the expected object-context pairing. Deficits in this task following seizures were reversed by COX-2 inhibition, which prevented severe postictal hypoxia. These results support a key role for hypoperfusion/hypoxia in postictal memory impairments and identify that many aspects of hippocampal network function are resilient during severe hypoxia except for long-term synaptic plasticity.

Abstract P791: A Lesion-Based Toolbox to Study Ischemic Stroke in Primates

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Karam Khateeb ◽  
Julien Bloch ◽  
Mona Rahimi ◽  
Devon Griggs ◽  
Shaozhen Song ◽  
...  
Keyword(s):  
Neural Activity ◽  
Clinical Studies ◽  
Complex Structure ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Lesion Size ◽  
Memory Storage ◽  
Long Term Memory ◽  
Underlying Network

The primate cortex is a highly complex structure responsible for a variety of sophisticated tasks and behaviors including long-term memory storage, sensation, movement, and vision. However, little is understood with respect to the underlying cortical physiology and dynamics following injury. It is essential that these phenomena are studied in a model which shares a high degree of complexity and evolutionary history with human cortex: the non-human primate (NHP) cortex. Such studies would allow for the development of improved tools and strategies for treating neurological disorders such as stroke. However, current methods of inducing cortical lesions in NHP pre-clinical studies often require surgical skill, produce variable results, and lack controllability of lesion size and location. Methods: To address these challenges for the development of effective therapies, we developed a versatile lesion-based toolbox for studying NHP cortical physiology.First, we demonstrated the photothrombotic technique, wherein intravenous infusion of a photosensitive dye followed by targeted cortical illumination leads to the formation of localized thrombi in the vasculature. With this method, we induced ischemic lesions extending through all layers of sensorimotor cortex in 5 adult macaques. To validate the disruption of blood flow in cortical microvasculature in vivo , we employed optical coherence tomography angiography (OCTA) imaging. Additionally, we implanted a semi-transparent electrocorticography array to record neural activity before, during, and after the induction of lesions. The transparency of the array enabled us to illuminate through the array to induce lesions and acquire OCTA images to register electrodes to ischemic areas in vivo . Thus, we observed the dynamics of the underlying network neural activity as lesions were developing. Histological staining validated neuronal cell death and was used to estimate lesion volumes. Finally, we developed a computational model to predict lesion sizes based on illumination parameters. In combination with behavioral findings, this toolbox can drive the development of future rehabilitative therapies for stroke at clinically relevant time scales in pre-clinical studies.

scholarly journals Functional MRI of long-term potentiation: imaging network plasticity

2014 ◽  
Vol 369 (1633) ◽  
pp. 20130152 ◽  
Author(s):  
Efrén Álvarez-Salvado ◽  
Vicente Pallarés ◽  
Andrea Moreno ◽  
Santiago Canals
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Plastic Property ◽  
Cellular Level ◽  
Synaptic Activity ◽  
Long Term Memory ◽  
Cellular Mechanisms ◽  
Term Potentiation

Neurons are able to express long-lasting and activity-dependent modulations of their synapses. This plastic property supports memory and conveys an extraordinary adaptive value, because it allows an individual to learn from, and respond to, changes in the environment. Molecular and physiological changes at the cellular level as well as network interactions are required in order to encode a pattern of synaptic activity into a long-term memory. While the cellular mechanisms linking synaptic plasticity to memory have been intensively studied, those regulating network interactions have received less attention. Combining high-resolution fMRI and in vivo electrophysiology in rats, we have previously reported a functional remodelling of long-range hippocampal networks induced by long-term potentiation (LTP) of synaptic plasticity in the perforant pathway. Here, we present new results demonstrating an increased bilateral coupling in the hippocampus specifically supported by the mossy cell commissural/associational pathway in response to LTP. This fMRI-measured increase in bilateral connectivity is accompanied by potentiation of the corresponding polysynaptically evoked commissural potential in the contralateral dentate gyrus and depression of the inactive convergent commissural pathway to the ipsilateral dentate. We review these and previous findings in the broader context of memory consolidation.

scholarly journals Noradrenergic signaling in wakeful states inhibits microglial surveillance and synaptic plasticity in the mouse visual cortex

2019 ◽  
Author(s):  
Rianne D. Stowell ◽  
Grayson O. Sipe ◽  
Ryan P. Dawes ◽  
Hanna N. Batchelor ◽  
Katheryn A. Lordy ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Immune Cells ◽  
Neural Activity ◽  
Adrenergic Receptors ◽  
Brain Parenchyma ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Mouse Visual Cortex ◽  
The Brain

AbstractMicroglia are the innate immune cells of the brain with roles in neuroimmunology and synaptic plasticity. Microglial processes continuously survey the brain parenchyma interacting with synaptic elements and maintaining tissue homeostasis. However, the mechanisms that control surveillance and its role in synaptic plasticity are poorly understood. Microglial dynamics in vivo have been primarily studied in anesthetized animals, where slow-wave neural activity resembles sleep-like states. We report that microglial surveillance and injury response in awake animals are reduced compared to when animals are anesthetized, suggesting that arousal state profoundly modulates microglial roles in the physiological brain. Stimulating β2-adrenergic receptors recapitulated these observations and also disrupted experience-dependent plasticity only when intact β2-adrenergic receptors were present in microglia specifically. These results indicate that microglial roles in surveillance and synaptic plasticity in the healthy brain are modulated by noradrenergic fluctuations between arousal states and raises new considerations for sleep/wake disruption in neurodevelopment and neuropathology.

Pharmacological treatment with L-DOPA may reduce striatal dopamine transporter binding in in vivo imaging studies

2016 ◽  
Vol 55 (01) ◽  
pp. 21-28 ◽  
Author(s):  
C. Antke ◽  
H. Hautzel ◽  
H.-W. Mueller ◽  
S. Nikolaus
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Binding Sites ◽  
Human Subjects ◽  
Synaptic Cleft ◽  
Presynaptic Terminal ◽  
Imaging Studies ◽  
Psychiatric Conditions ◽  
Da Release

SummaryNumerous neurologic and psychiatric conditions are treated with pharmacological compounds, which lead to an increase of synaptic dopamine (DA) levels. One example is the DA precursor L-3,4-dihydroxyphenylalanine (L-DOPA), which is converted to DA in the presynaptic terminal. If the increase of DA concentrations in the synaptic cleft leads to competition with exogenous radioligands for presynaptic binding sites, this may have implications for DA transporter (DAT) imaging studies in patients under DAergic medication.This paper gives an overview on those findings, which, so far, have been obtained on DAT binding in human Parkinson’s disease after treatment with L-DOPA. Findings, moreover, are related to results obtained on rats, mice or non-human primates. Results indicate that DAT imaging may be reduced in the striata of healthy animals, in the unlesioned striata of animal models of unilateral Parkinson’s disease and in less severly impaired striata of Parkinsonian patients, if animal or human subjects are under acute or subchronic treatment with L-DOPA. If also striatal DAT binding is susceptible to alterations of synaptic DA levels, this may allow to quantify DA reuptake in analogy to DA release by assessing the competition between endogenous DA and the administered exogenous DAT radioligand.

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