Dendritic Integration of Sensory Evidence in Perceptual Decision-Making

Perceptual decisions require the accumulation of sensory information to a response criterion. Most accounts of how the brain performs this process of temporal integration have focused on evolving patterns of spiking activity. We report that subthreshold changes in membrane voltage can represent accumulating evidence before a choice. αβ core Kenyon cells (αβc KCs) in the mushroom bodies of fruit flies integrate odor-evoked synaptic inputs to action potential threshold at timescales matching the speed of olfactory discrimination. The forkhead box P transcription factor (FoxP) sets neuronal integration and behavioral decision times by controlling the abundance of the voltage-gated potassium channel Shal (KV4) in αβc KC dendrites. αβc KCs thus tailor, through a particular constellation of biophysical properties, the generic process of synaptic integration to the demands of sequential sampling

Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice

AIMS/HYPOTHESIS: Lysosomal acid lipase (LAL) hydrolyses cholesteryl esters and triacylglycerols (TG) within lysosomes to mobilise NEFA and cholesterol. Since LAL-deficient (Lal (-/-) ) mice suffer from progressive loss of adipose tissue and severe accumulation of lipids in hepatic lysosomes, we hypothesised that LAL deficiency triggers alternative energy pathway(s). METHODS: We studied metabolic adaptations in Lal (-/-) mice. RESULTS: Despite loss of adipose tissue, Lal (-/-) mice show enhanced glucose clearance during insulin and glucose tolerance tests and have increased uptake of [(3)H]2-deoxy-D-glucose into skeletal muscle compared with wild-type mice. In agreement, fasted Lal (-/-) mice exhibit reduced glucose and glycogen levels in skeletal muscle. We observed 84% decreased plasma leptin levels and significantly reduced hepatic ATP, glucose, glycogen and glutamine concentrations in fed Lal (-/-) mice. Markedly reduced hepatic acyl-CoA concentrations decrease the expression of peroxisome proliferator-activated receptor α (PPARα) target genes. However, treatment of Lal (-/-) mice with the PPARα agonist fenofibrate further decreased plasma TG (and hepatic glucose and glycogen) concentrations in Lal (-/-) mice. Depletion of hepatic nuclear factor 4α and forkhead box protein a2 in fasted Lal (-/-) mice might be responsible for reduced expression of microsomal TG transfer protein, defective VLDL synthesis and drastically reduced plasma TG levels. CONCLUSIONS/INTERPRETATION: Our findings indicate that neither activation nor inactivation of PPARα per se but rather the availability of hepatic acyl-CoA concentrations regulates VLDL synthesis and subsequent metabolic adaptations in Lal (-/-) mice. We conclude that decreased plasma VLDL production enhances glucose uptake into skeletal muscle to compensate for the lack of energy supply

Dendritic integration of sensory information in perceptual decision-making

Perceptual decisions require the temporal integration of sensory evidence to a response threshold. How the brain performs this operation is unknown. In fruit flies, expression of the forkhead box P transcription factor (FoxP) in αβ core (αβc) Kenyon cells of the mushroom bodies influences decision times in odour discrimination tasks. Flies with a hypomorphic mutation in the FoxP locus take longer to commit to a choice than wild-type flies, especially in difficult tasks. Using calcium imaging and patch clamp electrophysiology in vivo, I investigate how FoxP shapes the biophysical properties of αβc neurons and link these properties to the flies’ olfactory decision-making behaviour. I find that αβc Kenyon cells integrate individual odour-evoked synaptic inputs to action potential threshold at time scales matching the speed of olfactory discrimination. FoxP, by controlling the abundance of the voltage-gated potassium channel Shal (KV4) in αβc Kenyon cell dendrites, determines the integrative properties of these neurons and dictates decision times. Targeted expression of dominant-negative or functional Shal in αβc Kenyon cells is sufficient to correct or reproduce, respectively, the FoxP mutant phenotype. Subthreshold dynamics in membrane voltage thus have a previously unrecognised influence on temporal aspects of decision-making.</p

Voltage responses of Mi9 neurons to visual stimulation of the bowl-shaped screen.

A Average spatiotemporal receptive field of three Mi9 neurons (top), temporal kernel density estimation at the center of the spatial receptive field (center), and relative location and coordinates of the centers of mass of the three receptive fields on the screen (center inset). (I) Time-averaged spatial receptive field in a time interval from 0 s to 0.1 s. (II) Time-averaged spatial receptive field in a time interval from 0.2 s to 0.6 s. B Average (black) and single-trail (gray) membrane voltage responses of one Mi9 neuron (n = 12 trails) to a 60°-wide horizontal square-wave pattern, moving at four different velocities (15°/s, 30°/s, 60°/s, 120°/s). C Exemplary average membrane voltage responses of one Mi9 neuron (n = 3 trials) to bright and dark edges, moving at four different velocities (15°/s, 30°/s, 60°/s, 120°/s). Traces were aligned relative to the position of the receptive field.</p

Application concepts of the bowl-shaped screen.

A 3D rendering of a tethered walking behavior set-up, which also provides microscopic access to the brain. The field of view of the screen was designed in a way which enables closed loop bar fixation experiments, while recording neuronal activity. B 3D rendering of a tethered walking behavior setup, which creates an immersive virtual world around the fly. The system requires two projectors and allows tracking cameras to be installed at various locations using cut-outs.</p

Technical validation of the operating principle.

A Overview of Lambertian and specular reflectance properties of the screen surface. The blue vectors describe the diffuse, the red vectors the specular reflection component of an entering light ray. Flat angles of incidence cause a reflective cascade on the screen surface. B Raw images of bright rectangular squares displayed at different locations along the elevation. C Luminance profile along the elevation of a glossy (red) and a matte (blue) surface. The matte surface was evaluated with bright squares projected onto different locations along the elevation. In contrast to the matte surface, the uncoated, glossy surface showed a pronounced reflection cascade. D, E Luminance profiles along the azimuth (D) and the elevation (E), measured with a 360° camera (blue). Measurements along the azimuth were validated using an optical power meter (black).</p

Technical validation of spatial and temporal stimulus control.

A 3D view of the fly inside a virtual cube with colored walls. B Input image, an equidistant cylindrical projection of the virtual cube. The entire image is shown in light color, the image displayed on the screen is shown in dark color. C Image from the viewpoint of the projector to be displayed on the bowl-shaped screen. D Captured image of the bowl-shaped screen from the 360° camera in equidistant cylindrical projection, the direct comparison to the dark region in B. E Sinewave gratings moving across the screen at three different velocities captured by a photodiode and resampled to a framerate of 120 Hz. F Spatiotemporal “receptive field” of the photodiode, measured over 8 minutes.</p

Technical validation of spatiotemporal receptive field measurements.

A Equidistant cylindrical projection of the reverse correlation between input white noise and voltage signal of the photodiode. The “receptive fields” are displayed in their original positions. B Reverse correlation after rotation to the distortion-free center of the spherical projection map (left) and detailed views of the respective receptive fields after rotation for direct comparison (right).</p

Behavioural responses to visual stimulation of the bowl-shaped screen.

A View of the tethered flight setup, the bowl-shaped screen and a representation of a virtual cylinder with a height (h) of 54° and a diameter/height (d/h) ratio of 2.3. (I) View from above used to track the wing beat envelope. (II) View from the side used to determine the horizon. B Exemplary open-loop optomotor responses to a cylinder with a height of 36° and a spatial grating period of 30° rotating clockwise (red) or counterclockwise (blue) at a velocity of 60°/s. The gray area indicates the time of stimulation. The black trace corresponds to a stationary grating. C Equirectangular projection of the stimulation field (grating) and visual field of the left (blue) and right (red) eye of the fly under microscopic constraints. The field of view was adapted from reference [20] and inclined by 45° to reflect the position of the fly head under the microscope. The black area is obscured by the fly holder. D Raw image of the screen brightness distribution measured with an 360° camera from the fly’s point of view. The black area is covered by the flat fly holder. E Mean rectified wingbeat amplitude difference in response to rotating virtual cylinders of different heights (n = 6 flies, 50 trails). The gray area indicates stimulation duration, the different shades of red correspond to the respective cylinder heights. F Time-averaged optomotor responses from E at different cylinder heights (n = 6 flies, 50 trails). Red dots, individual flies; solid line, mean; red shading, standard error of the mean (SEM); d/h, diameter/height ratio of the virtual cylinder. The number of stimulated ommatidia was estimated based on reference [20]. G Closed-loop bar fixation experiment. Top: Probability of finding a 15°-wide dark vertical bar at a certain position along the azimuth. Solid line, average probability density; shaded area, standard deviation (n = 6 flies, 54 trials); dashed line, uniform distribution. Bottom: Representative screen image with central bar. H Closed-loop fixation behavior in response to a texture with four dark edges. Top: Average fixation probability (top) relative to the texture (bottom). Solid line, average probability density; shaded area, standard deviation (n = 6 flies, 42 trials); dashed line, uniform distribution. The central luminance of two edges was 67%, that of the other two was 77%; the screen luminance in between edges was 98%.</p

Geometry of the bowl-shaped screen.

A-C Renderings of a virtual projection of a hexagonal grid onto a planar (A), a cylindrical (B), and a bowl-shaped screen (C). The colors correspond to area sizes and are normalized to a standard undistorted hexagon at the center (gray). One hexagon corresponds to the visual space covered by approximately nine ommatidia of Drosophila melanogaster. D Cross-section of the model used to calculate the screen geometry (Eq 3). (I) Spherical photoreceptor arrangement of the fly, assuming a constant inter-ommatidial angle of 5°. (II) Projector designed to produce a uniform illumination and resolution on a planar screen. (III) The shape of the screen and its Lambertian reflection properties guarantee homogeneous spatial luminance distribution across the entire surface. E View of the bowl-shaped screen, the mirrors and the projector. F Projector perspective of the screen with the necessary equidistant azimuthal projection of the pattern in E.</p