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Background Peripheral nerve injury can cause neuroinflammation and neuromodulation that lead to mitochondrial dysfunction and neuronal apoptosis in the dorsal root ganglion (DRG) and spinal cord, contributing to neuropathic pain and motor dysfunction. Hyperbaric oxygen therapy (HBOT) has been suggested as a potential therapeutic tool for neuropathic pain and nerve injury. However, the specific cellular and molecular mechanism by which HBOT modulates the development of neuropathic pain and motor dysfunction through mitochondrial protection is still unclear. Methods Mechanical and thermal allodynia and motor function were measured in rats following sciatic nerve crush (SNC). The HBO treatment (2.5 ATA) was performed 4 h after SNC and twice daily (12 h intervals) for seven consecutive days. To assess mitochondrial function in the spinal cord (L2–L6), high-resolution respirometry was measured on day 7 using the OROBOROS-O2k. In addition, RT-PCR and Immunohistochemistry were performed at the end of the experiment to assess neuroinflammation, neuromodulation, and apoptosis in the DRG (L3–L6) and spinal cord (L2–L6). Results HBOT during the early phase of the SNC alleviates mechanical and thermal hypersensitivity and motor dysfunction. Moreover, HBOT modulates neuroinflammation, neuromodulation, mitochondrial stress, and apoptosis in the DRG and spinal cord. Thus, we found a significant reduction in the presence of macrophages/microglia and MMP-9 expression, as well as the transcription of pro-inflammatory cytokines (TNFa, IL-6, IL-1b) in the DRG and (IL6) in the spinal cord of the SNC group that was treated with HBOT compared to the untreated group. Notable, the overexpression of the TRPV1 channel, which has a high Ca 2+ permeability, was reduced along with the apoptosis marker (cleaved-Caspase3) and mitochondrial stress marker (TSPO) in the DRG and spinal cord of the HBOT group. Additionally, HBOT prevents the reduction in mitochondrial respiration, including non-phosphorylation state, ATP-linked respiration, and maximal mitochondrial respiration in the spinal cord after SNC. Conclusion Mitochondrial dysfunction in peripheral neuropathic pain was found to be mediated by neuroinflammation and neuromodulation. Strikingly, our findings indicate that HBOT during the critical period of the nerve injury modulates the transition from acute to chronic pain via reducing neuroinflammation and protecting mitochondrial function, consequently preventing neuronal apoptosis in the DRG and spinal cord.

Depression and anxiety disorders are highly prevalent. Selective serotonin reuptake inhibitors (SSRIs) are the current first-line treatment for depression, but they have pronounced limitations. Traditional Chinese medicine can serve as a safe and effective alternative to conventional drugs, particularly since many herbal remedies have already been approved for human use as food additives, making the transition from bench to bedside more efficient. We previously demonstrated that a novel herbal treatment (NHT) induces anxiolytic- and antidepressant-like effects. NHT consists of four herbs: Crataegus pinnatifida (Shan Zha), Triticum aestivum (Fu Xiao Mai), Lilium brownii (Baihe), and the fruit of Ziziphus jujuba (Da Zao). In the current study, we examined the antidepressant-like and anxiolytic-like activities of each individual herb on stressed mice and compared those to the effects of NHT and escitalopram. We show here that Shan Zha is sufficient to produce an anxiolytic and antidepressant-like effect similar to NHT or the escitalopram through activation of 5-HT1A receptor and an elevation in BDNF levels in the hippocampus and Pre-frontal cortex (PFC). Chronic treatment with Shan Zha did not alter serotonin transporter levels in the PFC, as opposed to escitalopram treatment. These results were confirmed in vitro, as none of the herbs blocked SERT activity in Xenopus oocytes. Notably, Shan Zha is sold as a nutritional supplement; thus, its transition to clinical trials can be easier. Once its efficacy and safety are substantiated, Shan Zha may serve as an alternative to conventional antidepressants.

There is a growing interest in ToM performance among individuals with psychiatric disorders. However, the difference and the performance level between different diagnoses are unclear. Here, we compared the ToM abilities of schizophrenia (SZ), schizoaffective (SZaff), and borderline personality individuals (BPD) with healthy individuals. Individuals with SZ (n = 44), SZaff (n = 11), BPD (n = 11), and healthy individuals (n = 18) were recruited from Mazor Mental Health Center. All groups underwent the Reading Mind in the Eyes (RME) and the Faux Pas recognition test (FB) to assess TOM ability and completed empathy and autism questionnaires. The current results show that the three diagnostic groups performed worse in the RME and FB test compared to healthy individuals. However, women with BPD performed significantly better in ToM tasks than women with SZ and SZaff. Individuals with schizophrenia and BPD scored higher on the autism spectrum questionnaire, while all the diagnostic groups scored lower on the empathy quotient scale than healthy individuals. Finally, a positive correlation was found between ToM ability and empathy. Strikingly, our findings challenge the ability to use ToM as a differential clinical diagnostic tool, especially among men, and strengthen the correlation between decreased empathy and impaired ToM.

Anhedonia is defined as a diminished ability to obtain pleasure from otherwise positive stimuli. Anxiety and mood disorders have been previously associated with dysregulation of the reward system, with anhedonia as a core element of major depressive disorder (MDD). The aim of the present study was to investigate whether stress-induced anhedonia could be prevented by treatments with escitalopram or novel herbal treatment (NHT) in an animal model of depression. Unpredictable chronic mild stress (UCMS) was administered for 4 weeks on ICR outbred mice. Following stress exposure, animals were randomly assigned to pharmacological treatment groups (i.e., saline, escitalopram or NHT). Treatments were delivered for 3 weeks. Hedonic tone was examined via ethanol and sucrose preferences. Biological indices pertinent to MDD and anhedonia were assessed: namely, hippocampal brain-derived neurotrophic factor (BDNF) and striatal dopamine receptor D2 (Drd2) mRNA expression levels. The results indicate that the UCMS-induced reductions in ethanol or sucrose preferences were normalized by escitalopram or NHT. This implies a resemblance between sucrose and ethanol in their hedonic-eliciting property. On a neurobiological aspect, UCMS-induced reduction in hippocampal BDNF levels was normalized by escitalopram or NHT, while UCMS-induced reduction in striatal Drd2 mRNA levels was normalized solely by NHT. The results accentuate the association of stress and anhedonia, and pinpoint a distinct effect for NHT on striatal Drd2 expression.

Abstract Background Maternal inflammation during pregnancy is associated with a higher incidence of mental disorders (e.g., schizophrenia and autism) in the offspring. In the central nervous system (CNS), ErbB signaling implicated in a broad range of roles, including neuronal migration, axonal pathfinding, synaptic function, and neuronal plasticity. While there are conceptual paradigms of how prenatal inflammation may affect the developing fetal brain, the precise mechanisms, and the gestation period by which prenatal inflammation contributes to long-term adverse neurobehavioral outcomes remains to be fully elucidated. Methods In our study, we investigate the involvement of the NRG-ErbB signaling pathway in rodent fetal brains four hours following maternal immune activation (MIA) insult at two different gestational days (i.e. early vs late). Furthermore, we test the long-term behavioral alternation of the exposed MIA mice at juvenile and adulthood. Results We demonstrate that MIA at late, but not at early gestation day, altered the expression of NRG1, its receptor ErbB4, and the dopamine D2 receptor four hours post injection of viral or bacterial mimic material. Adult MIA exposed females at late gestation day display hyperlocomotion activity and lack preference to a novel object but no change in juvenile. While working memory alteration observed only in adult male MIA exposed offspring at late gestation day. On the other hand, early gestation infection, but not late, significantly affects male offspring social interaction at juvenile, but not in adulthood. Moreover, juvenile MIA-exposed mice during early, but not late, gestation display decreased motor activity in the open field. Discussion Our results suggest that MIA during late gestation immediately influences the expression levels of the NRG1 and ErbB4 genes and affects long-term behavioral changes at adulthood. These behavioral changes are time related and sex-specific. Thus, immune activation at late stages of the embryonic brain development initiates the activation of the NRG1-ErbB4 pathway and this disturbance might result in cognitive dysfunction in adulthood.

[...]there is currently no reliable biomarker for the early detection of mood disorders. [...]pretreatment with the GLT1 inhibitor DHK significantly alleviated the rapid antidepressant-like effect of ketamine infusion. While Ketamine is a promising candidate for treating depression and anxiety, it has some acute side effects, and more importantly, its chronic use is associated with potentially severe and possibly persistent toxic effects (Short et al., 2018). [...]the search for a safe and side-effect-free treatment is still ongoing. Ten-day treatment alleviated anxiety and depression like-behaviors, attenuated plasma corticosterone concentrations, decreased pro-inflammatory cytokines mRNA levels, and increased hippocampal phosphorylated cAMP response element-binding protein (pCREB) and brain-derived neurotrophic factor (BDNF).

Maternal stress has debilitating implications for both mother and child, including increased risk for anxiety. The current COVID-19 pandemic escalates these phenomena, thus, urging the need to further explore and validate feasible therapeutic options. Unlike the protracted nature of clinical studies, animal models could offer swift evidence. Prominent candidates for treatment are selective serotonin reuptake inhibitors (SSRIs) to the mother, that putatively accommodate maternal functioning, and, thereby, also protect the child. However, SSRIs might have deleterious effects. It is important to assess whether SSRIs and other pharmacotherapies can moderate the transference of anxiety by soothing maternal anxiety and to examine the extent of offspring’s exposure to the drugs via lactation. To our knowledge, the possibility that antenatal stress exacerbates lactation-driven exposure to SSRIs has not been tested yet. Thirty ICR-outbred female mice were exposed to stress during gestation and subsequently administered with either the SSRI, escitalopram, or the novel herbal candidate, shan-zha, during lactation. Upon weaning, both dams’ and pups’ anxiety-like behavior and serum escitalopram levels were assessed. The major findings of the current study show that both agents moderated the antenatal stress-induced transgenerational transference of anxiety by ameliorating dams’ anxiety. Interestingly though, pups’ exposure to escitalopram via lactation was exacerbated by antenatal stress. The latter finding provides a significant insight into the mechanism of lactation-driven exposure to xenobiotics and calls for a further consideration vis-à-vis the administration of other drugs during breastfeeding.

MgSO4 has been used for the past two decades as neuroprotective treatment in a variety of preterm conditions. Despite the putative advantages of MgSO4 as a neuroprotective agent in the preterm brain, the short- and long-term molecular function of MgSO4 as a neuroprotective agent has not been fully elucidated. Neuregulin (NRG1)-ErbB4 signaling plays a critical role in embryonic brain development, in the biology of dopaminergic, GABAergic, and glutamatergic systems. We hypothesize that this pathway may be associated with the neuroprotective role of MgSO4. The current study aims to investigate the ability of MgSO4 to modulate the normal developing expression pattern of selected genes related to the NRG1-ErbB, dopaminergic, GABAergic, and glutamatergic systems. We demonstrate that overall short-term treatment of dam rats with MgSO4 affects the expression of fetal brain NRG1, NRG3, ErbB4, GAD67, tyrosine hydroxylase (TH), dopamine D2 and D1 receptors, GluN1, and GluN2B. More specifically, the administration of MgSO4 alters the expression of NRG-ErbB, GAD67, TH, and D2R at early gestation day 16 (GD16) regardless of the activation of the maternal immune system by lipopolysaccharide (LPS). Our data suggest that MgSO4 treatment may affect the expression of major neuronal systems and pathways mostly at an early gestation day. These changes might be an initial clue (foundation stone) in the molecular mechanism that underlies the beneficial effect of MgSO4 as a neuroprotective agent for the developmental brain.

Lithium has been the standard pharmacological treatment for bipolar disorder over the last 50 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. We characterized the phenotype of mice with a dysfunctional IMPA1 gene ( IMPA1 −/− ) to study the in vivo physiological functions of IMPA1 , in general, and more specifically its potential role as a molecular target in mediating lithium-dependent physiological effects. Homozygote IMPA1 −/− mice died in utero between days 9.5 and 10.5 post coitum (p.c.) demonstrating the importance of IMPA1 in early embryonic development. Intriguingly, the embryonic lethality could be reversed by myo-inositol supplementation via the pregnant mothers. In brains of adult IMPA1 −/− mice, IMPase activity levels were found to be reduced (up to 65% in hippocampus); however, inositol levels were not found to be altered. Behavioral analysis of the IMPA1 −/− mice indicated an increased motor activity in both the open-field test and the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures, the latter supporting the idea that IMPA1 represents a physiologically relevant target for lithium. In conclusion the IMPA1 −/− mouse represents a novel model to study inositol homeostasis, and indicates that genetic inactivation of IMPA1 can mimic some actions of lithium.

Lithium is a potent mood-stabilizing medication in bipolar disorder. Despite 50 years of clinical use, the mechanism of action is unknown. Multiple effects have been attributed to lithium including the uncompetitive inhibition of inositol monophosphatase (IMPase). IMPA2 , one of the genes that encode IMPase, is located in a region with linkage to bipolar disorder. Owing to the role of IMPase in cell signaling and the possibility that this enzyme is a target for mood-stabilizing drugs, we generated IMPA2 −/− mice. Possible involvement of IMPase in complex behaviors related to affective disorders was assessed by monitoring the behavior of the IMPA2 −/− mice in the forced swim test, the tail suspension test (TST), the elevated zero-maze and open field test. It has been described that chronically lithium-treated mice exhibit reduced immobility time in the forced swim test and decreased exploratory behavior. We found increased rearing of IMPA2 −/− mice in the open field, suggesting an increased exploratory behavior. Although immobility time of IMPA2 −/− female but not male mice in the forced swim test was reduced, no difference was found between male and female IMPA2 −/− and IMPA2 +/+ mice in the TST and overall there was no clear effect of the deletion of IMPA2 on depression-like behavior. Frontal cortex IMPase activity and inositol levels in the IMPA2 −/− mice did not differ from IMPA2 +/+ mice, but kidney inositol levels were reduced. In conclusion, phenotypic characterization of the IMPA2 −/− mouse indicates that deleting IMPA2 does not mimic the effects of lithium treatment.