High frequency deep brain stimulation of the dorsal raphe nucleus prevents methamphetamine priming-induced reinstatement of drug seeking in rats.

Drug addiction represents a multifaceted and recurrent brain disorder that possesses the capability to create persistent and ineradicable pathological memory. Deep brain stimulation (DBS) has shown a therapeutic potential for neuropsychological disorders, while the precise stimulation targets and therapeutic parameters for addiction remain deficient. Among the crucial brain regions implicated in drug addiction, the dorsal raphe nucleus (DRN) has been found to exert an essential role in the manifestation of addiction memory. Thus, we investigated the effects of DRN DBS in the treatment of addiction and whether it might produce side effects by a series of behavioral assessments, including methamphetamine priming-induced reinstatement of drug seeking behaviors, food-induced conditioned place preference (CPP), open field test and elevated plus-maze test, and examined brain activity and connectivity after DBS of DRN. We found that high-frequency DBS of the DRN significantly lowered the CPP scores and the number of active-nosepokes in the methamphetamine-primed CPP test and the self-administration model. Moreover, both high-frequency and sham DBS group rats were able to establish significant food-induced place preference, and no significant difference was observed in the open field test and in the elevated plus-maze test between the two groups. Immunofluorescence staining and functional magnetic resonance imaging revealed that high-frequency DBS of the DRN could alter the activity and functional connectivity of brain regions related to addiction. These results indicate that high-frequency DBS of the DRN effectively inhibits methamphetamine priming-induced relapse and seeking behaviors in rats and provides a new target for the treatment of drug addiction.

The Regulatory Role of miR-107-Cdk6-Rb Pathway in Airway Smooth Muscle Cells in Asthma.

Purpose: Airway remodeling is a significant pathological change of asthma. This study aimed to detect differentially expressed microRNAs in the serum of asthma patients and airway smooth muscle cells (ASMCs) of asthmatic mice, exploring their role in the airway remodeling of asthma. Methods: The differentially expressed microRNAs in the serum of mild and moderate-severe asthma patients compared to healthy subjects were revealed using the "limma" package. Gene Ontology (GO) analysis was used to annotate the functions of microRNA target genes. The relative expressions of miR-107 (miR-107-3p in mice sharing the same sequence) in the primary airway smooth muscle cells (ASMCs) of the asthma mice model were tested by RT-qPCR. Cyclin-dependent kinases 6 (Cdk6), a target gene of miR-107, was predicted by algorithms and validated by dual-luciferase reporter assay and Western blot. The roles of miR-107, Cdk6, and protein Retinoblastoma (Rb) in ASMCs were examined by transwell assay and EDU KIT in vitro. Results: The expression of miR-107 was down-regulated in both mild and moderate-severe asthma patients. Intriguingly, the level of miR-107 was also decreased in ASMCs of the asthma mice model. Up-regulating miR-107 suppressed ASMCs' proliferation by targeting Cdk6 and the phosphorylation level of Rb. Increasing the expression of Cdk6 or suppressing Rb activity abrogated the proliferation inhibition effect of ASMCs induced by miR-107. In addition, miR-107 also inhibits ASMC migration by targeting Cdk6. Conclusion: The expression of miR-107 is down-regulated in serums of asthma patients and ASMCs of asthmatic mice. It plays a critical role in regulating the proliferation and migration of ASMCs via targeting Cdk6.

Hyper-excitability of corticothalamic PT neurons in mPFC promotes irritability in the mouse model of Alzheimer's disease.

Neuropsychiatric symptoms in patients with Alzheimer's disease (AD) are presented as early as the mild cognitive impairment (MCI) stage. However, it remains unclear whether separate neuronal populations encode distinct aspects of the neuropsychiatric symptoms and drive them differently. Here, we report that pyramidal tract (PT) neurons projecting to the thalamus, but not to the pons or medulla, in the medial prefrontal cortex (mPFC) of the mouse model of AD show increased excitability, which is associated with increased irritability and aggressivity. Decreased Kv6.3 in corticothalamic PT neurons contributes to hyper-excitability, which is tightly associated with aggressive behaviors. Overexpression of Kv6.3 not only prevents abnormal excitability of corticothalamic PT neurons in mPFC, but also rescues aggressive behaviors of 3xTg model mice. Our study provides causal evidence for the contribution of corticothalamic PT neurons to irritability in the 3xTg model of AD and reveals circuit mechanisms used by PT neurons to regulate neuropsychiatric symptoms in AD.

Comprehensive analysis of circRNA expression profiles and circRNA-associated competing endogenous RNA networks in the development of mouse thymus.

The thymus plays an irreplaceable role as a primary lymphoid organ. However, the complicate processes of its development and involution are incompletely understood. Accumulating evidence indicates that non-coding RNAs play key roles in the regulation of biological development. At present, the studies of the circRNA profiles and of circRNA-associated competing endogenous RNAs (ceRNAs) in the thymus are still scarce. Here, deep-RNA sequencing was used to study the biological mechanisms underlying the development process (from 2-week-old to 6-week-old) and the recession process (from 6-week-old to 3-month-old) of the mouse thymus. It was found that 196 circRNAs, 233 miRNAs and 3807 mRNAs were significantly dysregulated. The circRNA-associated ceRNA networks were constructed in the mouse thymus, which were mainly involved in early embryonic development and the proliferation and division of T cells. Taken together, these results elucidated the regulatory roles of ceRNAs in the development and involution processes of the mouse thymus.