-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
-
Cosmetic Ingredient
- Water Treatment Chemical
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
Source—Privy Seal
Responsible editor—Wang Sizhen, Fang Yiyi
Editor—Summer Leaf
Dopamine (DA) is a key regulator of mood, and dysfunction of DA signaling has been linked to the pathophysiology of a number of psychiatric disorders, including anxiety disorders [2].
Dopamine regulates neuronal activity by binding to dopamine receptors to coordinate brain function
.
Dopamine D1 receptors (Drd1) and D2 receptors (Drd2) are the two main dopamine receptors
expressed in the brain.
D1 receptor coupled with Gαs activates adenylate cyclase (AC), increasing cyclic adenylate (cAMP) levels; D2 receptors inhibit AC and calcium channels
by conjugating G i/o.
The ventral tegmental area (VTA) of the midbrain limbic brain region is one of the main regions where DA-producing neurons are located [3].
Previous studies have shown that the DA released by VTA DA neurons targets multiple mesocortical limbic brain regions to regulate mood, including the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and amygdala
。 Studies have shown that pyramidal neurons that activate mPFC-expressing D1 receptors produce rapid and durable antidepressant and anxiolytic responses
.
In addition to regulating downstream brain regions, VTA DA neurons can also release DA® locally in VTA [4], however, VTA The function of internal DA signaling in regulating mood remains unclear
.
October 4, 2022, Institute of Brain Sciences, Fudan University/ The team of researchers from the State Key Laboratory of Medical Neurobiology by Xiaolei presented a paper in Molecular Psychiatry "D1 receptor-expressing neurons in ventral tegmental area alleviate mouse anxiety-like behaviors via glutamatergic projection to lateral septum" research paper, revealed The important role and neural circuit mechanism of D1 receptors and D1 neurons in the regulation of anxiety-like behavior in the ventral tegmental area (VTA).
In this paper, the researchers found that pharmacological activation/inhibition of VTA D1 receptor alleviated/aggravated anxiety-like behavior in mice, and knockdown VTA D1 receptor expression produced anxiety-causing effects
。 Through fluorescence in situ hybridization and electrophysiological recording, D1 receptor was found to be functionally expressed
in VTA neurons.
Silencing/activating VTA D1 neurons bidirectionally modulates anxiety-like behavior
in mice.
In addition, knocking down D1 receptors in VTA DA and glutamate neurons boosted anxiety-like states, but the opposite
was true in GABA neurons.
In addition, the authors identified that glutamatergic projection from VTA D1 neurons to the lateral septum nucleus (LS) is primarily responsible for activating the anxiolytic effects
induced by VTA D1 neurons.
Therefore, this study not only characterized the functional expression of D1 receptors in VTA neurons, but also revealed the key role of VTA local DA signaling in the regulation of anxiety-like behavior, and found Role
of VTA-LS glutamatergic neural circuits in alleviating anxiety-like behavior.
1.
Manipulating the D1 receptor of VTA regulates anxiety-like behavior in mice bidirectionally
The researchers first injected a D1 receptor agonist (A68930) and antagonist (SCH23390) into the VTA brain region of male and female mice by cannula administration, and performed a procedure by open-field experiments ( OFT) and the elevated cross maze experiment (EPM) to evaluate the effects
on anxiety-like behavior in mice.
The results showed that the D1 receptor that activated VTA in male and female mice had no effect on movement, and the residence time of the central region and open arm increased, showing anxiolytic-like effects.
The D1 receptor, which inhibits VTA, induces anxiety-like behavior in mice, manifested by reduced
time to explore the central region and open arms.
In addition, D1 receptor expression of VTA is reduced by RNA interference technology (RNAi), qPCR The results showed that VTA Drd1 mRNA expression decreased to about 70%.
To evaluate the effect of reducing the expression of the D1 receptor of VTA neurons on anxiety-like behavior in mice, the results showed that the reduction of the D1 receptor increased the speed of movement in mice and reduced the central region and open arm residence time.
It has been shown that anxiety-like behavior in mice can also be induced (Figures 1-2).
, Mol Psychiatry, 2022)
Figure 2.
RNA interference down-regulates D1 receptor expression of VTA to induce anxiety-like behavior in mice
(Source: Tong Q, et al.
, Mol Psychiatry, 2022).
2.
D1 receptor is functionally expressed in VTA neurons
In addition to DA neurons, VTA also contains GABA and glutamate neurons
.
Previous studies have shown that the composition of neurons (Drd1+) expressing the D1 receptor in VTA includes about 48.
8%.
Th+ neurons, about 24.
4% of Vgat+ neurons and about 43.
1% Vglut2+ neurons
.
VTA DA neurons can jointly release glutamate and GABA, so the authors further analyzed Drd1+ and Th + Colocalization status of neurons with glutamate and GABA neurons
.
The expression of D1 receptors in VTA neurons was studied by fluorescence in situ hybridization (FISH) technology, utilizing Th (tyrosine hydroxylase, magenta).
Drd1 (white), vesicle GABA transporter-Slc32a1 (labeled Vgat, blue-green/ cyan) and vesicle glutamate transporter 2-SLC17a6 (labeled Vglut2, yellow) probes, quantitative analysis of Drd1 and Vgat, respectively Colocalization of Vglut2 and Th
.
It was found that about 68.
1% of Drd1+ and Th+ neurons were Vglu2+, but rarely Vgat+ (about 8.
7%) (Figure 3).
Figure 3.
Functional expression of D1 receptors in VTA neurons
(Source: Tong Q, et al.
, Mol Psychiatry, 2022).
Activation/silence of VTA D1 neurons bidirectionally regulates anxiety-like behavior in mice
D1 neurons activating VTA using optogenetic techniques significantly increased central region time in OFT and open arm time in EPM, reducing anxiety-like behavior
in mice.
Chemogenetic techniques to activate VTA D1 neurons significantly increased the central region time in OFT in mice, while chemogenetic inhibition of VTA D1 neurons significantly reduced mouse presence in OFT Central District time
.
Further viral injection in VTA D1 neurons expressing light chains of tetanus toxin (TetTox, a protease that specifically degrades VAMP2 and inhibits synaptic glutamate transmitter vesicle release, Interrupting neuroelectrical signaling) to block synaptic transmission, it was found that the time in the central region of OFT was significantly reduced, indicating that the D1 neuronal activity of VTA can regulate anxiety-like behavior in mice (Figure 4).
Figure 4 D1 neurons that activate/silence VTA regulate anxiety-like behavior in mice bidirectionally
(Source: Tong Q, et al.
, Mol Psychiatry, 2022).
4.
The role of the D1 receptor of VTA in excitatory and inhibitory neurons
Optogenetic techniques combined with tool mice of different neuron types, DA neurons activating VTA can significantly increase the central region time in OFT in mice, and activating glutamatergic neurons can significantly increase mouse OFT The central zone time in and the open arm time in EPM both alleviate anxiety-like behavior
in mice.
Use RNAi technology to reduce the DA of VTA and D1 receptors on glutamatergic neurons Increased anxiety-like behavior (reduced time to explore the central zone with open arms), while decreased D1 receptors on GABAergic neurons of VTA can Reduces anxiety-like behaviors (central zone time increase) (Figure 5).
Figure 5.
Role of the D1 receptor of VTA in excitatory and inhibitory neurons
(Source: Tong Q, et al.
, Mol Psychiatry, 2022).
5.
VTA-LS glutamate projection reduces anxiety-like behavior in mice
Previous studies have shown VTA neurons projecting to many brain regions, including NAc, mPFC, and lateral septum (LS).
), basolateral amygdala (BLA), ventral hippocampus (vHipp) to regulate emotional behavior
.
This suggests that VTA D1 neurons may target these brain regions to regulate anxiety-like behavior
.
Optogenetic activation of LS axon terminals, increasing the time of mice in the central region in OFT and the time in the open arm in EPM, these results indicate that LS is Potential targets for VTA D1 neurons to relieve anxiety-like behavior
.
Optogenetically activated VTA D1 neurons, and the expression of c-fos in both VTA and LS brain regions increased, indicating that neuronal activity was increased
.
D1 neurons of VTA confirmed in conjunction with electrophysiological recordings activate LS brain regions
by releasing glutamate.
Blocks the NMDA and AMPA receptors of LS by microinjection of AP5 and NBQX through the cannula ( After glutamate receptor), activation of VTA D1 neurons had no effect on the time of the mice in the central region and open arms.
On the other hand, SCH23390 optogenetically activates VTA D1 neurons after inhibiting the D1 receptor of LS There is still a tendency to increase the time that mice are in the central region and the time
that the arm is open in EPM.
Taken together, these results suggest that VTA D1 neurons are responsible for alleviating anxiety-like behaviors by glutamatergic projection to LS (Figure 6).
。
Figure 6.
VTA D1 neuronal glutamatergic projection to LS reduces anxiety-like behavior
in mice (Credit: Tong Q, et al.
, Mol Psychiatry, 2022).
Figure 7 Mode diagram: Mechanism by which the VTA-LS loop regulates anxiety-like behavior in mice
(Source: Tong Q, et al.
, Mol Psychiatry, 2022).
。 This article not only provides a new mechanism of action for the study of local DA signaling and emotion in VTA brain region, but also points out a new intervention direction
for the clinical treatment of anxiety disorders.
Original link: style="margin-bottom: 0px;white-space: normal;text-align: center;background: white;line-height: 1.
6em;">
。 This research was funded and supported
by the National Natural Science Foundation of China, Shanghai Science and Technology Major Project and Zhangjiang Laboratory.
Corresponding author bio (swipe up and down to read).
Xiao Lei, Researcher, PI, Institute of Brain Sciences
, Fudan University.
Research interests: Regulatory roles and mechanisms
of neuromodulators in brain function and brain diseases.
The mammalian brain contains millions of neurons that communicate electrochemically to maintain brain function
.
In addition to rapid excitatory and inhibitory neurotransmitters, slow neuromodulators are important for vertebrate behavior, and disorders of the neuromodulator system can lead to neurodegenerative diseases, neurodevelopmental disorders, and mental health disorders, including Parkinson's disease, autism, and depression
.
The long-term goal of Researcher Xiaolei's laboratory is to combine a variety of cutting-edge experimental techniques to study the circuit structure and function
of neuromodulator systems such as oxytocin, vasopressin, and dopamine.
Welcome to scan the code to join Logical Neuroscience Literature Study 2
Group Note Format: Name--Field of Research-Degree/Title/Title/PositionSelected Previous Articles[1] The INT J CANCER-LIANG XIA/LIANG PENG TEAM REVEALED THAT GLIOMA CELL-NEURON SYNAPTIC CONNECTION IS AN IMPORTANT FACTOR AFFECTING THE SPATIAL PATHOGENESIS OF CELL TUMOR
[2] Neurology—Han Liyuan's team systematically assessed the global and regional and national burden of stroke among young adults
【3】 The GLIA-Baek Hyun-Sook/Frank Kirchhoff team found that a group of OPCs did not express Olig2, and that acute brain injury and learning activities promoted the formation of this group of cells
【4】 Protein Sci—Wang Shuyu's team reported that Bayesian binding to graph neural networks predicted the effect of mutations on protein stability
【5】 Dev Cell—Tian Ye's team found that the GPCR signaling pathway coordinates the body's mitochondrial stress response in a pair of sensory neurons
【6】 J Neurol—melanin-sensitive magnetic resonance imaging studies reveal blue spot degeneration and cerebellar volume changes in patients with essential tremor
[7] eLife-Wang Liping group found that causal inference is neural computing in the frontal parietal loop of macaques
【8】 Nat Commun-Yingjie Zhu's team revealed a new mechanism by which the brain regulates the nucleus accumbens parallel circuits of reward and aversion
[9] The BMC Med-Dai Fangyin team has made important progress in constructing a Parkinson's syndrome model and evaluating efficacy by using silkworms
[10] Sci Adv-Tai Yanlong's research group proposed an artificial remote sensing tactile device with three-dimensional depth perception
Recommended high-quality scientific research training courses [1] The 10th NIR Training Camp (online: 2022.11.
30~12.
20) [2] The 9th EEG Data Analysis Flight (Training Camp: 2022.
11.
23-12.
24) Welcome to join "Logical Neuroscience" [1] " Logical Neuroscience " Recruitment Editor/Operation Position ( Online Office [2] Talent Recruitment - "Logical Neuroscience" Recruitment Article Interpretation/Writing Position ( Online Part-time, Online Office)
References
COVID-19 Mental Disorders Collaborators.
Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic.
Lancet 2021; 398:1700–12.
2.
Zweifel LS, Fadok JP, Argilli E, Garelick MG, Jones GL, Dickerson TMK, et al.
Activation of dopamine neurons is critical for aversive conditioning and prevention of generalized anxiety.
Nat Neurosci.
2011; 14:620–8.
3.
Missale C, Russel Nash S, Robinson SW, Jaber M, Caron MG.
Dopamine receptors: from structure to function.
Physiol Rev.
1998; 78:189–225.
4.
Hare BD, Duman RS.
Prefrontal cortex circuits in depression and anxiety: contribution of discrete neuronal populations and target regions.
Mol Psychiatry.
2020; 25:2742–58.
End of article
