Carbon dioxide (CO2) elicits an attractive host-seeking response from mosquitos 1–3 yet is innately aversive to Drosophila melanogaster 4, 5 despite being a plentiful byproduct of attractive ...fermenting food sources. Prior studies used walking flies exclusively, yet adults track distant food sources on the wing 6. Here we show that a fly tethered within a magnetic field allowing free rotation about the yaw axis 7 actively seeks a narrow CO2 plume during flight. Genetic disruption of the canonical CO2-sensing olfactory neurons does not alter in-flight attraction to CO2; however, antennal ablation and genetic disruption of the Ir64a acid sensor do. Surprisingly, mutation of the obligate olfactory coreceptor (Orco 8) does not abolish CO2 aversion during walking 4 yet eliminates CO2 tracking in flight. The biogenic amine octopamine regulates critical physiological processes during flight 9–11, and blocking synaptic output from octopamine neurons inverts the valence assigned to CO2 and elicits an aversive response in flight. Combined, our results suggest that a novel Orco-mediated olfactory pathway that gains sensitivity to CO2 in flight via changes in octopamine levels, along with Ir64a, quickly switches the valence of a key environmental stimulus in a behavioral-state-dependent manner.
► During flight, flies actively orient toward a narrow CO2 plume ► CO2 tracking requires both Ir64a and the olfactory coreceptor Orco ► Synaptic output from octopamine neurons mediates CO2 tracking in flight
Several studies now provide evidence of ketamine hydrochloride's ability to produce rapid and robust antidepressant effects in patients with mood and anxiety disorders that were previously resistant ...to treatment. Despite the relatively small sample sizes, lack of longer-term data on efficacy, and limited data on safety provided by these studies, they have led to increased use of ketamine as an off-label treatment for mood and other psychiatric disorders.
This review and consensus statement provides a general overview of the data on the use of ketamine for the treatment of mood disorders and highlights the limitations of the existing knowledge. While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.
The suggestions provided are intended to facilitate clinical decision making and encourage an evidence-based approach to using ketamine in the treatment of psychiatric disorders considering the limited information that is currently available. This article provides information on potentially important issues related to the off-label treatment approach that should be considered to help ensure patient safety.
Pharmacogenomic technology is a developing field with enthusiastic interest and broad application potential. Three large, controlled studies have been published exploring the benefit of ...pharmacogenomically guided antidepressant treatment selection. Though all three studies did not show significant benefit of using this technology, these studies laid the foundation for further research that should address the limitations of this previous research and currently available commercial platforms. Future research needs to include large scale pharmacogenomic trials with GWAS analytics across diverse groups with attention to cost-effectiveness models, particularly for cases of treatment resistance and polypharmacy. The application of results from these large scale pharmacogenomic trials must also include exploring optimal EHR user interface design.
During their trajectories in still air, fruit flies (Drosophila melanogaster) explore their landscape using a series of straight flight paths punctuated by rapid 90 degrees body-saccades 1. Some ...saccades are triggered by visual expansion associated with collision avoidance. Yet many saccades are not triggered by visual cues, but rather appear spontaneously. Our analysis reveals that the control of these visually independent saccades and the flight intervals between them constitute an optimal scale-free active searching strategy. Two characteristics of mathematical optimality that are apparent during free-flight in Drosophila are inter-saccade interval lengths distributed according to an inverse square law, which does not vary across landscape scale, and 90 degrees saccade angles, which increase the likelihood that territory will be revisited and thereby reduce the likelihood that near-by targets will be missed. We also show that searching is intermittent, such that active searching phases randomly alternate with relocation phases. Behaviorally, this intermittency is reflected in frequently occurring short, slow speed inter-saccade intervals randomly alternating with rarer, longer, faster inter-saccade intervals. Searching patterns that scale similarly across orders of magnitude of length (i.e., scale-free) have been revealed in animals as diverse as microzooplankton, bumblebees, albatrosses, and spider monkeys, but these do not appear to be optimised with respect to turning angle, whereas Drosophila free-flight search does. Also, intermittent searching patterns, such as those reported here for Drosophila, have been observed in foragers such as planktivorous fish and ground foraging birds. Our results with freely flying Drosophila may constitute the first reported example of searching behaviour that is both scale-free and intermittent.
Many animals rely on vision to detect objects such as conspecifics, predators, and prey. Hypercomplex cells found in feline cortex and small target motion detectors found in dragonfly and hoverfly ...optic lobes demonstrate robust tuning for small objects, with weak or no response to larger objects or movement of the visual panorama 1–3. However, the relationship among anatomical, molecular, and functional properties of object detection circuitry is not understood. Here we characterize a specialized object detector in Drosophila, the lobula columnar neuron LC11 4. By imaging calcium dynamics with two-photon excitation microscopy, we show that LC11 responds to the omni-directional movement of a small object darker than the background, with little or no responses to static flicker, vertically elongated bars, or panoramic gratings. LC11 dendrites innervate multiple layers of the lobula, and each dendrite spans enough columns to sample 75° of visual space, yet the area that evokes calcium responses is only 20° wide and shows robust responses to a 2.2° object spanning less than half of one facet of the compound eye. The dendrites of neighboring LC11s encode object motion retinotopically, but the axon terminals fuse into a glomerular structure in the central brain where retinotopy is lost. Blocking inhibitory ionic currents abolishes small object sensitivity and facilitates responses to elongated bars and gratings. Our results reveal high-acuity object motion detection in the Drosophila optic lobe.
•LC11 columnar projection neurons form an optic glomerulus in the brain•Dendrites of individual LC11s span many individual columns and overlap each other•LC11 is activated only by the movement of small dark visual objects•Object selectivity and sensitivity are tuned by inhibitory currents
Keleş and Frye report on a novel columnar visual projection neuron in Drosophila. Each LC11 has a large anatomical receptive field innervating many surrounding columns of the lobula. LC11 is excited by the omni-directional movement of objects as small as 2.2° and is inhibited by larger objects or movement of the visual panorama.
Tracking visual objects while maintaining stable gaze is complicated by the different computational requirements for figure-ground discrimination, and the distinct behaviors that these computations ...coordinate.
uses smooth optomotor head and body movements to stabilize gaze, and impulsive saccades to pursue elongated vertical bars. Directionally selective motion detectors T4 and T5 cells provide inputs to large-field neurons in the lobula plate, which control optomotor gaze stabilization behavior. Here, we hypothesized that an anatomically parallel pathway represented by T3 cells, which provide inputs to the lobula, drives bar tracking body saccades. We combined physiological and behavioral experiments to show that T3 neurons respond omnidirectionally to the same visual stimuli that elicit bar tracking saccades, silencing T3 reduced the frequency of tracking saccades, and optogenetic manipulation of T3 acted on the saccade rate in a push-pull manner. Manipulating T3 did not affect smooth optomotor responses to large-field motion. Our results show that parallel neural pathways coordinate smooth gaze stabilization and saccadic bar tracking behavior during flight.
•Pharmacological recommendations for augmentation treatments in depression have been controversial.•Our findings support the use of atypical antipsychotics, lithium, thyroid hormones, modafinil, ...lisdexamfetamine, as effective augmentation agents.•Lithium and thyroid hormones constitute an important augmentation strategy in the general pharmacopeia for TRD despite being overly underutilized.•Pharmacological recommendations should outweigh the potential risk and benefits in the context of side-effect burden and patients’ preference to ameliorate depressive symptoms.
To compare the efficacy and discontinuation of augmentation agents in adult patients with treatment-resistant depression (TRD). We conducted a systematic review and network meta-analyses (NMA) to combine direct and indirect comparisons of augmentation agents.
We included randomized controlled trials comparing one active drug with another or with placebo following a treatment course up to 24 weeks. Nineteen agents were included: stimulants, atypical antipsychotics, thyroid hormones, antidepressants, and mood stabilizers. Data for response/remission and all-cause discontinuation rates were analyzed. We estimated effect-size by relative risk using pairwise and NMA with random-effects model.
A total of 65 studies (N = 12,415) with 19 augmentation agents were included in the NMA. Our findings from the NMA for response rates, compared to placebo, were significant for: liothyronine, nortriptyline, aripiprazole, brexpiprazole, quetiapine, lithium, modafinil, olanzapine (fluoxetine), cariprazine, and lisdexamfetamine. For remission rates, compared to placebo, were significant for: thyroid hormone(T4), aripiprazole, brexpiprazole, risperidone, quetiapine, and olanzapine (fluoxetine). Compared to placebo, ziprasidone, mirtazapine, and cariprazine had statistically significant higher discontinuation rates. Overall, 24% studies were rated as having low risk of bias (RoB), 63% had moderate RoB and 13% had high RoB.
Heterogeneity in TRD definitions, variable trial duration and methodological clinical design of older studies and small number of trials per comparisons.
This NMA suggests a superiority of the regulatory approved adjunctive atypical antipsychotics, thyroid hormones, dopamine compounds (modafinil and lisdexamfetamine) and lithium. Acceptability was lower with ziprasidone, mirtazapine, and cariprazine. Further research and head-to-head studies should be considered to strengthen the best available options for TRD.
Like many visually active animals, including humans, flies generate both smooth and rapid saccadic movements to stabilize their gaze. How rapid body saccades and smooth movement interact for ...simultaneous object pursuit and gaze stabilization is not understood. We directly observed these interactions in magnetically tethered Drosophila free to rotate about the yaw axis. A moving bar elicited sustained bouts of saccades following the bar, with surprisingly little smooth movement. By contrast, a moving panorama elicited robust smooth movement interspersed with occasional optomotor saccades. The amplitude, angular velocity, and torque transients of bar-fixation saccades were finely tuned to the speed of bar motion and were triggered by a threshold in the temporal integral of the bar error angle rather than its absolute retinal position error. Optomotor saccades were tuned to the dynamics of panoramic image motion and were triggered by a threshold in the integral of velocity over time. A hybrid control model based on integrated motion cues simulates saccade trigger and dynamics. We propose a novel algorithm for tuning fixation saccades in flies.
•Under naturalistic conditions, object fixation is enabled by body saccades•Saccade dynamics are finely tuned to object dynamics•Saccades are triggered by the temporal integral of object position•Object fixation and ground stabilization is enabled by parallel controllers
Visual animals generate smooth and saccadic eye movements, which must interact to both stabilize gaze and track salient features. Mongeau and Frye examine magnetically tethered fruit flies and show that they temporally integrate visual cues to trigger and tune object-fixation saccades independently from smooth movement for ground stabilization.
Mycobacterium tuberculosis infection presents across a spectrum in humans, from latent infection to active tuberculosis. Among those with latent tuberculosis, it is now recognized that there is also ...a spectrum of infection and this likely contributes to the variable risk of reactivation tuberculosis. Here, functional imaging with 18F-fluorodeoxygluose positron emission tomography and computed tomography (PET CT) of cynomolgus macaques with latent M. tuberculosis infection was used to characterize the features of reactivation after tumor necrosis factor (TNF) neutralization and determine which imaging characteristics before TNF neutralization distinguish reactivation risk. PET CT was performed on latently infected macaques (n = 26) before and during the course of TNF neutralization and a separate set of latently infected controls (n = 25). Reactivation occurred in 50% of the latently infected animals receiving TNF neutralizing antibody defined as development of at least one new granuloma in adjacent or distant locations including extrapulmonary sites. Increased lung inflammation measured by PET and the presence of extrapulmonary involvement before TNF neutralization predicted reactivation with 92% sensitivity and specificity. To define the biologic features associated with risk of reactivation, we used these PET CT parameters to identify latently infected animals at high risk for reactivation. High risk animals had higher cumulative lung bacterial burden and higher maximum lesional bacterial burdens, and more T cells producing IL-2, IL-10 and IL-17 in lung granulomas as compared to low risk macaques. In total, these data support that risk of reactivation is associated with lung inflammation and higher bacterial burden in macaques with latent Mtb infection.
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