A Nucleus Accumbens Tac1 Neural Circuit Regulates Avoidance Responses to Aversive Stimuli.

Neural circuits that control aversion are essential for motivational regulation and survival in animals. The nucleus accumbens (NAc) plays an important role in predicting aversive events and translating motivations into actions. However, the NAc circuits that mediate aversive behaviors remain elusive. Here, we report that tachykinin precursor 1 (Tac1) neurons in the NAc medial shell regulate avoidance responses to aversive stimuli. We show that NAcTac1 neurons project to the lateral hypothalamic area (LH) and that the NAcTac1→LH pathway contributes to avoidance responses. Moreover, the medial prefrontal cortex (mPFC) sends excitatory inputs to the NAc, and this circuit is involved in the regulation of avoidance responses to aversive stimuli. Overall, our study reveals a discrete NAc Tac1 circuit that senses aversive stimuli and drives avoidance behaviors.

A Novel Netrin-1-Derived Peptide Enhances Protection against Neuronal Death and Mitigates of Intracerebral Hemorrhage in Mice.

It has been reported that Netrin-1 is involved in neuroprotection following injury to the central nervous system. However, the minimal functional domain of Netrin-1 which can preserve the neuroprotection but avoid the major side effects of Netrin remains elusive. Here, we investigated the neuroprotective effect of a peptide E1 derived from Netrin-1's EGF3 domain (residues 407-422). We found that it interacts with deleted colorectal carcinoma (DCC) to activate focal adhesion kinase phosphorylation exhibiting neuroprotection. The administration of the peptide E1 was able to improve functional recovery through reduced apoptosis in an experimental murine model of intracerebral hemorrhage (ICH). In summary, we reveal a functional sequence of Netrin-1 that is involved in the recovery process after ICH and identify a candidate peptide for the treatment of ICH.

Feasibility and effectiveness of unintended pregnancy prevention with low-dose mifepristone combined with misoprostol before expected menstruation.

STUDY QUESTION: What is the efficacy of maintaining or restoring non-pregnant status with low-dose mifepristone combined with misoprostol administered before expected menstruation? SUMMARY ANSWER: Low-dose mifepristone and misoprostol administered at the time of expected menstruation was effective and safe in maintaining or restoring non-pregnant status, with no obvious menstrual disturbance. WHAT IS KNOWN ALREADY: Menstrual regulation involves the medical or mechanical stimulation of uterine sloughing in women with up to 2-3 weeks of menstrual delay. Low-dose mifepristone plus misoprostol is efficacious for termination of ultra-early pregnancy (≤ 35 days of amenorrhoea) with no obvious menstrual disturbance. STUDY DESIGN, SIZE, DURATION: A total of 678 women fulfilled all criteria and were recruited. Seventeen women dropped out after deciding to remain pregnant and 11 others were lost to follow-up. Thus, data from 650 women who completed the procedure were included in analyses. Participants were enrolled at any time during their menstrual cycle and administered medication 1 day before expected menstruation. The end of the study was defined on a per-patient basis as the date of completion of the post-treatment menstrual cycle. The primary outcome was the efficacy of abortion induction (for pregnant women) or menstrual regulation (for non-pregnant women). PARTICIPANTS, SETTING, METHODS: Women with regular menstrual cycles (25-35 days) were voluntarily recruited for this study between February 2012 and December 2014. Serum ß-hCG was measured before mifepristone intake. Mifepristone (50 mg) was administered orally 1 day before expected menstruation and 200 µg misoprostol was administered orally on the day of expected menstruation. Efficacy, disturbance in bleeding patterns in the treatment and post-treatment cycles, satisfaction with the treatment, and subsequent contraception preference were analysed. MAIN RESULTS AND THE ROLE OF CHANCE: Retrospective analysis of serum ß-hCG levels at admission indicated that 23.3% (158/678) of the women were pregnant. The success rate for pregnancy termination was 98.6% (136/138). Two women (1.5%, 2/138) had ongoing pregnancy that was subsequently terminated surgically. The overall bleeding induction rate within 7 days was 98.3% (639/650), with 100% (138/138) in pregnant participants and 97.9% (501/512) in non-pregnant participants. Most pregnant and non-pregnant participants experienced no significant menstrual disturbance during the treatment [96.3% (131/136) versus 97.6% (489/501)] or post-treatment [97.8% (133/136) versus 98.4% (493/501)] menstrual cycle. The general rate of satisfaction with the treatment was 96.7% (618/639). Generally, 36.0% (230/639) of participants preferred to use the regimen as a routine contraception method versus the 64.0% (409/639) who preferred to use it as a remedy for pregnancy prevention after unprotected sex (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Study participants were recruited from a single region; further studies should include participants from multiple centres in different cities and nations. Given the uncertain efficacy of regimen reuse, the assessment of efficacy was based solely on the first treatment administration. Studies with larger samples and long-term follow-up may provide more data on whether repeated use of this regimen hampers its efficacy. WIDER IMPLICATIONS OF THE FINDINGS: Menstrual regulation with low-dose mifepristone and misoprostol at expected menstruation can be efficacious and highly acceptable to maintain or restore non-pregnant status, which may have potential for routine contraception.

Substance P in the medial amygdala regulates aggressive behaviors in male mice.

Behavioral and clinical studies have revealed a critical role of substance P (SP) in aggression; however, the neural circuit mechanisms underlying SP and aggression remain elusive. Here, we show that tachykinin-expressing neurons in the medial amygdala (MeATac1 neurons) are activated during aggressive behaviors in male mice. We identified MeATac1 neurons as a key mediator of aggression and found that MeATac1→ventrolateral part of the ventromedial hypothalamic nucleus (VMHvl) projections are critical to the regulation of aggression. Moreover, SP/neurokinin-1 receptor (NK-1R) signaling in the VMHvl modulates aggressive behaviors in male mice. SP/NK-1R signaling regulates aggression by influencing glutamate transmission in neurons in the VMHvl. In summary, these findings place SP as a key node in aggression circuits.