Control of Stress-Induced Persistent Anxiety by an Extra-Amygdala Septohypothalamic Circuit

The extended amygdala has dominated research on the neural circuitry of fear and anxiety, but the septohippocampal axis also plays an important role. The lateral septum (LS) is thought to suppress fear and anxiety through its outputs to the hypothalamus. However, this structure has not yet been dissected using modern tools. The type 2 CRF receptor (Crfr2) marks a subset of LS neurons whose functional connectivity we have investigated using optogenetics. Crfr2^+ cells include GABAergic projection neurons that connect with the anterior hypothalamus. Surprisingly, we find that these LS outputs enhance stress-induced behavioral measures of anxiety. Furthermore, transient activation of Crfr2^+ neurons promotes, while inhibition suppresses, persistent anxious behaviors. LS Crfr2^+ outputs also positively regulate circulating corticosteroid levels. These data identify a subset of LS projection neurons that promote, rather than suppress, stress-induced behavioral and endocrinological dimensions of persistent anxiety states and provide a cellular point of entry to LS circuitry

Advancing global & regional reanalyses

This report outlines the structure of and summarizes the recommendations made at the 5th International Conference on Reanalysis (ICR5), attended by 259 participants from 37 countries, in Rome (Italy), on 13-17 November 2017. It first summarizes the conference structure. Then, the key recommendations of ICR5 are given for the five main conference topics: production; observations (data rescue and preparation); data assimilation methods; quality assurance of reanalysis; and applications in science, services, and policymaking. Lastly, five high-level recommendations are proposed to managing agencies on how best to advance the field of reanalyses, which serves tens of thousands of users, via enhanced research, development, and operations

Enhancer viruses and a transgenic platform for combinatorial cell subclass-specific labeling

The rapid pace of cell type identification by new single-cell analysis methods has not been met with efficient experimental access to the newly discovered types. To enable flexible and efficient access to specific neural populations in the mouse cortex, we collected chromatin accessibility data from individual cells and clustered the single-cell data to identify enhancers specific for cell classes and subclasses. When cloned into adeno-associated viruses (AAVs) and delivered to the brain by retro-orbital injections, these enhancers drive transgene expression in specific cell subclasses in the cortex. We characterize several enhancer viruses in detail to show that they result in labeling of different projection neuron subclasses in mouse cortex, and that one of them can be used to label the homologous projection neuron subclass in human cortical slices. To enable the combinatorial labeling of more than one cell type by enhancer viruses, we developed a three-color Cre-, Flp- and Nigri- recombinase dependent reporter mouse line, Ai213. The delivery of three enhancer viruses driving these recombinases via a single retroorbital injection into a single Ai213 transgenic mouse results in labeling of three different neuronal classes/subclasses in the same brain tissue. This approach combines unprecedented flexibility with specificity for investigation of cell types in the mouse brain and beyond

A randomised controlled trial assessing the use of citalopram, sertraline, fluoxetine and mirtazapine in preventing relapse in primary care patients who are taking long-term maintenance antidepressants (ANTLER : ANTidepressants to prevent reLapse in dEpRession): study protocol for a randomised controlled trial

BACKGROUND: Antidepressants are used both for treating acute episodes and for prophylaxis to prevent future episodes of depression, also called maintenance treatment. This article describes the protocol for a randomised controlled trial (ANTLER: ANTidepressants to prevent reLapse in dEpRession) to investigate the clinical effectiveness and cost-effectiveness in UK primary care of continuing on long-term maintenance antidepressants compared with a placebo in preventing relapse of depression in those who have taken antidepressants for more than 9 months and who are currently well enough to consider stopping maintenance treatment. METHODS/DESIGN: The ANTLER trial is an individually randomised, double-blind, placebo-controlled trial in which participants are randomised to remain on active medication or to take an identical placebo after a tapering period of 2 months. Eligible participants are those who: are between the ages of 18 and 74 years; have had at least two episodes of depression; and have been taking antidepressants for 9 months or more and are currently taking citalopram 20 mg, sertraline 100 mg, fluoxetine 20 mg or mirtazapine 30 mg but are well enough to consider stopping their medication. The participants will be followed up at 6, 12, 26, 39 and 52 weeks. The primary outcome will be the time in weeks to the beginning of the first episode of depression after randomisation. This will be measured using a retrospective version of the Clinical Interview Schedule-Revised administered at 12, 26, 39 and 52 weeks. Secondary outcomes will include depressive and anxiety symptoms, adverse effects, withdrawal symptoms, emotional processing tasks, quality of life and the resources and costs used. We will also perform a cost-effectiveness analysis based on results of the trial. DISCUSSION: The ANTLER trial findings will inform primary care prescribing practice by providing a valid and generalisable estimate of the clinical effectiveness and cost-effectiveness of long-term maintenance treatment with antidepressants in UK primary care. TRIAL REGISTRATION: Controlled Trials ISRCTN Registry, ISRCTN15969819. Registered on 21 September 2015