SignificanceThe mammalian/mechanistic target of rapamycin (mTOR) kinase resides at the crux of an intracellular signaling network that controls fundamental biological processes. Dysregulation of mTOR signaling is linked to neurological and psychiatric diseases. However, the physiological functions of mTOR signaling in the adult brain are not fully understood. In the current study, we discovered that mTOR in vasoactive intestinal peptide (VIP) neurons plays a key role in regulating neurophysiology in the brain circadian clock and the olfactory system. The conditional mTOR knockout mouse will be a useful model for future investigations of mTOR and/or VIP.

Although circadian and sleep disorders are frequently associated with autism spectrum disorders (ASD), it remains elusive whether clock gene disruption can lead to autistic-like phenotypes in animals. The essential clock gene Bmal1 has been associated with human sociability and its missense mutations are identified in ASD. Here we report that global Bmal1 deletion led to significant social impairments, excessive stereotyped and repetitive behaviors, as well as motor learning disabilities in mice, all of which resemble core behavioral deficits in ASD. Furthermore, aberrant cell density and immature morphology of dendritic spines were identified in the cerebellar Purkinje cells (PCs) of Bmal1 knockout (KO) mice. Electrophysiological recordings uncovered enhanced excitatory and inhibitory synaptic transmission and reduced firing rates in the PCs of Bmal1 KO mice. Differential expression of ASD- and ataxia-associated genes ( Ntng2 , Mfrp , Nr4a2 , Thbs1 , Atxn1 , and Atxn3 ) and dysregulated pathways of translational control, including hyperactivated mammalian target of rapamycin complex 1 (mTORC1) signaling, were identified in the cerebellum of Bmal1 KO mice. Interestingly, the antidiabetic drug metformin reversed mTORC1 hyperactivation and alleviated major behavioral and PC deficits in Bmal1 KO mice. Importantly, conditional Bmal1 deletion only in cerebellar PCs was sufficient to recapitulate autistic-like behavioral and cellular changes akin to those identified in Bmal1 KO mice. Together, these results unveil a previously unidentified role for Bmal1 disruption in cerebellar dysfunction and autistic-like behaviors. Our findings provide experimental evidence supporting a putative role for dysregulation of circadian clock gene expression in the pathogenesis of ASD.

The main objective of the meta-analysis was to investigate whether intratympanic steroid injections in combination with systemic steroids would provide an additional advantage over systemic steroid therapy (SST) alone in patients with idiopathic sudden sensorineural hearing loss (ISSNHL). The results will provide a meaningful suggestion in clinical therapy of ISSNHL. The electronic database search was based on the database in OVID Medline, Embase and PubMed up to December 15, 2015 with the goal of identifying all available observational studies examining the effects of combination therapy and SST in ISSNHL patients. Observational studies that compared the pure tone average (PTA) improvement and recovery rate between combination therapy and SST group in ISSNHL patients were selected. Finally we have identified eight eligible studies that focused on comparing the combination therapy and SST in ISSNHL from designated researches. In the PTA improvement group, seven studies have been analyzed to compare the pooled mean differences between two therapy modalities and subgroups based on initial hearing loss and treatment delay. In the recovery rate group, six studies were calculated for pooled risk ratios and subgroup analysis was also conducted. Through our meta-analysis, we have reached the conclusion that combination therapy exhibited better outcomes in PTA improvement than SST alone, especially in severe-profound initial hearing loss cases. Combination therapy also showed advantages in recovery rate. Whether time of treatment delay would influence the PTA improvement and recovery rate requires further researches.