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The dorsal raphe (DR) is a heterogeneous nucleus containing dopamine (DA), serotonin (5HT), γ-aminobutyric acid (GABA) and glutamate neurons. Consequently, investigations of DR circuitry require Cre-driver lines that restrict transgene expression to precisely defined cell populations. Here, we present a systematic evaluation of mouse lines targeting neuromodulatory cells in the DR. We find substantial differences in specificity between lines targeting DA neurons, and in penetrance between lines targeting 5HT neurons. Using these tools to map DR circuits, we show that populations of neurochemically distinct DR neurons are arranged in a stereotyped topographical pattern, send divergent projections to amygdala subnuclei, and differ in their presynaptic inputs. Importantly, targeting DR DA neurons using different mouse lines yielded both structural and functional differences in the neural circuits accessed. These results provide a refined model of DR organization and support a comparative, case-by-case evaluation of the suitability of transgenic tools for any experimental application.

In this issue of Nature Neuroscience, Owen et al. show that widely used optogenetic light delivery can heat brain tissue and produce changes in neural activity and behavior in the absence of opsins. How will this finding influence experimental design in the optical age of neuroscience?

Midbrain dopamine (DA) neurons have received significant attention in brain research because of their central role in reward processing and their dysfunction in neuropsychiatric disorders such as Parkinson's disease, drug addiction, depression and schizophrenia. Until recently, it has been thought that DA neurons form a homogeneous population whose primary function is the computation of reward prediction errors. However, through the implementation of viral vector strategies, an unexpected complexity and diversity has been revealed at the anatomical, molecular and functional level. In this review, we discuss recent viral vector approaches that have been leveraged to dissect how different circuits involving distinct DA neuron subpopulations may contribute to the role of DA in reward- and aversion-related behaviors. We focus on studies that have used cell type- and projection-specific optogenetic manipulations, discuss the strengths and limitations of each approach, and critically examine emergent organizational principles that have led to a reclassification of midbrain DA neurons.

INTRODUCTION:While OA literature indicates greater pain is related to less time being physically active, it is not known if time curtailment occurs primarily for moderate intensity activities or for light activities or in both. We examine the cross-sectional association of knee pain with physical activity using data from 1874 Osteoarthritis Initiative participants. METHODS:Knee pain characteristics of constant and intermittent pain were each scored by the Intermittent and Constant Osteoarthritis Pain instrument and categorized into four pain levels (no pain, intermittent pain below and above median level, and constant pain). The relationships between knee pain levels and objectively measured physical activity (average weekly moderate or light intensity minutes) were assessed by quantile regression adjusted for socio-demographics and health factors. RESULTS:Knee pain levels had a strong negative relationship with moderate intensity physical activities (p-value for trend =0.029). Compared to the no pain group, persons with more severe knee pain, particularly those reporting higher intermittent or constant pain spent less time in moderate activity. In contrast, there was no notable trend related to pain with time spent in light intensity activity. These patterns remained when restricted to persons with clinical evidence (symptoms and/or radiographic) of knee OA and among persons not using medications for knee symptoms. CONCLUSION:Greater knee pain levels were strongly related to less moderate intensity activity time, but not time spent in light intensity physical activity. This relationship suggests that light activity may be a more acceptable way to increase physical activity than moderate activity for people with symptomatic knee pain.

Infection by Leishmania (Viannia) panamensis, the predominant etiologic agent for cutaneous leishmaniasis in Colombia, is characterized by a chronic mixed inflammatory response. Current treatment options are plagued by toxicity, lengthy treatment regimens, and growing evidence of drug resistance. Immunotherapy, modulating the immune system to mount a protective response, may provide an alternate therapeutic approach. We investigated the ability of the Toll-like receptor 9 (TLR9) ligand CpG to modulate established disease in the L (V) panamensis mouse model. Treatment of established infection with a high dose (50 μg) of CpG ameliorated disease and lowered parasite burden. Interestingly, immediately after treatment there was a significant increase in transforming growth factor β (TGF-β) and concomitantly an increase in T regulatory cell (Treg) function. Although a general reduction in cell-mediated immune cytokine and chemokine (gamma interferon [IFN-γ], interleukin 10 [IL-10], IL-13, IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-4, and MIP-1α) responses of the treated mice was observed, certain chemokines (RANTES, monocyte chemoattractant protein 1[MCP-1], and IP-10) were increased. Further, in peripheral blood mononuclear cells (PBMCs) from patients with cutaneous leishmaniasis, CpG treatment similarly exhibited a dose-response effect on the production of IFN-γ, IL-17, IL-10, and IL-13, with reductions observed at higher doses. To further understand the underlying mechanisms and cell populations driving the CpG mediated response, we examined the ex vivo dose effects mediated by the TLR9+ cell populations (dendritic cells, macrophages, and B cells) found to accumulate labeled CpG in vivo Notably, B cells altered the production of IL-17, IL-13, and IFN-γ, supporting a role for B cells functioning as antigen-presenting cells (APCs) and/or regulatory cells during infection. Interestingly, B cells have been previously demonstrated as a primary type of APC in patients infected with L (V) panamensis and thus may be useful targets of immunotherapy. Collectively, our results show that CpG-induced immune regulation leads to a dampening of the host immune response and healing in the mouse model, and it may provide an alternate approach to treatment of cutaneous leishmaniasis caused by L (V) panamensis.

Introduction: The factors associated with impaired quality of life in patients with chronic limb-threatening ischemia are not well established. Objective: Check whether there is an association between quality of life and arterial stiffness indexes, pulse wave velocity (PWV) and the augmentation index corrected to 75 beats per minute heart rate (AIx@75). Methods: This is a cross-sectional, observational study, with the participation of 17 patients (65.65 ± 11.79 years) with chronic limb-threatening ischemia defined by the Rutherford classification 4, 5 and 6, and with the ankle-arm index (ABI) < 0.80. The evaluation of vascular parameters and arterial stiffness indeces was performed with the MobilO-Graph ® device that generates the aortic pulse wave from the brachial artery oscillometry. Quality of life was assessed using the questionnaire Vascular quality of life questionaire (VascuQoL-6), short version, developed specifically to evaluate patients with circulatory, arterial or venous involvement. Results: The values of the ITB and the quality of life score were 0.48 ± 0.14 and 15.88 ± 1.03; respectively. Of the 17 patients, 12 had systolic arterial hypertension and sixteen had PWV greater than 10 m / s. No correlations were observed between the quality of life score with AIx @ 75 (p = 0.54 and r = 0.16), PWV (p = 0.332 and r = 0.248) and ABI (p = 0.707 and r = 0.098). Conclusion: The present study demonstrated that patients with chronic limb-threatening ischemia present significant impairment of quality of life without association with arterial stiffness and ABI.