Dopamine D1 receptor in medial prefrontal cortex mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits.

Trace amine-associated receptor 1 (TAAR1) is an intracellular expressed G-protein-coupled receptor that is widely expressed in major dopaminergic areas and plays a crucial role in modulation of central dopaminergic neurotransmission and function. Pharmacological studies have clarified the roles of dopamine D1 receptor (D1R) in the medial prefrontal cortex (mPFC) in cognitive function and social behaviors, and chronic stress can inhibit D1R expression due to its susceptibility. Recently, we identified TAAR1 in the mPFC as a potential target for treating chronic stress-induced cognitive and social dysfunction, but whether D1R is involved in mediating the effects of TAAR1 agonist remains unclear. Combined genomics and transcriptomic studies revealed downregulation of D1R in the mPFC of TAAR1-/- mice. Molecular dynamics simulation showed that hydrogen bond, salt bridge, and Pi-Pi stacking interactions were formed between TAAR1 and D1R indicating a stable TAAR1-D1R complex structure. Using pharmacological interventions, we found that D1R antagonist disrupted therapeutic effect of TAAR1 partial agonist RO5263397 on stress-related cognitive and social dysfunction. Knockout TAAR1 in D1-type dopamine receptor-expressing neurons reproduced adverse effects of chronic stress, and TAAR1 conditional knockout in the mPFC led to similar deficits, along with downregulation of D1R expression, all of these effects were ameliorated by viral overexpression of D1R in the mPFC, suggesting the functional interaction between TAAR1 and D1R. Collectively, our data elucidate the possible molecular mechanism that D1R in the mPFC mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits.

TAAR1 in dentate gyrus is involved in chronic stress-induced impairments in hippocampal plasticity and cognitive function.

Multiple lines of evidence suggest that the trace amine-associated receptor 1 (TAAR1) holds promise as a potential target for stress-related disorders, such as treating major depressive disorder (MDD). The role of TAAR1 in the regulation of adult neurogenesis is recently supported by transcriptomic data. However, it remains unknown whether TAAR1 in dentate gyrus (DG) mediate chronic stress-induced negative effects on hippocampal plasticity and related behavior in mice. The present study consisted of a series of experiments using RNAscope, genetic approaches, behavioral tests, immunohistochemical staining, Golgi-Cox technique to unravel the effects of TAAR1 on alterations of dentate neuronal plasticity and cognitive function in the chronic social defeat stress model. The mice subjected to chronic defeat stress exhibited a noteworthy decrease in the mRNA level of TAAR1 in DG. Additionally, they exhibited compromised social memory and spatial object recognition memory, as well as impaired proliferation and maturation of adult-born dentate granule cells. Moreover, the selective knockout TAAR1 in DG mostly mimicked the cognitive function deficits and neurogenesis impairment induced by chronic stress. Importantly, the administration of the selective TAAR1 partial agonist RO5263397 during stress exposure attenuated the adverse effects of chronic stress on cognitive function, adult neurogenesis, dendritic arborization, and the synapse number of dentate neurons in DG. In summary, our findings suggest that TAAR1 plays a crucial role in mediating the detrimental effects of chronic stress on hippocampal plasticity and cognition. TAAR1 agonists exhibit therapeutic potential for individuals suffering from cognitive impairments associated with MDD.

The causal involvement of the BDNF-TrkB pathway in dentate gyrus in early-life stress-induced cognitive deficits in male mice.

Cognitive dysfunction is a significant, untreated clinical need in patients with psychiatric disorders, for which preclinical studies are needed to understand the underlying mechanisms and to identify potential therapeutic targets. Early-life stress (ELS) leads to long-lasting deficits of hippocampus-dependent learning and memory in adult mice, which may be associated with the hypofunction of the brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin receptor kinase B (TrkB). In this study, we carried out eight experiments using male mice to examine the causal involvement of the BDNF-TrkB pathway in dentate gyrus (DG) and the therapeutic effects of the TrkB agonist (7,8-DHF) in ELS-induced cognitive deficits. Adopting the limited nesting and bedding material paradigm, we first demonstrated that ELS impaired spatial memory, suppressed BDNF expression and neurogenesis in the DG in adult mice. Downregulating BDNF expression (conditional BDNF knockdown) or inhibition of the TrkB receptor (using its antagonist ANA-12) in the DG mimicked the cognitive deficits of ELS. Acute upregulation of BDNF (exogenous human recombinant BDNF microinjection) levels or activation of TrkB receptor (using its agonist, 7,8-DHF) in the DG restored ELS-induced spatial memory loss. Finally, acute and subchronic systemic administration of 7,8-DHF successfully restored spatial memory loss in stressed mice. Subchronic 7,8-DHF treatment also reversed ELS-induced neurogenesis reduction. Our findings highlight BDNF-TrkB system as the molecular target of ELS-induced spatial memory deficits and provide translational evidence for the intervention at this system in the treatment of cognitive deficits in stress-related psychiatric disorders, such as major depressive disorder.

[Research progress on the immunomodulatory effects and mechanisms of trace amine-associated receptor 1].

Trace amines are endogenous molecules distributed in the central nervous system and peripheral tissues that resemble common biogenic amines in terms of subcellular localization, chemical structure, and metabolism. Trace amine-associated receptor (TAAR) is a kind of evolutionarily conserved G-protein-coupled receptors in vertebrates, in which TAAR1 is a functional regulator of monoamine transmitters such as dopamine and serotonin. TAAR1 is widely considered as a potential therapeutic target for schizophrenia, depression and drug addiction. Moreover, TAAR1 is also expressed in peripheral tissues. The homeostasis imbalance of trace aminergic system can induce over-activation of peripheral immune system and central immune inflammatory response. TAAR1 modulators are becoming potential emerging drugs for the treatment of immune-related illnesses, because they may play a major role in the activation or modulation of immune response.

Vortioxetine attenuates the effects of early-life stress on depression-like behaviors and monoamine transporters in female mice.

Major depressive disorder is a major psychiatric disorder and a leading cause of disability around the world. Females have about twice as high an incidence of depression as males. However, preclinical animal models of depression have seldom investigated the molecular alterations associated with higher depression risk in females. In this study, adopting the early-life stress (ELS) paradigm of limited bedding and nesting material, we found that ELS induced depression-like behaviors only in adult female mice, as evaluated by sucrose preference and tail suspension tests. We then examined the ELS effects on monoamine neurotransmission (transporters for monoamine reuptake and release) in depression-related brain regions in female mice. We found that ELS resulted in widespread changes of the expression levels of these transporters in four brain regions. Moreover, systemic 21-day treatment with vortioxetine, a novel multimodal antidepressant, successfully reversed depression-like behaviors and normalized some molecular changes, including that of the norepinephrine transporter in the medial prefrontal cortex, vesicular monoamine transporter 2 in nucleus accumbens core, and serotonin transporter in amygdala. Collectively, these results provide evidence for the validity of using the limited bedding and nesting material paradigm to investigate sex differences in depression and demonstrate that the region-specific alterations of monoamine neurotransmission may be associated with depression-like behaviors in female mice. This article is part of the special issue on 'Stress, Addiction and Plasticity'.

[Scopolamine and hyoscyamine synthesis in hair roots culture of Datura metel].

OBJECTIVE: To establish the hair roots culture system of Datura metel and study the hair roots growth and biosynthesis of scopolamine and hyoscyamine in hair roots culturing system. METHOD: Direct degermed cotyledon of wild D. metel was infected by Agrobacterium tumefaciens strain C58C1 to obtain hair roots. Growth curves and scopolamine and hyoscyamine biosynthesis curves were determined. The scopolamine and hyoscyamine from different hair roots lines were examined by HPLC. RESULT: Hair roots induction rate reached 70%. After 25 days cultured in 1/2 MS liquid nutrient medium, the hair roots weight, content of scopolamine and hyoscyamine reached maximum, tow high efficient accumulation hyoscyamine and scopolamine hair roots lines M1 and M2 were obtained. The medial accumulation coefficient of hyoscyamine and scopolamine were 2.53 times and 5.37 times compared with the leaves of wild D. metel respectively. CONCLUSION: The established hair roots induction and culture system of D. metel provided a foundation for further obtaining scopolamine and hyoscyamine.

Role of long non-coding RNAs in gene regulation and oncogenesis.

OBJECTIVE: This article aims to review recent studies on the biological characteristics of long non-coding RNAs (lncRNAs), transcription regulation by lncRNAs, and the results of recent studies on the mechanism of action of lncRNAs in tumor development. DATA SOURCES: The data cited in this review were mainly obtained from the articles listed in PubMed and HighWire that were published from January 2002 to June 2010. The search terms were "long non-coding RNA", "gene regulation", and "tumor". STUDY SELECTION: The mechanism of lncRNAs in gene expression regulation, and tumors concerned with lncRNAs and the role of lncRNAs in oncogenesis. RESULTS: lncRNAs play an important role in transcription regulation by controlling chromatin remodeling, transcriptional control, and post-transcriptional controlling. lncRNAs are involved in many kinds of tumors and play key roles as both suppressing and promoting factors. CONCLUSION: lncRNAs could perfectly regulate the balance of gene expression system and play important roles in oncogenic cellular transformation.

[Culture in vitro and plant regeneration of Panax japonicus].

OBJECTIVE: To study the condition of culture in vitro and plant regeneration of Panax japonicus. METHODS: Embryos, stems and leaves of P. japonicus were used as explants, effects of different hormones for callus induction and plant regeneration were studied and optimized. RESULTS: The optimal way to obtain sterile explant for seeds was sterilized in 75% ethyl alcohol for 60 s then 0.1% HgCL2 for 12 min; Stems and leaves were sterilized in 75% ethyl alcohol for 15 s then 5% NaClO for 5 min. Used MS as basic medium, the optimal hormones combination for callus induction of embryos, stems and leaves were MS + 1.5 mg/L NAA + 1.5 mg/L 2, 4-D + 0.1 mg/L KT; MS + 1.5 mg/L NAA + 1.0 mg/L 2,4-D + 0.1 mg/L KT; MS + 1.5 mg/L NAA + 1.0 mg/L 2,4-D + 0.2 mg/L KT respectindy under the illumination. But under the darkness,the optimal callus induction hormones combination for embryos leaves were MS + 1.0 mg/L NAA + 1.5 mg/L 2,4-D +0.2 mg/L KT; 1.5 mg/L NAA + 1.5 mg/L 2,4-D + 0.1 mg/L KT; MS + 1.5 mg/L NAA + 1.0 mg/L 2,4-D + 0.1 mg/L KT respectivety. The optimal medium for germination was MS + 3.0 mg/L 6-BA + 1.0 mg/L GA3. The optimal medium for roots generation was MS + 1.0 mg/L 6-BA + 3.0 mg/L IBA. CONCLUSION: We establish the system of culture in vitro and plant regeneration for P. japonicus.

[Study on the association between severe chronic hepatitis B and HLA-DRB1 gene polymorphism].

OBJECTIVE: To study the association between HLA-DRB1 gene polymorphism and severe chronic hepatitis B. METHODS: 26 patients with severe chronic hepatitis B were investigated for HLA-DRB1 gene polymorphism by polymerase chain reaction-sequence specific primers technique. The results were compared with those from 45 normal healthy people by use of chi2-test of Microsoft SPSS 13.0. RESULTS: The frequency of HLA-DRB1 * 1301/1302 allele in severe chronic hepatitis B group was significantly higher than the frequency in the control group, while the frequencies of HLA-DRB1 * 1201/1202, 1501/1502 allele were not significantly different. CONCLUSION: HLA-DRB1 * 1301,1302 is closely associated with the suseptibility to severe chronic hepatitis B, While HLA-DRB1 * 1201/1202, 1501/1502 have no association with severe chronic hepatitis B.