Nested neural circuits generate distinct acoustic signals during Drosophila courtship.

Many motor control systems generate multiple movements using a common set of muscles. How are premotor circuits able to flexibly generate diverse movement patterns? Here, we characterize the neuronal circuits that drive the distinct courtship songs of Drosophila melanogaster. Male flies vibrate their wings toward females to produce two different song modes-pulse and sine song-which signal species identity and male quality. Using cell-type-specific genetic reagents and the connectome, we provide a cellular and synaptic map of the circuits in the male ventral nerve cord that generate these songs and examine how activating or inhibiting each cell type within these circuits affects the song. Our data reveal that the song circuit is organized into two nested feedforward pathways with extensive reciprocal and feedback connections. The larger network produces pulse song, the more complex and ancestral song form. A subset of this network produces sine song, the simpler and more recent form. Such nested organization may be a common feature of motor control circuits in which evolution has layered increasing flexibility onto a basic movement pattern.

A Multi-regional Network Encoding Heading and Steering Maneuvers in Drosophila.

An internal sense of heading direction is computed from various cues, including steering maneuvers of the animal. Although neurons encoding heading and steering have been found in multiple brain regions, it is unclear whether and how they are organized into neural circuits. Here we show that, in flying Drosophila, heading and turning behaviors are encoded by population dynamics of specific cell types connecting the subregions of the central complex (CX), a brain structure implicated in navigation. Columnar neurons in the fan-shaped body (FB) of the CX exhibit circular dynamics that multiplex information about turning behavior and heading. These dynamics are coordinated with those in the ellipsoid body, another CX subregion containing a heading representation, although only FB neurons flip turn preference depending on the visual environment. Thus, the navigational system spans multiple subregions of the CX, where specific cell types show coordinated but distinct context-dependent dynamics.

A relative frame of reference underlies reversed depth perception in anticorrelated random-dot stereograms.

Binocular disparity is represented by interocular cross-correlation of visual images in the striate and some extrastriate cortices. This correlation-based representation produces reversed depth perception in a binocularly anticorrelated random-dot stereogram (aRDS) when it is accompanied by an adjacent correlated RDS (cRDS). Removal of the cRDS or spatial separation between the aRDS and cRDS abolishes reversed depth perception. However, how an immediate plane supports reversed depth perception is unclear. One possible explanation is that the correlation-based representation generates reversed depth based on the relative disparity between the aRDS and cRDS rather than the absolute disparity of the aRDS. Here, we psychophysically tested this hypothesis. We found that participants perceived reversed depth in an aRDS with zero absolute disparity when it was surrounded by a cRDS with nonzero absolute disparity (i.e., nonzero relative disparity), suggesting a role of relative disparity on the depth reversal. In addition, manipulation of the absolute disparities of the central aRDS and surrounding cRDS caused depth perception to reverse with respect to the depth of the surround. Further, depth reversal persisted after swapping the locations of the two RDSs. A model of relative-disparity encoding explains all these results. We conclude that reversed depth perception in aRDSs occurs in a relative frame of reference and suggest that the visual system contains correlation-based representation that encodes relative disparity.

Parallel encoding of recent visual experience and self-motion during navigation in Drosophila.

Animal navigation requires multiple types of information for decisions on directional heading. We identified neural processing channels that encode multiple cues during navigational decision-making in Drosophila melanogaster. In a flight simulator, we found that flies made directional choices on the basis of the location of a recently presented landmark. This experience-guided navigation was impaired by silencing neurons in the bulb (BU), a region in the central brain. Two-photon calcium imaging during flight revealed that the dorsal part of the BU encodes the location of a recent landmark, whereas the ventral part of the BU tracks self-motion reflecting turns. Photolabeling-based circuit tracing indicated that these functional compartments of the BU constitute adjacent, yet distinct, anatomical pathways that both enter the navigation center. Thus, the fly's navigation system organizes multiple types of information in parallel channels, which may compactly transmit signals without interference for decision-making during flight.

Pooled, but not single-neuron, responses in macaque V4 represent a solution to the stereo correspondence problem.

Binocular disparity is an important cue for depth perception. To correctly represent disparity, neurons must find corresponding visual features between the left- and right-eye images. The visual pathway ascending from V1 to inferior temporal cortex solves the correspondence problem. An intermediate area, V4, has been proposed to be a critical stage in the correspondence process. However, the distinction between V1 and V4 is unclear, because accumulating evidence suggests that the process begins within V1. In this article, we report that the pooled responses in macaque V4, but not responses of individual neurons, represent a solution to the correspondence problem. We recorded single-unit responses of V4 neurons to random-dot stereograms of varying degrees of anticorrelation. To achieve gradual anticorrelation, we reversed the contrast of an increasing proportion of dots as in our previous psychophysical studies, which predicted that the neural correlates of the solution to correspondence problem should gradually eliminate their disparity modulation as the level of anticorrelation increases. Inconsistent with this prediction, the tuning amplitudes of individual V4 neurons quickly decreased to a nonzero baseline with small anticorrelation. By contrast, the shapes of individual tuning curves changed more gradually so that the amplitude of population-pooled responses gradually decreased toward zero over the entire range of graded anticorrelation. We explain these results by combining multiple energy-model subunits. From a comparison with the population-pooled responses in V1, we suggest that disparity representation in V4 is distinctly advanced from that in V1. Population readout of V4 responses provides disparity information consistent with the correspondence solution.

Clinical features and prognostic factors of bone metastases from colorectal cancer.

PURPOSE: To investigate the clinical features and prognoses of patients with diagnosed bone metastases from colorectal cancer (CRC). METHODS: This was a 16-year retrospective study of 32 patients with bone metastases secondary to CRC, who were seen at National Kokura Hospital between 1993 and 2008. The influence of clinical and pathologic variables on survival was assessed by univariate and multivariate analyses. RESULTS: The bone most commonly involved was the spinal column. The mean disease-free interval was 17.6 months and mean survival from the diagnosis of bone metastases was 9.3 months. On univariate analysis, the serum CEA level at the time of diagnosis of bone metastases (p = 0.020) and history of pulmonary metastases (p = 0.013) were significant. On multivariate analysis, a history of bone metastases in the ribs (hazard ratio 3.669, p = 0.025) and a history of pulmonary metastases (hazard ratio 3.854, p = 0.022) significantly affected survival. CONCLUSIONS: It is important to investigate for bone metastases in patients who complain of back pain and lumbago after CRC surgery.

Neural activity in cortical area V4 underlies fine disparity discrimination.

Primates are capable of discriminating depth with remarkable precision using binocular disparity. Neurons in area V4 are selective for relative disparity, which is the crucial visual cue for discrimination of fine disparity. Here, we investigated the contribution of V4 neurons to fine disparity discrimination. Monkeys discriminated whether the center disk of a dynamic random-dot stereogram was in front of or behind its surrounding annulus. We first behaviorally tested the reference frame of the disparity representation used for performing this task. After learning the task with a set of surround disparities, the monkey generalized its responses to untrained surround disparities, indicating that the perceptual decisions were generated from a disparity representation in a relative frame of reference. We then recorded single-unit responses from V4 while the monkeys performed the task. On average, neuronal thresholds were higher than the behavioral thresholds. The most sensitive neurons reached thresholds as low as the psychophysical thresholds. For subthreshold disparities, the monkeys made frequent errors. The variable decisions were predictable from the fluctuation in the neuronal responses. The predictions were based on a decision model in which each V4 neuron transmits the evidence for the disparity it prefers. We finally altered the disparity representation artificially by means of microstimulation to V4. The decisions were systematically biased when microstimulation boosted the V4 responses. The bias was toward the direction predicted from the decision model. We suggest that disparity signals carried by V4 neurons underlie precise discrimination of fine stereoscopic depth.

Role of erythrocytes as a reservoir for ribavirin and relationship with adverse reactions in the early phase of interferon combination therapy for chronic hepatitis C virus infections.

We investigated the relationship between serum ribavirin concentrations and clearance, as well as therapeutic efficacy and adverse reactions, in 97 Japanese patients with chronic hepatitis C virus infections treated with a 6-month course of high-dose alpha2b interferon (6 million units/day) plus ribavirin (600 to 800 mg/day) combination therapy. This randomized trial showed that the saturation of ribavirin uptake after taking ribavirin capsules does not occur within a dose range of 600 to 800 mg/day, which is a standard dosage used clinically in Japan. Serum ribavirin concentrations and clearance did not correlate with sustained virological response rates. Fourteen patients discontinued therapy because of adverse reactions, and sustained virological response rates were significantly reduced by discontinuation of therapy, while dose reduction of ribavirin did not alter the therapeutic effects. Ribavirin concentrations after 1 week and ribavirin clearance were significantly correlated with discontinuation of ribavirin; however, a multiple-regression analysis revealed that only hemoglobin concentration, but not ribavirin clearance, was a significant factor for discontinuation of therapy (odds ratio, 0.514; 95% confidence interval, 0.311 to 0.85; P = 0.0095). It appears that peripheral erythrocytes may act as a reservoir for ribavirin and regulate serum ribavirin levels in the very early phase of treatment.