Jutta Kretzberg

OMR-arena: automated measurement and stimulation system to determine mouse visual thresholds based on optomotor responses.

Measurement of the optomotor response is a common way to determine thresholds of the visual system in animals. Particularly in mice, it is frequently used to characterize the visual performance of different genetically modified strains or to test the effect of various drugs on visual performance. Several methods have been developed to facilitate the presentation of stimuli using computer screens or projectors. Common methods are either based on the measurement of eye movement during optokinetic reflex behavior or rely on the measurement of head and/or body-movements during optomotor responses. Eye-movements can easily and objectively be quantified, but their measurement requires invasive fixation of the animals. Head movements can be observed in freely moving animals, but until now depended on the judgment of a human observer who reported the counted tracking movements of the animal during an experiment. In this study we present a novel measurement and stimulation system based on open source building plans and software. This system presents appropriate 360 stimuli while simultaneously video-tracking the animals head-movements without fixation. The on-line determined head gaze is used to adjust the stimulus to the head position, as well as to automatically calculate visual acuity. Exemplary, we show that automatically measured visual response curves of mice match the results obtained by a human observer very well. The spatial acuity thresholds yielded by the automatic analysis are also consistent with the human observer approach and with published results. Hence, OMR-arena provides an affordable, convenient and objective way to measure mouse visual performance.

Roles for Coincidence Detection in Coding Amplitude-Modulated Sounds.

Many sensory neurons encode temporal information by detecting coincident arrivals of synaptic inputs. In the mammalian auditory brainstem, binaural neurons of the medial superior olive (MSO) are known to act as coincidence detectors, whereas in the lateral superior olive (LSO) roles of coincidence detection have remained unclear. LSO neurons receive excitatory and inhibitory inputs driven by ipsilateral and contralateral acoustic stimuli, respectively, and vary their output spike rates according to interaural level differences. In addition, LSO neurons are also sensitive to binaural phase differences of low-frequency tones and envelopes of amplitude-modulated (AM) sounds. Previous physiological recordings in vivo found considerable variations in monaural AM-tuning across neurons. To investigate the underlying mechanisms of the observed temporal tuning properties of LSO and their sources of variability, we used a simple coincidence counting model and examined how specific parameters of coincidence detection affect monaural and binaural AM coding. Spike rates and phase-locking of evoked excitatory and spontaneous inhibitory inputs had only minor effects on LSO output to monaural AM inputs. In contrast, the coincidence threshold of the model neuron affected both the overall spike rates and the half-peak positions of the AM-tuning curve, whereas the width of the coincidence window merely influenced the output spike rates. The duration of the refractory period affected only the low-frequency portion of the monaural AM-tuning curve. Unlike monaural AM coding, temporal factors, such as the coincidence window and the effective duration of inhibition, played a major role in determining the trough positions of simulated binaural phase-response curves. In addition, empirically-observed level-dependence of binaural phase-coding was reproduced in the framework of our minimalistic coincidence counting model. These modeling results suggest that coincidence detection of excitatory and inhibitory synaptic inputs is essential for LSO neurons to encode both monaural and binaural AM sounds.

Multiplexed Population Coding of Stimulus Properties by Leech Mechanosensory Cells

Sensory coding has long been discussed in terms of a dichotomy between spike timing and rate coding. However, recent studies found that in primate mechanoperception and other sensory systems, spike rates and timing of cell populations complement each other. They simultaneously carry information about different stimulus properties in a multiplexed way. Here, we present evidence for multiplexed encoding of tactile skin stimulation in the tiny population of leech mechanoreceptors, consisting of only 10 cells of two types with overlapping receptive fields. Each mechanoreceptor neuron of the leech varies spike count and response latency to both touch intensity and location, leading to ambiguous responses to different stimuli. Nevertheless, three different stimulus estimation techniques consistently reveal that the neuronal population allows reliable decoding of both stimulus properties. For the two mechanoreceptor types, the transient responses of T (touch) cells and the sustained responses of P (pressure) cells, the relative timing of the first spikes of two mechanoreceptors encodes stimulus location, whereas summed spike counts represent touch intensity. Differences between the cell types become evident in responses to combined stimulus properties. The best estimation performance for stimulus location is obtained from the relative first spike timing of the faster and temporally more precise T cells. Simultaneously, the sustained responses of P cells indicate touch intensity by summed spike counts and stimulus duration by the duration of spike responses. The striking similarities of these results with previous findings on primate mechanosensory afferents suggest multiplexed population coding as a general principle of somatosensation. SIGNIFICANCE STATEMENT Multiplexing, the simultaneous encoding of different stimulus properties by distinct neuronal response features, has recently been suggested as a mechanism used in several sensory systems, including primate somatosensation. While a rigorous experimental verification of the multiplexing hypothesis is difficult to accomplish in a complex vertebrate system, it is feasible for a small population of individually characterized leech neurons. Monitoring the responses of all four mechanoreceptors innervating a patch of skin revealed striking similarities between touch encoding in the primate and the leech: summed spike counts represent stimulus intensity, whereas relative timing of first spikes encodes stimulus location. These findings suggest that multiplexed population coding is a general mechanism of touch encoding common to species as different as man and worm.

A comparative study of seven human cochlear filter models

Auditory models have been developed for decades to simulate characteristics of the human auditory system, but it is often unknown how well auditory models compare to each other or perform in tasks they were not primarily designed for. This study systematically analyzes predictions of seven publicly-available cochlear filter models in response to a fixed set of stimuli to assess their capabilities of reproducing key aspects of human cochlear mechanics. The following features were assessed at frequencies of 0.5, 1, 2, 4, and 8 kHz: cochlear excitation patterns, nonlinear response growth, frequency selectivity, group delays, signal-in-noise processing, and amplitude modulation representation. For each task, the simulations were compared to available physiological data recorded in guinea pigs and gerbils as well as to human psychoacoustics data. The presented results provide application-oriented users with comprehensive information on the advantages, limitations and computation costs of these seven mainstream cochlear filter models.

Single and Multiple Change Point Detection in Spike Trains: Comparison of Different CUSUM Methods

In a natural environment, sensory systems are faced with ever-changing stimuli that can occur, disappear or change their properties at any time. For the animal to react adequately the sensory systems must be able to detect changes in external stimuli based on its neuronal responses. Since the nervous system has no prior knowledge of the stimulus timing, changes in stimulus need to be inferred from the changes in neuronal activity, in particular increase or decrease of the spike rate, its variability, and shifted response latencies. From a mathematical point of view, this problem can be rephrased as detecting changes of statistical properties in a time series. In neuroscience, the CUSUM (cumulative sum) method has been applied to recorded neuronal responses for detecting a single stimulus change. Here, we investigate the applicability of the CUSUM approach for detecting single as well as multiple stimulus changes that induce increases or decreases in neuronal activity. Like the nervous system, our algorithm relies exclusively on previous neuronal population activities, without using knowledge about the timing or number of external stimulus changes. We apply our change point detection methods to experimental data obtained by multi-electrode recordings from turtle retinal ganglion cells, which react to changes in light stimulation with a range of typical neuronal activity patterns. We systematically examine how variations of mathematical assumptions (Poisson, Gaussian, and Gamma distributions) used for the algorithms may affect the detection of an unknown number of stimulus changes in our data and compare these CUSUM methods with the standard Rate Change method. Our results suggest which versions of the CUSUM algorithm could be useful for different types of specific data sets.

Comparison of valley seeking and T-distributed EM algorithm for spike sorting

Most analysis methods for neural spike data require knowledge about the exact spike times of individual neurons. To obtain this information from extracellular recordings, spike sorting is necessary to exclude measurement artifacts and to separate spikes from different neurons. The quality of spike sorting can have significant effects on the results of spike train analyses [1]. However, manual spike sorting leads to extremely variable results due to different sorting strategies of individual persons [2]. Therefore, reproducible results require automated spike-sorting methods, even though they also lead to sorting errors.

Encoding of Tactile Stimuli by Mechanoreceptors and Interneurons of the Medicinal Leech

For many animals processing of tactile information is a crucial task in behavioral contexts like exploration, foraging, and stimulus avoidance. The leech, having infrequent access to food, developed an energy efficient reaction to tactile stimuli, avoiding unnecessary muscle movements: The local bend behavior moves only a small part of the body wall away from an object touching the skin, while the rest of the animal remains stationary. Amazingly, the precision of this localized behavioral response is similar to the spatial discrimination threshold of the human fingertip, although the leech skin is innervated by an order of magnitude fewer mechanoreceptors and each midbody ganglion contains only 400 individually identified neurons in total. Prior studies suggested that this behavior is controlled by a three-layered feed-forward network, consisting of four mechanoreceptors (P cells), approximately 20 interneurons and 10 individually characterized motor neurons, all of which encode tactile stimulus location by overlapping, symmetrical tuning curves. Additionally, encoding of mechanical force was attributed to three types of mechanoreceptors reacting to distinct intensity ranges: T cells for touch, P cells for pressure, and N cells for strong, noxious skin stimulation. In this study, we provide evidences that tactile stimulus encoding in the leech is more complex than previously thought. Combined electrophysiological, anatomical, and voltage sensitive dye approaches indicate that P and T cells both play a major role in tactile information processing resulting in local bending. Our results indicate that tactile encoding neither relies on distinct force intensity ranges of different cell types, nor location encoding is restricted to spike count tuning. Instead, we propose that P and T cells form a mixed type population, which simultaneously employs temporal response features and spike counts for multiplexed encoding of touch location and force intensity. This hypothesis is supported by our finding that previously identified local bend interneurons receive input from both P and T cells. Some of these interneurons seem to integrate mechanoreceptor inputs, while others appear to use temporal response cues, presumably acting as coincidence detectors. Further voltage sensitive dye studies can test these hypotheses how a tiny nervous system performs highly precise stimulus processing.

Virtual experimental arena for behavioral experiments on small vertebrates

In this study, we present a virtual experimental arena to perform behavioral experiments on small vertebrates. It consists of a 360° visual stimulation realized by four LC displays and an automated camera-based head tracking system. Based on these two components, visual stimuli are repositioned depending of the animals head position in a closed-loop approach. We present two algorithms to automatically perform robust head tracking on mice and compare their precision to manual tracking by a human observer.

Estimation of neuronal activity based on voltage-sensitive dye imaging in a moving preparation.

Voltage-sensitive dye imaging allows simultaneous recording of graded voltage changes of multiple neurons. While this experimental technique is a great tool to study neuronal network activity in neuroscience, the optical recording suffers from artifacts. In particular, bleaching of the dye and cell movement impede the analysis and interpretation of imaging results. In this paper, we present methods to tackle these two main artifacts. Cell movement during the experiment is corrected by an optical flow method. Bleaching decay is estimated based on a line fit of recordings without stimulus, which is subtracted from the rest of the recordings in the same experiment. Here, we use a leech ganglion as an example tissue to evaluate these processing procedures. This preparation allows simultaneous voltage-sensitive dye imaging of the entire neuronal network and intracellular recording of one cells membrane voltage. Using the intracellularly recorded voltage as the ground truth reference, we show that our processing methods for the VSD imaging signal clearly improve the correlation between the real and the estimated voltage. Since other imaging techniques (e.g., calcium imaging) suffer from the same type of artifacts as voltage-sensitive dye imaging, our processing method might be useful for a wide range of biomedical imaging studies.

Automated measurement of spectral sensitivity of motion vision during optokinetic behavior

Optokinetic behavior is a commonly used paradigm to conveniently determine sensitivities of motion vision in animals. The optokinetic reflex (OKR) compensates global image motion on the retina by head and eye movements. It can reliably be elicited without training the test animal. In most OKR behavior experiments the animal is stimulated either with a rotating drum containing a pattern of vertical stripes or with computer monitors displaying a moving stripe pattern. In many of these studies, sensitivity thresholds are measured based on the subjective judgment of the experimenter. In this paper, we describe an alternative method to induce and measure OKR behavior. Our setup consists of a metal drum into which a slide is projected via a 360^o panoramic mirror, using a spectrally filtered LED as light source. The slide is mounted on a motor-driven turntable whose rotation leads to a horizontal movement of the stimulus on the drums wall, accordingly. By this means a spatial, temporal, and spectral well-defined and flexible panoramic stimulation is achieved. The animals head movements are video recorded under infrared illumination and tracked online. We introduce an objective criterion to automatically determine sensitivity thresholds based on the correlation of the animals head angle with the stimulus position. We exemplarily used this setup for an experiment that could not be performed with the state-of-the-art setup consisting of four monitors-the measurement of spectral sensitivity thresholds of the OKR behavior in turtles.