Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits. The dorsal hippocampus (dHPC), a well-defined region responsible for learning and memory, displays maladaptive plasticity upon injury, which is assumed to underlie pain hypersensitivity and cognitive deficits. However, much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes. Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix (ECM) and decreases ECM rigidity in the dHPC. Despite this, it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits. Laminin, a key element of the ECM, consists of α-, β-, and γ-chains and has been implicated in several pathophysiological processes. Here, we showed that peripheral nerve injury downregulates laminin β1 (LAMB1) in the dHPC. Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction. Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrin β1, leading to decreased Ca²⁺ levels in pyramidal neurons, which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits. In this study, we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits, and reveal a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified hippocampal LAMB1/integrin β1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
Animals ; Laminin/genetics* ; Hippocampus/metabolism* ; Neuralgia/metabolism* ; Cognitive Dysfunction/etiology* ; Male ; Peripheral Nerve Injuries/metabolism* ; Extracellular Matrix/metabolism* ; Integrin beta1/metabolism* ; Pyramidal Cells/metabolism* ; Signal Transduction

Objective:To observe the effects of electroacupuncture(EA)intervention on norepinephrine(NE)andα2A adrenergic receptors(α2A-R)in the dorsal root ganglion(DRG)of mice with spared nerve injury(SNI).Methods:Male C57BL/6 mice were randomly divided into sham surgery group(Sham),model group(SNI),negative control EA group(SNI+NC-EA),and EA group(SNI+EA).Mechanical and thermal stimuli were used to measure the paw withdrawal mechanical threshold(PWMT)and paw withdrawal thermal latency(PWTL).Immunofluorescence staining was used to detect the sprouting of sympathetic nerve fibers and the co-localization of α2A-R with large-diameter sensory neurons in mouse DRG.Enzyme-linked immunosorbent assay(ELISA)kits were used to measure NE levels in mouse serum and DRG,and Western Blot was used to detect tyrosine hydroxylase(TH)and α2A-R expression levels in DRG.Results:After SNI,the PWMT and PWTL were significantly decreased,and after electroacupuncture treatment,PWMT and PWTL were reversed and increased.Immune fluorescence staining showed that sympathetic ganglion sprouting increased in DRG after SNI,and significantly decreased after electroacupuncture;After SNI,NE,α2A-R,and TH in DRG all significantly increased,and their expression decreased after electroacupuncture intervention,but NE in the serum did not change significantly.Conclusion:In the SNI model,electroacupuncture may regulate the sympathetic-sensory coupling by inhibiting the release of NE and the expression of α2A-R in DRG,thereby producing analgesic effects.

Tweety-homolog 1 (Ttyh1) is expressed in neural tissue and has been implicated in the generation of several brain diseases. However, its functional significance in pain processing is not understood. By disrupting the gene encoding Ttyh1, we found a loss of Ttyh1 in nociceptors and their central terminals in Ttyh1-deficient mice, along with a reduction in nociceptor excitability and synaptic transmission at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) in the basal state. More importantly, the peripheral inflammation-evoked nociceptor hyperexcitability and spinal synaptic potentiation recorded in spinal-PAG projection neurons were compromised in Ttyh1-deficient mice. Analysis of the paired-pulse ratio and miniature excitatory postsynaptic currents indicated a role of presynaptic Ttyh1 from spinal nociceptor terminals in the regulation of neurotransmitter release. Interfering with Ttyh1 specifically in nociceptors produces a comparable pain relief. Thus, in this study we demonstrated that Ttyh1 is a critical determinant of acute nociception and pain sensitization caused by peripheral inflammation.

OBJECTIVE To observe the clinical therapeutic effects of the formula capable of resolving turbidity, removing toxin, activating blood circulation and dredging collectrals in improving patients with vascular cognitive impairment of none dementia(VCIND) after stroke.MEHTODS 128 cases with VCIND after stroke were randomly divided into treatment group and control group, with 64 cases in each group.Patients in the treatment group were given compound Changpu Yizhi Decociton warmly both early in the morning and late in the afternoon, one bag per day.While those in the control group were treated with nimodipine, 30mg at a time, three times per day.Both groups received three-month treatment.TCM syndromes, cognitive ability, activity of daily living before and after treatment were evaluated and the levels of homocysteine and acetylcholinesterase were tested to detect the safety index and side effects.RESULTS There experienced an evident improvement of the treatment group in TCM syndrome curative effects and scores, together with obvious increases in the scores of mini-mental state examination(MMSE) and Activity of Daily Living (ADL), decreased scores in ADAS-cog and declined levels in homocysteine and acetylcholinesterase when compared to the control group.The difference was statistically significant(P<0.05).Neither evident abnormalities nor side effects were detected before and after treatment in the test.CONCLUSION Compound Changpu Yizhi Decoction can efficiently improve the TCM syndromes, cognitive function and daily living activity and reduce the levels of homocysteine and acetylcholinesterase of patients with VCIND after stroke.

Objective To study the effect of hyperbaric oxygen (HBO) on the proliferation and differentiation of neural stem cells (NSCs) in rats after middle cerebral artery occlusion (MCAO).Methods Seventy-two adult,male,Sprague-Dawley rats were randomly divided into a control (CON) group,a hyperbaric air (HBA) group,a normobaric oxygen (NBO) group and a hyperbaric oxygen (HBO) group.All were subjected to MCAO.Rats in the CON group did not receive any treatment; those in the other groups were treated with HBA,NBO or HBO daily beginning 2 hours after the operation.Western blotting was applied to detect the expression of nestin,MAP2 and GFAP at 2,3,7 and 14 days after the MCAO.Results The expression of nestin in the HBO group was significantly higher than in the other groups on the 3rd,7th and 14th days.It peaked at day 3 but remained high until day 14.Similarly,expression of MAP2 was significantly higher than in the other groups at least until day 14.GFAP expression was significantly lower than in the other groups.Conclusion HBO can increase neural stem cell proliferation and neuronal differentiation,and inhibit the proliferation of astrocytes.