Yu-Qiu Zhang

Chronic pain is sustained by complex neuroimmune interplay within the spinal cord, yet how astrocytes constrain immune amplification remains poorly understood. Here we identified Src‐homology 2 domain‐containing protein tyrosine phosphatase‐1 (SHP1; encoded by Ptpn6 ) as a key suppressor of spinal neuroinflammation and nociceptive hypersensitivity. Astrocyte‐specific SHP1 deletion in the spinal dorsal horn induced profound astrocytic morphological changes, increased C‐X‐C motif chemokine ligand 10 (CXCL10) expression, disrupted blood‐brain barrier (BBB) integrity, and facilitated the infiltration of activated T lymphocytes into the spinal parenchyma. These infiltrating T cells promoted microglial activation, enhanced excitatory synaptic transmission, increased the excitability of somatostatin (SOM)‐positive neurons, and ultimately triggered nociceptive hypersensitivity. Mechanistically, T cell recruitment was governed by an SHP1‐dependent regulatory circuit, in which SHP1‐mediated Signal transducer and activator of transcription 1 (STAT1) dephosphorylation restrained Cxcl10 transcription. Blocking the STAT1–CXCL10–CXCR3 signaling axis alleviated T cell infiltration and nociceptive hypersensitivity. Notably, we found that during the development of neuropathic pain, spinal SHP1 expression was significantly downregulated, accompanied by upregulation of CXCL10. Overexpression of SHP1 in astrocytes markedly attenuated astrocyte activation and alleviated mechanical allodynia induced by spared nerve injury (SNI). Collectively, our findings revealed an astrocyte‐defined immune checkpoint that restrains neuroinflammatory escalation and pain persistence, emphasizing SHP1 as a promising therapeutic target for chronic pain.

Astrocytes in the spinal dorsal horn (SDH) exhibit diverse reactive phenotypes under neuropathic conditions, yet the mechanisms driving this diversity and its implications in chronic pain remain unclear. Here, we report that spared nerve injury (SNI) induces marked upregulation of both complement component 3 (C3⁺, A1-like) and S100 calcium-binding protein A10 (S100A10⁺, A2-like) astrocyte subpopulations in the SDH, with elevated microglial cytokines including interleukin-1α, tumor necrosis factor-α, and complement component 1q. Transcriptomic, immunohistochemical, and Western blot analyses reveal co-activation of multiple reactive astrocyte states over a unidirectional shift toward an A1-like phenotype. Fibroblast growth factor 8 (FGF8), a neuroprotective factor via FGFR3, mitigated microglia-induced C3⁺ astrocyte reactivity in vitro and suppressed spinal C3 expression and mechanical allodynia following intrathecal administration in SNI mice. These findings reveal a microglia–astrocyte signaling axis that promotes A1 reactivity and position FGF8 as a promising therapeutic candidate for neuropathic pain by modulating astrocyte heterogeneity.

Cortical descending modulation of sensory processing in the spinal cord has been revealed, the role of cortico-brainstem projections in sensory and motor regulation remains poorly investigated. Here, we identified two previously unappreciated subpopulations in the primary sensorimotor cortex (SM1), which are anatomically and electrophysiologically distinct but functionally similar, projecting to the periaqueductal gray (PAG) and rostroventral medulla (RVM), respectively. Postsynaptic PAG glutamatergic neurons then project to the noradrenergic (NA) neurons in the locus coeruleus (LC) and 5-HT neurons in the RVM to drive spinal NA and 5-HT anti-nociception, while RVM enkephalinergic neurons that receive SM1 projections directly drive spinal opioid analgesia. Intriguingly, silencing these two SM1 subpopulations impair motor behaviors and motor-induced analgesia, but does not affect behavioral responses to cutaneous sensory stimuli. Our findings indicate that these brainstem-projecting SM1 subpopulations are crucial for cortical descending pain modulation, which could be exploited to optimize pain relief approaches.

Optogenetics with high temporal and spatial resolution hold great potentials to replace the traditional drug and electrical stimulation techniques, which calls for optical probing devices with low crosstalk and organic damages. Here, we report a fabrication method of optoelectrical probes for precise modulation of neurons. A linear array of flip-chipped green resonant-cavity μLEDs (RCLED) with an emitting aperture of 50 μm is integrated on Si platform as the stimulation source. Due to the top/bottom Bragg reflectors, the RCLEDs' output light view-angle is narrowed to <90°. The emission wavelength demonstrates remarkable stability under various injection current densities. Under the 50 A/cm2 driving current density, the RCLEDs' output optical density is 100 mW/mm2 and maximum temperature rise is 0.5 °C, both of which exhibit great improvement compared with those of the optical probes on sapphire substrate. Using these green RCLED probes to stimulate Mac-mCherry photosensitive protein, the analgesia and inhibition effects for medium prefrontal cortex GABAergic neurons are verified. This work provides an effective approach to fabricate integrated microscale light sources for precise stimulation and modulation of neurons, which facilitate the study of complex neural functions.

In patients with major depressive disorder (MDD) and animal models of depression, key pathological hallmarks include activation of microglia as well as atrophy and loss of astrocytes. Under certain pathological conditions, microglia can inflict damage to neurons and astrocytes. However, the precise mechanisms underlying how activated microglia induced astrocyte atrophy and loss remain enigmatic. In this study, a depression model induced by chronic social defeat stress (CSDS) is utilized. The results show that CSDS induces significant anxiety‐ and depression‐like behaviors, along with notable astrocyte atrophy and apoptosis, microglial activation, and elevated levels of microglial interleukin‐6 (IL‐6). Subsequent studies demonstrate that IL‐6 released from activated microglia promotes astrocyte apoptosis. Furthermore, the knockdown of the P2X7 receptor (P2X7R) in microglia, which is implicated in the stress response, reduces stress‐induced microglial activation, IL‐6 release, and astrocyte apoptosis. Direct inhibition of microglia by minocycline corroborates these effects. The selective knockdown of IL‐6 in microglia and IL‐6 receptors in astrocytes effectively mitigates depression‐like behaviors and reduces astrocyte atrophy. This study identifies microglial IL‐6 as a key factor that contributes to astrocyte apoptosis and depressive symptoms. Consequently, the IL‐6/IL‐6R pathway has emerged as a promising target for the treatment of depression.

Background/Objectives: Levo-Stepholidine (l-SPD), a compound extracted from Chinese herbs, has the potential to treat psychotic disorders where cognitive deficits are a critical challenge. L-SPD displays a D1R agonism/D2R antagonism pharmacological profile, and its effect on cognitive function is still vague and lacks comprehensive study. Here, we investigated the impact of l-SPD on two core indexes of executive function, working memory and response inhibition, and learning and memory. Methods: Using a delayed alternation T-maze task (DAT), we investigated the impact of l-SPD on working memory, evaluated its effect on response inhibition using the stop-signal task (SST), and assessed the impact on learning and memory using trace fear conditioning in Sprague-Dawley rats. We further evaluated its effects on prefrontal glutamate receptor expression using western blot. Results: Rats receiving l-SPD made fewer errors in the T-maze, exhibited faster stop action in response to the stop signal, and showed longer-lasting memory retention. Molecular mechanism investigations reveal that l-SPD upregulates the expression of prefrontal glutamate receptors. These results demonstrate that l-SPD improves executive function and memory. Conclusions: Here, we show the enhancement effect of l-SPD on cognitive function, which provides essential implicants for the treatment of cognitive deficits, which is a critical unmet need in psychiatric care.

Extracellular ATP (eATP) signaling through the P2X7 receptor pathway is widely believed to trigger NLRP3 inflammasome assembly in microglia, potentially contributing to depression. However, the cellular stress responses of microglia to both eATP and stress itself remain largely unexplored. Mitochondria-associated membranes (MAMs) is a platform facilitating calcium transport between the endoplasmic reticulum (ER) and mitochondria, regulating ER stress responses and mitochondrial homeostasis. This study aims to investigate how MAMs influence microglial reaction and their involvement in the development of depression-like symptoms in response to chronic social defeat stress (CSDS). CSDS induced ER stress, MAMs’ modifications, mitochondrial damage, and the formation of the IP3R3-GRP75-VDAC1 complex at the ER-mitochondria interface in hippocampal microglia, all concomitant with depression-like behaviors. Additionally, exposing microglia to eATP to mimic CSDS conditions resulted in analogous outcomes. Furthermore, knocking down GRP75 in BV2 cells impeded ER-mitochondria contact, calcium transfer, ER stress, mitochondrial damage, mitochondrial superoxide production, and NLRP3 inflammasome aggregation induced by eATP. In addition, reduced GRP75 expression in microglia of Cx3cr1^CreER/+Hspa9^f/+ mice lead to reduce depressive behaviors, decreased NLRP3 inflammasome aggregation, and fewer ER-mitochondria contacts in hippocampal microglia during CSDS. Here, we show the role of MAMs, particularly the formation of a tripartite complex involving IP3R3, GRP75, and VDAC1 within MAMs, in facilitating communication between the ER and mitochondria in microglia, thereby contributing to the development of depression-like phenotypes in male mice.

Anxiety and depression are frequently observed in patients suffering from trigeminal neuralgia (TN), but neural circuits and mechanisms underlying this association are poorly understood. Here, we identified a dedicated neural circuit from the ventral hippocampus (vHPC) to the medial prefrontal cortex (mPFC) that mediates TN-related anxiodepression. We found that TN caused an increase in excitatory synaptic transmission from vHPC ^CaMK2A neurons to mPFC inhibitory neurons marked by the expression of corticotropin-releasing hormone (CRH). Activation of CRH ⁺ neurons subsequently led to feed-forward inhibition of layer V pyramidal neurons in the mPFC via activation of the CRH receptor 1 (CRHR1). Inhibition of the vHPC ^CaMK2A -mPFC ^CRH circuit ameliorated TN-induced anxiodepression, whereas activating this pathway sufficiently produced anxiodepressive-like behaviors. Thus, our studies identified a neural pathway driving pain-related anxiodepression and a molecular target for treating pain-related psychiatric disorders.