scholarly journals Effects of Chemogenetic Inhibition of D1 or D2 Receptor-Containing Neurons of the Substantia Nigra and Striatum in Mice With Tourette Syndrome

2021 ◽  
Vol 14 ◽  
Author(s):  
Lixue Lin ◽  
Yuye Lan ◽  
He Zhu ◽  
Lingling Yu ◽  
Shuang Wu ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Tourette Syndrome ◽  
D2 Receptor ◽  
Dorsal Striatum ◽  
Stereotyped Behavior ◽  
D1 Receptor ◽  
Substantia Nigra Pars Compacta ◽  
Motor Functions ◽  
New Treatment ◽  
Immunofluorescence Labeling

As tourette syndrome (TS) is a common neurobehavioral disorder, the primary symptoms of which include behavioral stereotypies. Dysfunction of the substantia nigra–striatum network could be the main pathogenesis of TS, which is closely associated with dopamine (DA) and its receptors. TS is often resistant to conventional treatments. Therefore, it is necessary to investigate the neurobiological mechanisms underlying its pathogenesis. In this study, we investigated whether chemogenetic activation or inhibition of dopaminergic D1 receptor (D1R)- or D2 receptor (D2R)-containing neurons in the substantia nigra pars compacta (SNpc) or dorsal striatum (dSTR) affected the stereotyped behavior and motor functions of TS mice. Intraperitoneal injection of 3,3′-iminodipropionitrile (IDPN) was used to induce TS in mice. Stereotyped behavior test and open-field, rotarod, and grip strength tests were performed to evaluate stereotyped behavior and motor functions, respectively. Immunofluorescence labeling was used to detect the co-labeling of virus fluorescence and D1R or D2R. We found that chemogenetic inhibition of D1R- or D2R-containing neurons in the SNpc and dSTR alleviated behavioral stereotypies and motor functions in TS mice. Chemogenetic activation of D1R-containing neurons in the dSTR aggravated behavioral stereotypies and motor functions in vehicle-treated mice, but neither was aggravated in TS mice. In conclusion, chemogenetic inhibition of D1R- or D2R-containing neurons in the SNpc and dSTR alleviated behavioral stereotypies of TS, providing a new treatment target for TS. Moreover, the activation of D1R-containing neurons in the dSTR may contribute to the pathogenesis of TS, which can be chosen as a more precise target for treatment.

scholarly journals The tectonigral pathway regulates appetitive locomotion in predatory hunting in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Meizhu Huang ◽  
Dapeng Li ◽  
Xinyu Cheng ◽  
Qing Pei ◽  
Zhiyong Xie ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Superior Colliculus ◽  
Dopamine Release ◽  
Dorsal Striatum ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Neuronal Circuitry ◽  
Locomotion Speed ◽  
Brain Circuit ◽  
Goal Directed Behavior

AbstractAppetitive locomotion is essential for animals to approach rewards, such as food and prey. The neuronal circuitry controlling appetitive locomotion is unclear. In a goal-directed behavior—predatory hunting, we show an excitatory brain circuit from the superior colliculus (SC) to the substantia nigra pars compacta (SNc) to enhance appetitive locomotion in mice. This tectonigral pathway transmits locomotion-speed signals to dopamine neurons and triggers dopamine release in the dorsal striatum. Synaptic inactivation of this pathway impairs appetitive locomotion but not defensive locomotion. Conversely, activation of this pathway increases the speed and frequency of approach during predatory hunting, an effect that depends on the activities of SNc dopamine neurons. Together, these data reveal that the SC regulates locomotion-speed signals to SNc dopamine neurons to enhance appetitive locomotion in mice.

Differential Modulation by Nicotine of Substantia Nigra Versus Ventral Tegmental Area Dopamine Neurons

2007 ◽  
Vol 98 (6) ◽  
pp. 3388-3396 ◽  
Author(s):  
J. Russel Keath ◽  
Michael P. Iacoviello ◽  
Lindy E. Barrett ◽  
Huibert D. Mansvelder ◽  
Daniel S. McGehee
Keyword(s):  
Substantia Nigra ◽  
Ventral Tegmental Area ◽  
Dorsal Striatum ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Synaptic Modulation ◽  
Afferent Projections ◽  
Ventral Tegmental ◽  
Midbrain Dopamine ◽  
Da Release

Midbrain dopamine (DA) neurons are found in two nuclei, the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). The SNc dopaminergic projections to the dorsal striatum are involved in voluntary movement and habit learning, whereas the VTA projections to the ventral striatum contribute to reward and motivation. Nicotine induces profound DA release from VTA dopamine neurons but substantially less from the SNc. Nicotinic acetylcholine receptor (nAChR) expression differs between these nuclei, but it is unknown whether there are differences in nAChR expression on the afferent projections to these nuclei. Here we have compared the nicotinic modulation of excitatory and inhibitory synaptic inputs to VTA and SNc dopamine neurons. Although nicotine enhances both the excitatory and inhibitory drive to SNc DA cells with response magnitudes similar to those seen in the VTA, the prevalence of these responses in SNc is much lower. We also found that a mixture of nAChR subtypes underlies the synaptic modulation in SNc, further distinguishing this nucleus from the VTA, where α7 nAChRs enhance glutamate inputs and non-α7 receptors enhance GABA inputs. Finally, we compared the nicotine sensitivity of DA neurons in these two nuclei and found larger response magnitudes in VTA relative to SNc. Thus the observed differences in nicotine-induced DA release from VTA and SNc are likely due to differences in nAChR expression on the afferent inputs as well as on the DA neurons themselves. This may explain why nicotine has a greater effect on behaviors associated with the VTA than the SNc.

Dopaminergic D2 receptor is a key player in the substantia nigra pars compacta neuronal activation mediated by REM sleep deprivation

2014 ◽  
Vol 76 ◽  
pp. 118-126 ◽  
Author(s):  
Mariana B. Proença ◽  
Patrícia A. Dombrowski ◽  
Claudio Da Cunha ◽  
Luana Fischer ◽  
Anete C. Ferraz ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Sleep Deprivation ◽  
Rem Sleep ◽  
D2 Receptor ◽  
Substantia Nigra Pars Compacta ◽  
Neuronal Activation ◽  
Rem Sleep Deprivation

scholarly journals Novel self-replicating α-synuclein polymorphs that escape ThT monitoring can spontaneously emerge and acutely spread in neurons

2020 ◽  
Vol 6 (40) ◽  
pp. eabc4364 ◽  
Author(s):  
Francesca De Giorgi ◽  
Florent Laferrière ◽  
Federica Zinghirino ◽  
Emilie Faggiani ◽  
Alons Lends ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Substantia Nigra ◽  
Cortical Neurons ◽  
Amyloid Fibrils ◽  
Dorsal Striatum ◽  
Insular Cortex ◽  
Substantia Nigra Pars Compacta ◽  
Strain Diversity ◽  
Clinical Presentations ◽  
Self Replication

The conformational strain diversity characterizing α-synuclein (α-syn) amyloid fibrils is thought to determine the different clinical presentations of neurodegenerative diseases underpinned by a synucleinopathy. Experimentally, various α-syn fibril polymorphs have been obtained from distinct fibrillization conditions by altering the medium constituents and were selected by amyloid monitoring using the probe thioflavin T (ThT). We report that, concurrent with classical ThT-positive products, fibrillization in saline also gives rise to polymorphs invisible to ThT (τ−). The generation of τ− fibril polymorphs is stochastic and can skew the apparent fibrillization kinetics revealed by ThT. Their emergence has thus been ignored so far or mistaken for fibrillization inhibitions/failures. They present a yet undescribed atomic organization and show an exacerbated propensity toward self-replication in cortical neurons, and in living mice, their injection into the substantia nigra pars compacta triggers a synucleinopathy that spreads toward the dorsal striatum, the nucleus accumbens, and the insular cortex.

scholarly journals Retrograde labeling illuminates distinct topographical organization of D1 and D2 receptor-positive neurons in the prefrontal cortex of mice

2020 ◽  
Author(s):  
Sara M. Green ◽  
Sanya Nathani ◽  
Joseph Zimmerman ◽  
David Fireman ◽  
Nikhil M. Urs
Keyword(s):  
Prefrontal Cortex ◽  
Dopamine Receptor ◽  
Pyramidal Neurons ◽  
D2 Receptor ◽  
Dorsal Striatum ◽  
Behavioral Flexibility ◽  
Substantia Nigra Pars Compacta ◽  
Projection Neurons ◽  
D1 And D2 Receptors ◽  
Topographical Organization

ABSTRACTThe cortex plays an important role in regulating motivation and cognition, and does so by regulating multiple subcortical brain circuits. Glutamatergic pyramidal neurons in the prefrontal cortex (PFC) are topographically organized in different subregions such as the prelimbic, infralimbic and orbitofrontal, and project to topographically-organized subcortical target regions. Dopamine D1 and D2 receptors are expressed on glutamatergic pyramidal neurons in the PFC. However, it is unclear whether D1 and D2 receptor-expressing pyramidal neurons in the PFC are also topographically organized. We used a retrograde adeno-associated virus (AAVRG)-based approach to illuminate the topographical organization of D1 and D2 receptor-expressing neurons, projecting to distinct striatal and midbrain subregions. Our experiments reveal that AAVRG injection in the nucleus accumbens (NAcc) or dorsal striatum (dSTR) of D1Cre mice labeled distinct neuronal subpopulations in medial orbitofrontal or prelimbic PFC, respectively. However, AAVRG injection in NAcc or dSTR of D2Cre mice labeled medial orbitofrontal, but not medial prelimbic PFC, respectively. Additionally, D2R+ but not D1R+ PFC neurons were labeled upon injection of AAVRG in substantia nigra pars compacta (SNpc). Thus, our data are the first to highlight a unique dopamine receptor-specific topographical pattern in the PFC, which could have profound implications for corticostriatal signaling in the basal ganglia.SIGNIFICANCE STATEMENTCorticostriatal connections play an important role in regulating goal-directed and habitual behavior, and neuromodulators such as cortical dopamine play an important role in behavioral flexibility. Dopamine receptor expressing D1R+ and D2R+ projection neurons in the cortex mediate the effects of cortical dopamine, but whether these neurons are anatomically organized in a manner that would explain how these neurons mediate these complex effects, is not clear. Our results show a distinct topographical organization of D1R+ and D2R+ PFC pyramidal neurons that project to distinct striatal and midbrain subregions. These results suggest that effects of cortical dopamine are mediated by anatomically localized distinct receptor- and target-defined subcircuits.

scholarly journals Dopamine receptor 1 neurons in the dorsal striatum regulate food anticipatory circadian activity rhythms in mice

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Christian M Gallardo ◽  
Martin Darvas ◽  
Mia Oviatt ◽  
Chris H Chang ◽  
Mateusz Michalik ◽  
...  
Keyword(s):  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dorsal Striatum ◽  
D1 Receptor ◽  
Circadian Oscillators ◽  
Food Anticipatory Activity ◽  
Dopamine Signaling ◽  
Anticipatory Activity ◽  
Dopamine Receptor 1 ◽  
Deficient Mice

Daily rhythms of food anticipatory activity (FAA) are regulated independently of the suprachiasmatic nucleus, which mediates entrainment of rhythms to light, but the neural circuits that establish FAA remain elusive. In this study, we show that mice lacking the dopamine D1 receptor (D1R KO mice) manifest greatly reduced FAA, whereas mice lacking the dopamine D2 receptor have normal FAA. To determine where dopamine exerts its effect, we limited expression of dopamine signaling to the dorsal striatum of dopamine-deficient mice; these mice developed FAA. Within the dorsal striatum, the daily rhythm of clock gene period2 expression was markedly suppressed in D1R KO mice. Pharmacological activation of D1R at the same time daily was sufficient to establish anticipatory activity in wild-type mice. These results demonstrate that dopamine signaling to D1R-expressing neurons in the dorsal striatum plays an important role in manifestation of FAA, possibly by synchronizing circadian oscillators that modulate motivational processes and behavioral output.

scholarly journals Nigral dopamine loss induces a global upregulation of presynaptic dopamine D1 receptor facilitation of the striatonigral GABAergic output

2015 ◽  
Vol 113 (6) ◽  
pp. 1697-1711 ◽  
Author(s):  
Shengyuan Ding ◽  
Li Li ◽  
Fu-Ming Zhou
Keyword(s):  
Transcription Factor ◽  
Substantia Nigra ◽  
Ventral Tegmental Area ◽  
Axon Terminal ◽  
Ventral Striatum ◽  
Dorsal Striatum ◽  
D1 Receptor ◽  
D1 Receptors ◽  
Axon Terminals ◽  
Axon Loss

In Parkinson's disease (PD), the dopamine (DA) neuron loss in the substantia nigra and the DA axon loss in the dorsal striatum are severe, but DA neurons in the ventral tegmental area and DA axons in middle and ventral striatal subregions are less affected. Severe DA loss leads to DA receptor supersensitivity, but it was not known whether the supersensitivity of the DA D1 receptors (D1Rs) on the striatonigral axon terminal is determined by the severe striatal or nigral DA loss. This question is important because these two possibilities affect the extent of the striatonigral terminals with supersensitive D1Rs and hence the strength of the direct pathway output. Here we have investigated this question in the transcription factor Pitx3 mutant mice that have a PD-like DA loss pattern. We found that the presynaptic D1R function was upregulated globally: the D1R-mediated facilitation was equally enhanced for the striatonigral GABA output originated in the dorsal striatum where the DA loss is severe and the somatic D1Rs are supersensitive, and for the striatonigral GABA output originated in the middle and ventral striatum where the DA loss is moderate and the somatic D1Rs are not supersensitive. These results suggest that severe nigral DA loss is sufficient to induce functional upregulation of the D1Rs on striatonigral axon terminals. Consequently, in PD, the globally enhanced D1Rs on striatonigral axon terminals originated in broad striatal subregions may strongly enhance the striatonigral GABA output upon D1R stimulation, potentially contributing to D1R agonism's profound motor-stimulating effects.

scholarly journals Subcellular Receptor Localization in the Substantia Nigra in a Superecliptic pHlourin-Tagged D2 Receptor Knockin Mouse

2021 ◽  
Author(s):  
Mason Trinkle ◽  
Jospeph J. Lebowitz ◽  
Brooks Robinson ◽  
Judith Joyce Balcita-Pedicino ◽  
Savas Hetelekides ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Fluorescent Protein ◽  
D2 Receptor ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Membrane Structures ◽  
Gold Particles ◽  
Receptor Localization ◽  
Dendritic Membrane ◽  
Green Fluorescent

Abstract Dopamine neurons use autoregulation for appropriate modulation of goal-directed behaviors, and yet the mechanisms for D2 receptor (D2R)-mediated autoregulation are not fully understood. Electrophysiology suggests close proximity between dopamine release and receipt, but actual dendro-dendritic synapses are rare. This ultrastructural study used transgenic mice with a knockin of superecliptic green fluorescent protein (SEP) on the D2R (SEP-D2R) to determine how often autoreceptors are localized at directly apposed dendrites in the substantia nigra pars compacta (SNc). Silver-enhanced immunogold labeling for SEP-D2R was observed within dendrites, axon varicosities, astrocytes, and soma. Although most gold particles were intracellular, 28% of SEP-D2R gold was irregularly distributed along the plasma membrane. Structures immediately adjacent to dendritic membrane gold particles were axons (40%), astrocytes (19%), and other dendrites (7%), with the remaining structures unidentified in single sections. Known limitations in antibody penetration suggest the actual incidence of D2R localization at apposed dendrites is probably greater than 7%. Nevertheless, these results indicate that intercellular dopamine communication in the SNc is primarily extrasynaptic. The thin astrocytic processes often seen separating adjacent dendrites may provide channels along which transmitter diffuses to access dendritic D2Rs. Expression of D2Rs by the astrocytes themselves suggests they may participate in dopamine autoregulation. A novel finding of SEP-D2R on the axon initial segments (AISs) of SNc neurons was confirmed by immunofluorescence to involve dopamine cells. While some of this may represent axonal trafficking, membrane D2Rs might serve an autoregulatory function at the AIS yet to be physiologically characterized for dopamine neurons.

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