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    Home > Active Ingredient News > Study of Nervous System > Depression and pain altogether "another city", Professor Zhang Zhi reveals the different neural circuits of different types of pain

    Depression and pain altogether "another city", Professor Zhang Zhi reveals the different neural circuits of different types of pain

    • Last Update: 2021-03-22
    • Source: Internet
    • Author: User
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    Chronic pain and depression are common clinically, and these patients are more difficult to treat.

    Depressive symptoms can lead to prolonged and deepened pain, which creates a vicious circle between pain and depressive symptoms.

    There may be a common pathogenesis behind the high comorbidity rate between these two diseases.

    However, it should also be noted that the neural circuit mechanisms of chronic pain caused by tissue damage and negative emotions (depression) may not be the same.

    On March 8, 2021, the joint research team of Zhang Zhi, Li Juan, and Jin Yan of the Department of Life Sciences and Medicine of the University of Science and Technology of China published an article in the journal Nature Neuroscience, revealing that the different nuclei of the thalamus regulate pain in depression and tissue damage.
    Neural circuit.

    The thalamus, amygdala, prefrontal cortex, and anterior cingulate cortex (ACC) are important brain areas in the pathogenesis of pain, and these brain areas are also involved in the pathogenesis of depression.

    The thalamus is the most important brain area in the pain pathway.
    Both the ascending pathway and the descending pathway of pain are involved in the regulation of the thalamus.

    The thalamus "shares" neural connections with the primary somatosensory cortex (S1), secondary somatosensory cortex (S2), insular cortex (IC), anterior cingulate cortex (ACC), and frontal cortex (PFC).

    Researchers established a mouse model of inflammatory pain by injecting complete Freund’s adjuvant (CFA) or a mouse model of neuralgia through conserved nerve injury (SNI), and found that in these pain model mice, the dorsal thalamus subnucleus thalamus The neuronal activity of the posterior nucleus (PO) increases, but the sub-nuclei such as the ventroposterolateral nucleus (VPL) of the thalamus, the ventromedial nucleus of the thalamus (VPM), and the parafascicular nucleus (PF) of the thalamus did not show such neurons Increased activity.

    Subsequent immunofluorescence experiments showed that 90% of the neurons activated by the PO nucleus in CFA or SNI pain model mice were glutamatergic neurons, which were subsequently called PO-Glu neurons.

    Electrophysiological experiments further found that the firing activity of these PO-Glu neurons was also enhanced, but the firing activity of PF nucleus neurons did not change.

    The optical fiber calcium imaging system records the changes in the calcium ion concentration of PO-Glu neurons in real time.
    To further confirm the changes in the above-mentioned neuronal activity in pain model mice, the researchers used the optical fiber calcium imaging recording system to dynamically observe the changes in the calcium ion concentration of PO-Glu neurons in real time.
    It was found that the calcium ion concentration of PO-Glu neurons in painful mice increased significantly.

    After the injection of the GABAA receptor agonist MUS quickly inactivated the PO neurons, the pain was significantly relieved.

    On the other hand, chronic restraint stress (CRS) or chronic unpredictable stress (CUS) induces depression-like behavior in mice and also causes pain.

    The classic paroxetine can relieve the pain caused by the above-mentioned chronic stress, but it has no effect on the pain caused by CFA or SNI.

    Immunofluorescence experiments found that chronic stress did not activate a large number of PF and PO nucleus neurons, but electrophysiological experiments found that the discharge activity of PF nucleus glutamatergic neurons (PF-Glu neurons) was weakened after stress.
    The PO-Glu neurons hardly changed.

    These results collectively indicate that different subnuclei of the dorsal thalamus regulate different types of pain emotions: PF-Glu neurons regulate pain in chronic stress-induced depression, and PO-Glu neurons regulate pain in tissue injury states .

    Heavy inventory|Nerve loop tracer virus tool In order to further reveal the neural loop of the above-mentioned subnucleus of the dorsal thalamus, the researchers injected the antegrade tracer virus into the PO and PF regions of CaMK2-Cre, and found that the PO nucleus The glutamatergic neurons of the PF project to the downstream primary sensory cortex (S1), the indefinite zone (ZI), the posterior ventral nucleus of the thalamus, and the insular cortex, while the glutamatergic neurons of the PF nucleus project to the downstream anterior buckle Belt cortex (ACC), secondary somatosensory cortex (S2), indeterminate belt, suprapapillary nucleus.

    The virus reveals the POGlu→S1Glu neural circuit.
    Researchers chose the S1 area as the downstream target area of ​​PO-Glu neurons.
    They further used retrograde tracer to find that PO-Glu neurons and the S1 area have a single synaptic direct connection, which will be referred to below.
    POGlu→S1Glu neural circuit.

    In CFA or SNI pain model mice, the excitability of glutamatergic neurons in the S1 region increased, and the firing activity also increased, but after chronic inhibition of PO-Glu neurons through chemical genetics technology, the above increased effects disappeared.
    In addition, To a certain extent, it can relieve pain.

    These results indicate that the POGlu→S1Glu neural circuit specifically regulates pain under tissue injury.

    The virus reveals the PPFGlu→ACCGABA→Glu neural circuit.
    On the other hand, researchers chose the anterior cingulate cortex (ACC) as the downstream target area of ​​the glutamatergic neurons of the PF nucleus.
    Further virus tracing experiments found that the PF nucleus valley The aminergic neurons project to the Gluergic neurons and GABAergic neurons of ACC, but prefer GABAergic neurons.

    However, there is a local microcircuit in the ACC area, and GABAergic neurons regulate Gluergic neurons.

    In this way, a more complicated neural circuit is formed: PFGlu→ACCGABA→GluCRS or CUS mouse ACC.
    The activity of Gluergic neurons increases and the discharge activity also increases, while the discharge activity of GABAergic neurons decreases.

    After chemical genetics chronically activates Gluergic neurons of PF, the excitability of Gluergic neurons of ACC decreases, and at the same time relieves depression and pain.

    In addition, light activation of PFGlu→ACCGABA→Glu can relieve the pain caused by stress, but it does not relieve depression-like behavior.

    These results indicate that PFGlu→ACCGABA→Glu specifically regulates pain emotions in depression.

    In general, this article reveals that different neural circuits regulate different types of pain, which may be a new strategy for achieving precise treatment of pain in the clinic.

    [References] 1.
    https://doi.
    org/10.
    1038/s41593-021-00811-x The pictures in the article are all from the references
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