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Register a new userWhole-brain calcium imaging with cellular resolution in freely behaving C. elegans
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The ability to acquire large-scale recordings of neuronal activity in awake and unrestrained animals poses a major challenge for studying neural coding of animal behavior. We present a new instrument capable of recording intracellular calcium transients from every neuron in the head of a freely behaving C. elegans with cellular resolution while simultaneously recording the animals position, posture and locomotion. We employ spinning-disk confocal microscopy to capture 3D volumetric fluorescent images of neurons expressing the calcium indicator GCaMP6s at 5 head-volumes per second. Two cameras simultaneously monitor the animals position and orientation. Custom software tracks the 3D position of the animals head in real-time and adjusts a motorized stage to keep it within the field of view as the animal roams freely. We observe calcium transients from 78 neurons and correlate this activity with the animals behavior. Across worms, multiple neurons show significant correlations with modes of behavior corresponding to forward, backward, and turning locomotion. By comparing the 3D positions of these neurons with a known atlas, our results are consistent with previous single-neuron studies and demonstrate the existence of new candidate neurons for behavioral circuits.
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A quantitative understanding of how sensory signals are transformed into motor outputs places useful constraints on brain function and helps reveal the brains underlying computations. We investigate how the nematode C. elegans responds to time-varying mechanosensory signals using a high-throughput optogenetic assay and automated behavior quantification. In the prevailing picture of the touch circuit, the animals behavior is determined by which neurons are stimulated and by the stimulus amplitude. In contrast, we find that the behavioral response is tuned to temporal properties of mechanosensory signals, like its integral and derivative, that extend over many seconds. Mechanosensory signals, even in the same neurons, can be tailored to elicit different behavioral responses. Moreover, we find that the animals response also depends on its behavioral context. Most dramatically, the animal ignores all tested mechanosensory stimuli during turns. Finally, we present a linear-nonlinear model that predicts the animals behavioral response to stimulus.
We present a high-throughput optogenetic illumination system capable of simultaneous closed-loop light delivery to specified targets in populations of moving Caenorhabditis elegans. The instrument addresses three technical challenges: it delivers targeted illumination to specified regions of the animals body such as its head or tail; it automatically delivers stimuli triggered upon the animals behavior; and it achieves high throughput by targeting many animals simultaneously. The instrument was used to optogenetically probe the animals behavioral response to competing mechanosensory stimuli in the the anterior and posterior soft touch receptor neurons. Responses to more than $10^4$ stimulus events from a range of anterior-posterior intensity combinations were measured. The animals probability of sprinting forward in response to a mechanosensory stimulus depended on both the anterior and posterior stimulation intensity, while the probability of reversing depended primarily on the posterior stimulation intensity. We also probed the animals response to mechanosensory stimulation during the onset of turning, a relatively rare behavioral event, by delivering stimuli automatically when the animal began to turn. Using this closed-loop approach, over $10^3$ stimulus events were delivered during turning onset at a rate of 9.2 events per worm-hour, a greater than 25-fold increase in throughput compared to previous investigations. These measurements validate with greater statistical power previous findings that turning acts to gate mechanosensory evoked reversals. Compared to previous approaches, the current system offers targeted optogenetic stimulation to specific body regions or behaviors with many-fold increases in throughput to better constrain quantitative models of sensorimotor processing.
We describe a large-scale functional brain model that includes detailed, conductance-based, compartmental models of individual neurons. We call the model BioSpaun, to indicate the increased biological plausibility of these neurons, and because it is a direct extension of the Spaun model cite{Eliasmith2012b}. We demonstrate that including these detailed compartmental models does not adversely affect performance across a variety of tasks, including digit recognition, serial working memory, and counting. We then explore the effects of applying TTX, a sodium channel blocking drug, to the model. We characterize the behavioral changes that result from this molecular level intervention. We believe this is the first demonstration of a large-scale brain model that clearly links low-level molecular interventions and high-level behavior.
By focusing on melancholic features with biological homogeneity, this study aimed to identify a small number of critical functional connections (FCs) that were specific only to the melancholic type of MDD. On the resting-state fMRI data, classifiers were developed to differentiate MDD patients from healthy controls (HCs). The classification accuracy was improved from 50 % (93 MDD and 93 HCs) to 70% (66 melancholic MDD and 66 HCs), when we specifically focused on the melancholic MDD with moderate or severer level of depressive symptoms. It showed 65% accuracy for the independent validation cohort. The biomarker score distribution showed improvements with escitalopram treatments, and also showed significant correlations with depression symptom scores. This classifier was specific to melancholic MDD, and it did not generalize in other mental disorders including autism spectrum disorder (ASD, 54% accuracy) and schizophrenia spectrum disorder (SSD, 45% accuracy). Among the identified 12 FCs from 9,316 FCs between whole brain anatomical node pairs, the left DLPFC / IFG region, which has most commonly been targeted for depression treatments, and its functional connections between Precuneus / PCC, and between right DLPFC / SMA areas had the highest contributions. Given the heterogeneity of the MDD, focusing on the melancholic features is the key to achieve high classification accuracy. The identified FCs specifically predicted the melancholic MDD and associated with subjective depressive symptoms. These results suggested key FCs of melancholic depression, and open doors to novel treatments targeting these regions in the future.
Reduced motor control is one of the most frequent features associated with aging and disease. Nonlinear and fractal analyses have proved to be useful in investigating human physiological alterations with age and disease. Similar findings have not been established for any of the model organisms typically studied by biologists, though. If the physiology of a simpler model organism displays the same characteristics, this fact would open a new research window on the control mechanisms that organisms use to regulate physiological processes during aging and stress. Here, we use a recently introduced animal tracking technology to simultaneously follow tens of Caenorhabdits elegans for several hours and use tools from fractal physiology to quantitatively evaluate the effects of aging and temperature stress on nematode motility. Similarly to human physiological signals, scaling analysis reveals long-range correlations in numerous motility variables, fractal properties in behavioral shifts, and fluctuation dynamics over a wide range of timescales. These properties change as a result of a superposition of age and stress-related adaptive mechanisms that regulate motility.
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