ErbB4 deficiency exacerbates olfactory dysfunction in an early-stage Alzheimer's disease mouse model.

Olfactory dysfunction is increasingly recognized as an early indicator of Alzheimer's disease (AD). Aberrations in GABAergic function and the excitatory/inhibitory (E/I) balance within the olfactory bulb (OB) have been implicated in olfactory impairment during the initial stages of AD. While the neuregulin 1 (NRG1)/ErbB4 signaling pathway is known to regulate GABAergic transmission in the brain and is associated with various neuropsychiatric disorders, its specific role in early AD-related olfactory impairment remains incompletely understood. This study demonstrated that olfactory dysfunction preceded cognitive decline in young adult APP/PS1 mice and was characterized by reduced levels of NRG1 and ErbB4 in the OB. Further investigation revealed that deletion of ErbB4 in parvalbumin interneurons reduced GABAergic transmission and increased hyperexcitability in mitral and tufted cells (M/Ts) in the OB, thereby accelerating olfactory dysfunction in young adult APP/PS1 mice. Additionally, ErbB4 deficiency was associated with increased accumulation of Aß and BACE1-mediated cleavage of APP, along with enhanced CDK5 signaling in the OB. NRG1 infusion into the OB was found to enhance GABAergic transmission in M/Ts and alleviate olfactory dysfunction in young adult APP/PS1 mice. These findings underscore the critical role of NRG1/ErbB4 signaling in regulating GABAergic transmission and E/I balance within the OB, contributing to olfactory impairment in young adult APP/PS1 mice, and provide novel insights for early intervention strategies in AD. This work has shown that ErbB4 deficiency increased the burden of Aß, impaired GABAergic transmission, and disrupted the E/I balance of mitral and tufted cells (M/Ts) in the OB, ultimately resulting in olfactory dysfunction in young adult APP/PS1 mice. NRG1 could enhance GABAergic transmission, rescue E/I imbalance in M/Ts, and alleviate olfactory dysfunction in young adult APP/PS1 mice. OB: olfactory bulb, E/I: excitation/inhibition, Pr: probability of release, PV: parvalbumin interneurons, Aß: ß-amyloid, GABA: gamma-aminobutyric acid.

The Anticonvulsant and Neuroprotective Effects of Oxysophocarpine on Pilocarpine-Induced Convulsions in Adult Male Mice.

Epilepsy is one of the prevalent and major neurological disorders, and approximately one-third of the individuals with epilepsy experience seizures that do not respond well to available medications. We investigated whether oxysophocarpine (OSC) had anticonvulsant and neuroprotective property in the pilocarpine (PILO)-treated mice. Thirty minutes prior to the PILO injection, the mice were administrated with OSC (20, 40, and 80 mg/kg) once. Seizures and electroencephalography (EEG) were observed, and then the mice were killed for Nissl and Fluoro-jade B (FJB) staining. The oxidative stress was measured at 24 h after convulsion. Western blot analysis was used to examine the expressions of the Bax, Bcl-2, and Caspase-3. In this study, we found that pretreatment with OSC (40, 80 mg/kg) significantly delayed the onset of the first convulsion and status epilepticus (SE) and reduced the incidence of SE and mortality. Analysis of EEG recordings revealed that OSC (40, 80 mg/kg) significantly reduced epileptiform discharges. Furthermore, Nissl and FJB staining showed that OSC (40, 80 mg/kg) attenuated the neuronal cell loss and degeneration in hippocampus. In addition, OSC (40, 80 mg/kg) attenuated the changes in the levels of Malondialdehyde (MDA) and strengthened glutathione peroxidase and catalase activity in the hippocampus. Western blot analysis showed that OSC (40, 80 mg/kg) significantly decreased the expressions of Bax, Caspase-3 and increased the expression of Bcl-2. Collectively, the findings of this study indicated that OSC exerted anticonvulsant and neuroprotective effects on PILO-treated mice. The beneficial effects should encourage further studies to investigate OSC as an adjuvant in epilepsy, both to prevent seizures and to protect neurons in brain.

Anticonvulsant Effect of Swertiamarin Against Pilocarpine-Induced Seizures in Adult Male Mice.

Epilepsy is one of the common and major neurological disorders, approximately a third of the individuals with epilepsy suffer from seizures and not able to successfully respond to available medications. Current study was designed to investigate whether Swertiamarin (Swe) had anticonvulsant activity in the pilocarpine (PILO)-treated mice. Thirty minutes prior to the PILO (280 mg/kg) injection, the mice were administrated with Swe (50, 150, and 450 mg/kg) and valproate sodium (VPA, 200 mg/kg) once. Seizures and electroencephalography (EEG) were observed, and then the mice were killed for Nissl, Fluoro-jade B (FJB) staining. Astrocytic activation was examined in the hippocampus. Western blot analysis was used to examine the expressions of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10). The results indicated that pretreatment with Swe (150, 450 mg/kg) and VPA (200 mg/kg) significantly delayed the onset of the first convulsion and reduced the incidence of status epilepticus and mortality. Analysis of EEG recordings demonstrated that Swe (150, 450 mg/kg) and VPA (200 mg/kg) sharply decreased epileptiform discharges. Furthermore, Nissl and FJB staining revealed that Swe (150, 450 mg/kg) and VPA (200 mg/kg) relieved the neuronal damage. Additionally, Swe (450 mg/kg) dramatically inhibited astrocytic activation. Western blot analysis showed that Swe (450 mg/kg) significantly decreased the expressions of IL-1ß, IL-6, TNF-α and elevated the expression of IL-10. Taken together, these findings revealed that Swe exerted anticonvulsant effects on PILO-treated mice. Further studies are encouraged to investigate these beneficial effects of Swe as an adjuvant in epilepsy.

Causal Relationship Between Post-Traumatic Stress Disorder and Immune Cell Traits: A Mendelian Randomization Study.

INTRODUCTION: Post-traumatic stress disorder (PTSD) is a debilitating psychological disorder that occurs after exposure to catastrophic-level experiences. Although alterations in immune function have been identified in individuals with PTSD, the causal relationship between the two remains unclear. METHODS: To investigate the causal relationship between PTSD and immune function, we conducted the forward and backward two-sample Mendelian randomization (MR) analyses, based on summary-level genome-wide association studies (GWAS) data on PTSD and immune cell traits. RESULTS: For the forward MR analysis, PTSD was found to reduce the levels of CD62L- dendritic cell (DC) (beta = -0.254, FDR = 0.01), CD86+ myeloid DC (beta = -0.238, FDR = 0.014), CD62L- myeloid DC (beta = -0.26, FDR = 0.01), CD62L- CD86+ myeloid DC absolute count (beta = -0.264, FDR = 0.024), and CD62L- CD86+ myeloid DC (beta = -0.328, FDR = 0.002). In contrast, PTSD was observed to increase the level of CD28- CD8dim T-cell absolute count (beta = 0.27, FDR = 0.029). For the backward MR analysis, the odds ratio (OR) for CD33 on CD33dim HLA DR+ CD11b- in relation to PTSD risk was found to be 1.045 (95% CI = 1.021-1.069, FDR = 0.008). The OR for FSC-A on HLA DR+ CD8br was 1.048 (95% CI = 1.018-1.079, FDR = 0.039) and for CCR2 on CD14- CD16+ monocyte was 1.059 (95% CI = 1.027-1.092, FDR = 0.008). No significant pleiotropy was detected in both forward and backward MR analyses. CONCLUSION: The bidirectional MR study shed light on the intricate interplay between immune function and PTSD. The identification of a bidirectional causal relationship between T cells and PTSD opens new avenues for considering innovative approaches to the prevention and early intervention of PTSD.

Amelioration of olfactory dysfunction in a mouse model of Parkinson's disease via enhancing GABAergic signaling.

BACKGROUND: Olfactory dysfunction is among the earliest non-motor symptoms of Parkinson's disease (PD). As the foremost pathological hallmark, α-synuclein initiates the pathology in the olfactory pathway at the early stage of PD, particularly in the olfactory epithelium (OE) and olfactory bulb (OB). However, the local neural microcircuit mechanisms underlying olfactory dysfunction between OE and OB in early PD remain unknown. RESULTS: We observed that odor detection and discrimination were impaired in 6-month-old SNCA-A53T mice, while their motor ability remained unaffected. It was confirmed that α-synuclein increased and accumulated in OB but not in OE. Notably, the hyperactivity of mitral/tufted cells and the excitation/inhibition imbalance in OB were found in 6-month-old SNCA-A53T mice, which was attributed to the impaired GABAergic transmission and aberrant expression of GABA transporter 1 and vesicular GABA transporter in OB. We further showed that tiagabine, a potent and selective GABA reuptake inhibitor, could reverse the impaired olfactory function and GABAergic signaling in OB of SNCA-A53T mice. CONCLUSIONS: Taken together, our findings demonstrate potential synaptic mechanisms of local neural microcircuit underlying olfactory dysfunction at the early stage of PD. These results highlight the critical role of aberrant GABAergic signaling of OB in early diagnosis and provide a potential therapeutic strategy for early-stage PD.

Propagation Methods Decide Root Architecture of Chinese Fir: Evidence from Tissue Culturing, Rooted Cutting and Seed Germination.

The root is the main organ of a plant for absorbing resources and whose spatial distribution characteristics play an important role in the survival of seedlings after afforestation. Chinese fir (Cunninghamia lanceolata) is one of China's most important plantation species. To clarify the effects of propagation methods on root growth and spatial distribution characteristics of Chinese fir trees, sampled trees cultivated by seed germination, tissue culture, and asexual cutting of Chinese fir were taken as the research objects. The root morphology, geometric configuration, and spatial distribution characteristics of different trees were analyzed. The influence of geometric root morphology on its spatial distribution pattern was explored by correlation analysis, and the resource acquisition characteristics reflected by the roots of Chinese fir trees with different propagation methods are discussed. The main results showed that the root mean diameter (1.56 mm, 0.95 mm, and 0.97 mm), root volume (2.98 m3, 10.25 m3, and 4.07 m3), root tip count (397, 522, and 440), main root branch angle (61°, 50° and 32°) and other geometric configurations of Chinese fir under seed germination, tissue culture and rooted cutting respectively, were significantly different, which resulted in different distribution characteristics of roots in space. Chinese fir seed germination had noticeable axial roots, and the growth advantage was obvious in the vertical direction. A fishtail branch structure (TI = 0.87) was constructed. The shallow root distribution of tissue culture and rooted cutting was obvious, and belonged to the fork branch structure (TI = 0.71 and 0.74, respectively). There was a tradeoff in the spatial growth of the root system of Chinese fir trees with different propagation methods to absorb nutrients from heterogeneous soil patches. A negative correlation was present between the root system and root amplitude. There was an opposite spatial growth trend of Chinese fir trees with different propagation methods in the vertical or horizontal direction. In conclusion, selecting suitable propagation methods to cultivate Chinese fir trees is beneficial to root development and the "ideal" configuration formation of resource acquisition to improve the survival rate of Chinese fir afforestation.

A Self-Assembled α-Synuclein Nanoscavenger for Parkinson's Disease.

Although emerging evidence suggests that the pathogenesis of Parkinson's disease (PD) is closely related to the aggregation of alpha-synuclein (α-syn) in the midbrain, the clearance of α-syn remains an unmet clinical need. Here, we develop a simple and efficient strategy for fabricating the α-syn nanoscavenger for PD via a reprecipitation self-assembly procedure. The curcumin analogue-based nanoscavenger (NanoCA) is engineered to be capable of a controlled-release property to stimulate nuclear translocation of the major autophagy regulator, transcription factor EB (TFEB), triggering both autophagy and calcium-dependent exosome secretion for the clearance of α-syn. Pretreatment of NanoCA protects cell lines and primary neurons from MPP+-induced neurotoxicity. More importantly, a rapid arousal intranasal delivery system (RA-IDDS) was designed and applied for the brain-targeted delivery of NanoCA, which affords robust neuroprotection against behavioral deficits and promotes clearance of monomer, oligomer, and aggregates of α-syn in the midbrain of an MPTP mouse model of PD. Our findings provide a clinically translatable therapeutic strategy aimed at neuroprotection and disease modification in PD.

Long-term follow-up of patients treated for psychotic symptoms that persist after stopping illicit drug use.

BACKGROUND: The long-term outcome of patients diagnosed with drug-induced psychotic disorders in China is unknown. AIM: Assess the course of illness and severity of psychiatric symptoms in patients previously admitted to a psychiatric hospital for treatment of psychotic symptoms that were induced by the use of illicit drugs. METHODS: Patients with psychotic symptoms at the time of their first psychiatric admission who had used illicit drugs in the month prior to admission were followed up 13 to 108 months after admission. Patients and coresident family members were interviewed about post-discharge drug use and psychotic symptoms. RESULTS: The 258 identified patients were primarily young, unemployed males whose most common drug of abuse was methamphetamines and who had been abusing drugs for an average of 7 years at the time of admission. Among these patients 189 (73%) were located and reinterviewed; 168 (89%) had restarted illicit drug use and 25 (13%) had required rehospitalization over the follow-up period. In 114 patients (60%) the psychotic symptoms resolved in less than 1 month after stopping the drugs, in 56 (30%) the symptoms persisted for 1 to 6 months, and in 19 (10%) the symptoms persisted for longer than 6 months (in 8 of these the diagnosis had changed to schizophrenia). Compared to the other two groups, patients whose symptoms persisted more than 6 months were more likely to have a family history of mental illness, an earlier age of onset and a longer duration of drug abuse prior to the index admission; they were also more likely to have been re-hospitalized during the follow-up period and to have psychotic symptoms at the time of follow-up. CONCLUSION: Most patients with substance-induced psychotic disorders in our sample had a good long-term prognosis but those who started illegal drug use early, used drugs for prolonged periods, or had a family history of psychiatric illnesses were more likely to develop a chronic psychosis. Further prospective studies are needed to determine the relationship of the neurotoxic effects of illicit drugs and the predisposing characteristics of the individuals in the development of chronic psychosis in persons who use illicit drugs.