scholarly journals A striatal plasticity that supports the long-term preservation of motor function in Parkinsonian mice.

2022 ◽  
Author(s):  
Joe C Brague ◽  
Rebecca P Seal
Keyword(s):  
Dopamine Neurons ◽  
Neuron Activity ◽  
Motor Deficits ◽  
Projection Neurons ◽  
Motor Symptoms ◽  
Indirect Pathway ◽  
Novel Approach ◽  
Midbrain Dopamine ◽  
Nigrostriatal Dopamine Neurons

Motor deficits of Parkinsons disease (PD) such as rigidity, bradykinesia and akinesia result from a progressive loss of nigrostriatal dopamine neurons. No therapies exist that slow their degeneration and the most effective treatments for the motor symptoms: L-dopa -the precursor to dopamine, and deep brain stimulation can produce dyskinesias and are highly invasive, respectively. Hence, alternative strategies targeted to slow the progression or delay the onset of motor symptoms are still highly sought. Here we report the identification of a long-term striatal plasticity mechanism that delays for several months, the onset of motor deficits in a mouse PD model. Specifically, we show that a one-week transient daily elevation of midbrain dopamine neuron activity during depletion preserves the connectivity of direct but not indirect pathway projection neurons. The findings are consistent with the balance theory of striatal output pathways and suggest a novel approach for treating the motor symptoms of PD.

scholarly journals Probiotics Alleviate the Progressive Deterioration of Motor Functions in a Mouse Model of Parkinson's Disease

2020 ◽  
Vol 10 (4) ◽  
pp. 206 ◽  
Author(s):  
Tsung-Hsun Hsieh ◽  
Chi-Wei Kuo ◽  
Kai-Hsuan Hsieh ◽  
Meng-Jyh Shieh ◽  
Chih-Wei Peng ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Motor Coordination ◽  
Dopamine Neurons ◽  
Motor Symptoms ◽  
Neuroprotective Effects ◽  
Motor Functions ◽  
Term Administration ◽  
Nigrostriatal Dopamine Neurons

Parkinson’s disease (PD) is one of the common long-term degenerative disorders that primarily affect motor systems. Gastrointestinal (GI) symptoms are common in individuals with PD and often present before motor symptoms. It has been found that gut dysbiosis to PD pathology is related to the severity of motor and non-motor symptoms in PD. Probiotics have been reported to have the ability to improve the symptoms related to constipation in PD patients. However, the evidence from preclinical or clinical research to verify the beneficial effects of probiotics for the motor functions in PD is still limited. An experimental PD animal model could be helpful in exploring the potential therapeutic strategy using probiotics. In the current study, we examined whether daily and long-term administration of probiotics has neuroprotective effects on nigrostriatal dopamine neurons and whether it can further alleviate the motor dysfunctions in PD mice. Transgenic MitoPark PD mice were chosen for this study and the effects of daily probiotic treatment on gait, beam balance, motor coordination, and the degeneration levels of dopaminergic neurons were identified. From the results, compared with the sham treatment group, we found that the daily administration of probiotics significantly reduced the motor impairments in gait pattern, balance function, and motor coordination. Immunohistochemically, a tyrosine hydroxylase (TH)-positive cell in the substantia nigra was significantly preserved in the probiotic-treated PD mice. These results showed that long-term administration of probiotics has neuroprotective effects on dopamine neurons and further attenuates the deterioration of motor dysfunctions in MitoPark PD mice. Our data further highlighted the promising possibility of the potential use of probiotics, which could be the relevant approach for further application on human PD subjects.

scholarly journals Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Nicolas X Tritsch ◽  
Won-Jong Oh ◽  
Chenghua Gu ◽  
Bernardo L Sabatini
Keyword(s):  
Dopaminergic Neurons ◽  
De Novo ◽  
Dopamine Neurons ◽  
Gaba Uptake ◽  
Projection Neurons ◽  
Dependent Manner ◽  
Gaba Transporters ◽  
Midbrain Dopamine ◽  
Nigrostriatal Dopamine Neurons ◽  
Midbrain Dopamine Neurons

Synaptic transmission between midbrain dopamine neurons and target neurons in the striatum is essential for the selection and reinforcement of movements. Recent evidence indicates that nigrostriatal dopamine neurons inhibit striatal projection neurons by releasing a neurotransmitter that activates GABAA receptors. Here, we demonstrate that this phenomenon extends to mesolimbic afferents, and confirm that the released neurotransmitter is GABA. However, the GABA synthetic enzymes GAD65 and GAD67 are not detected in midbrain dopamine neurons. Instead, these cells express the membrane GABA transporters mGAT1 (Slc6a1) and mGAT4 (Slc6a11) and inhibition of these transporters prevents GABA co-release. These findings therefore indicate that GABA co-release is a general feature of midbrain dopaminergic neurons that relies on GABA uptake from the extracellular milieu as opposed to de novo synthesis. This atypical mechanism may confer dopaminergic neurons the flexibility to differentially control GABAergic transmission in a target-dependent manner across their extensive axonal arbors.

scholarly journals Targeting Diacylglycerol Lipase to Reduce Alcohol Consumption

2021 ◽  
Author(s):  
Gaurav Bedse ◽  
Nathan D. Winters ◽  
Anastasia Astafyev ◽  
Toni A. Patrick ◽  
Vikrant R. Mahajan ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Treatment Options ◽  
Ethanol Vapor ◽  
Reward Processing ◽  
Dopamine Neurons ◽  
Free Access ◽  
Diacylglycerol Lipase ◽  
Reduce Alcohol Consumption ◽  
Novel Approach ◽  
Midbrain Dopamine

ABSTRACTAlcohol use disorder (AUD) is associated with substantial morbidity, mortality, and societal cost, and pharmacological treatment options for AUD are limited. The endogenous cannabinoid (eCB) signaling system is critically involved in reward processing and alcohol intake is positively correlated with release of the eCB ligand 2-Arachidonoylglycerol (2-AG) within reward neurocircuitry. Here we show that genetic and pharmacological inhibition of diacylglycerol lipase (DAGL), the rate limiting enzyme in the synthesis of 2-AG, reduces alcohol consumption in a variety of preclinical models ranging from a voluntary free-access model to aversion resistant-drinking, and dependence-like drinking induced via chronic intermittent ethanol vapor exposure in mice. DAGL inhibition also prevented ethanol-induced suppression of GABAergic transmission onto midbrain dopamine neurons, providing mechanistic insight into how DAGL inhibition could affect alcohol reward. Lastly, DAGL inhibition during either chronic alcohol consumption or protracted withdrawal was devoid of anxiogenic and depressive-like behavioral effects. These data suggest reducing 2-AG signaling via inhibition of DAGL could represent a novel approach to reduce alcohol consumption across the spectrum of AUD severity.

A Possible Role of Midbrain Dopamine Neurons in Short- and Long-Term Adaptation of Saccades to Position-Reward Mapping

2004 ◽  
Vol 92 (4) ◽  
pp. 2520-2529 ◽  
Author(s):  
Yoriko Takikawa ◽  
Reiko Kawagoe ◽  
Okihide Hikosaka
Keyword(s):  
Visual Cues ◽  
Early Stage ◽  
Intermediate Stage ◽  
Saccade Latency ◽  
Dopamine Neurons ◽  
Neuronal Responses ◽  
Sensory Stimuli ◽  
Reward Delivery ◽  
Midbrain Dopamine

Dopamine (DA) neurons respond to sensory stimuli that predict reward. To understand how DA neurons acquire such ability, we trained monkeys on a one-direction-rewarded version of memory-guided saccade task (1DR) only when we recorded from single DA neurons. In 1DR, position-reward mapping was changed across blocks of trials. In the early stage of training of 1DR, DA neurons responded to reward delivery; in the later stages, they responded predominantly to the visual cue that predicted reward or no reward (reward predictor) differentially. We found that such a shift of activity from reward to reward predictor also occurred within a block of trials after position-reward mapping was altered. A main effect of long-term training was to accelerate the within-block reward-to-predictor shift of DA neuronal responses. The within-block shift appeared first in the intermediate stage, but was slow, and DA neurons often responded to the cue that indicated reward in the preceding block. In the advanced stage, the reward-to-predictor shift occurred quickly such that the DA neurons' responses to visual cues faithfully matched the current position-reward mapping. Changes in the DA neuronal responses co-varied with the reward-predictive differentiation of saccade latency both in short-term (within-block) and long-term adaptation. DA neurons' response to the fixation point also underwent long-term changes until it occurred predominantly in the first trial within a block. This might trigger a switch between the learned sets. These results suggest that midbrain DA neurons play an essential role in adapting oculomotor behavior to frequent switches in position-reward mapping.

scholarly journals Instantiation of incentive value and movement invigoration by distinct midbrain dopamine circuits

2017 ◽  
Author(s):  
Benjamin T. Saunders ◽  
Jocelyn M. Richard ◽  
Elyssa B. Margolis ◽  
Patricia H. Janak
Keyword(s):  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Neuron Activity ◽  
Temporal Association ◽  
Conditioned Stimuli ◽  
Incentive Value ◽  
Pavlovian Learning ◽  
Midbrain Dopamine ◽  
Dopamine Circuits

Environmental cues, through Pavlovian learning, become conditioned stimuli that guide animals towards the acquisition of “rewards” (i.e., food) that are necessary for survival. Here, we test the fundamental role of midbrain dopamine neurons in conferring predictive or motivational properties to cues, independent of external rewards. We demonstrate that phasic optogenetic excitation of dopamine neurons throughout the midbrain, when presented in temporal association with discrete sensory cues, is sufficient to instantiate those cues as conditioned stimuli that subsequently both evoke dopamine neuron activity on their own, and elicit cue-locked conditioned behaviors. Critically, we identify highly parcellated behavioral functions for dopamine neuron subpopulations projecting to discrete regions of striatum, revealing dissociable mesostriatal systems for the generation of incentive value and movement invigoration. These results show that dopamine neurons orchestrate Pavlovian conditioning via functionally heterogeneous, circuit-specific motivational signals to shape cue-controlled behavior.

scholarly journals Dopamine Neuron Responses Depend Exponentially on Pacemaker Interval

2009 ◽  
Vol 101 (2) ◽  
pp. 926-933 ◽  
Author(s):  
Ilva Putzier ◽  
Paul H. M. Kullmann ◽  
John P. Horn ◽  
Edwin S. Levitan
Keyword(s):  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Inhibitory Synapses ◽  
Neuron Activity ◽  
Exponential Dependence ◽  
Mathematical Form ◽  
Short And Long Term ◽  
Midbrain Dopamine ◽  
Cell Variation ◽  
The Impact

Midbrain dopamine neuron activity results from the integration of the responses to metabo- and ionotropic receptors with the postsynaptic excitability of these intrinsic pacemakers. Interestingly, intrinsic pacemaker rate varies greatly between individual dopamine neurons and is subject to short- and long-term regulation. Here responses of substantia nigra dopamine neurons to defined dynamic-clamp stimuli were measured to quantify the impact of cell-to-cell variation in intrinsic pacemaker rate. Then this approach was repeated in single dopamine neurons in which pacemaker rate was altered by activation of muscarinic receptors or current injection. These experiments revealed a dramatic exponential dependence on pacemaker interval for the responses to voltage-gated A-type K+ channels, voltage-independent cation channels and ionotropic synapses. Likewise, responses to native metabotropic (GABAb and mGluR1) inhibitory synapses depended steeply on pacemaker interval. These results show that observed variations in dopamine neuron pacemaker rate are functionally significant because they produce a >10-fold difference in responses to diverse stimuli. Both the magnitude and the mathematical form of the relationship between pacemaker interval and responses were not previously anticipated.

Brief ischemia causes long-term depression in midbrain dopamine neurons

2007 ◽  
Vol 26 (6) ◽  
pp. 1489-1499 ◽  
Author(s):  
Vineeta Singh ◽  
Melissa Carman ◽  
Jochen Roeper ◽  
Antonello Bonci
Keyword(s):  
Dopamine Neurons ◽  
Long Term Depression ◽  
Midbrain Dopamine ◽  
Midbrain Dopamine Neurons

scholarly journals Regulation of dendritic calcium release in striatal spiny projection neurons

2013 ◽  
Vol 110 (10) ◽  
pp. 2325-2336 ◽  
Author(s):  
Joshua L. Plotkin ◽  
Weixing Shen ◽  
Igor Rafalovich ◽  
Luke E. Sebel ◽  
Michelle Day ◽  
...  
Keyword(s):  
Action Potentials ◽  
Metabotropic Glutamate Receptors ◽  
Glutamate Release ◽  
Brain Slices ◽  
Long Term Potentiation ◽  
Laser Scanning Microscopy ◽  
Projection Neurons ◽  
Indirect Pathway ◽  
Group I

The induction of corticostriatal long-term depression (LTD) in striatal spiny projection neurons (SPNs) requires coactivation of group I metabotropic glutamate receptors (mGluRs) and L-type Ca2+ channels. This combination leads to the postsynaptic production of endocannabinoids that act presynaptically to reduce glutamate release. Although the necessity of coactivation is agreed upon, why it is necessary in physiologically meaningful settings is not. The studies described here attempt to answer this question by using two-photon laser scanning microscopy and patch-clamp electrophysiology to interrogate the dendritic synapses of SPNs in ex vivo brain slices from transgenic mice. These experiments revealed that postsynaptic action potentials induce robust ryanodine receptor (RYR)-dependent Ca2+-induced-Ca2+ release (CICR) in SPN dendritic spines. Depolarization-induced opening of voltage-gated Ca2+ channels was necessary for CICR. CICR was more robust in indirect pathway SPNs than in direct pathway SPNs, particularly in distal dendrites. Although it did not increase intracellular Ca2+ concentration alone, group I mGluR activation enhanced CICR and slowed Ca2+ clearance, extending the activity-evoked intraspine transient. The mGluR modulation of CICR was sensitive to antagonism of inositol trisphosphate receptors, RYRs, src kinase, and Cav1.3 L-type Ca2+ channels. Uncaging glutamate at individual spines effectively activated mGluRs and facilitated CICR induced by back-propagating action potentials. Disrupting CICR by antagonizing RYRs prevented the induction of corticostriatal LTD with spike-timing protocols. In contrast, mGluRs had no effect on the induction of long-term potentiation. Taken together, these results make clearer how coactivation of mGluRs and L-type Ca2+ channels promotes the induction of activity-dependent LTD in SPNs.

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