A cerebellar internal model calibrates a feedback controller involved in sensorimotor control

Animals must adapt their behavior to survive in a changing environment. Behavioral adaptations can be evoked by two mechanisms: feedback control and internal-model-based control. Feedback controllers can maintain the sensory state of the animal at a desired level under different environmental conditions. In contrast, internal models learn the relationship between the motor output and its sensory consequences and can be used to recalibrate behaviors. Here, we present multiple unpredictable perturbations in visual feedback to larval zebrafish performing the optomotor response and show that they react to these perturbations through a feedback control mechanism. In contrast, if a perturbation is long-lasting, fish adapt their behavior by updating a cerebellum-dependent internal model. We use modelling and functional imaging to show that the neuronal requirements for these mechanisms are met in the larval zebrafish brain. Our results illustrate the role of the cerebellum in encoding internal models and how these can calibrate neuronal circuits involved in reactive behaviors depending on the interactions between animal and environment.

Panx1b Modulates the Luminance Response and Direction of Locomotion in the Zebrafish

Pannexin1 (Panx1) can form ATP-permeable channels that play roles in the physiology of the visual system. In the zebrafish two ohnologs of Panx1, Panx1a and Panx1b, have unique and shared channel properties and tissue expression patterns. Panx1a channels are located in horizontal cells of the outer retina and modulate light decrement detection through an ATP/pH-dependent mechanisms and adenosine/dopamine signaling. Here, we decipher how the strategic localization of Panx1b channels in the inner retina and ganglion cell layer modulates visually evoked motor behavior. We describe a panx1b knockout model generated by TALEN technology. The RNA-seq analysis of 6 days post-fertilization larvae is confirmed by real-time PCR and paired with testing of locomotion behaviors by visual motor and optomotor response tests. We show that the loss of Panx1b channels disrupts the retinal response to an abrupt loss of illumination and it decreases the larval ability to follow leftward direction of locomotion in low light conditions. We concluded that the loss of Panx1b channels compromises the final output of luminance as well as motion detection. The Panx1b protein also emerges as a modulator of the circadian clock system. The disruption of the circadian clock system in mutants suggests that Panx1b could participate in non-image forming processes in the inner retina.

Behavioural red-light sensitivity in fish according to the optomotor response

Various procedures have been adopted to investigate spectral sensitivity of animals, e.g. absorption spectra of visual pigments, electroretinography, optokinetic response, optomotor response (OMR) and phototaxis. The use of these techniques has led to various conclusions about animal vision. However, visual sensitivity should be evaluated consistently for a reliable comparison. In this study, we retrieved behavioural data of several fish species using a single OMR procedure and compared their sensitivities to near-infrared light. Besides cavefish that lack eyes, some species were not appropriate for the OMR test because they either stayed still or changed swimming direction frequently. Eight of 13 fish species tested were OMR positive. Detailed analyses using medaka, goldfish, zebrafish, guppy, stickleback and cichlid revealed that all the fish were sensitive to light at a wavelength greater than or equal to 750 nm, where the threshold wavelengths varied from 750 to 880 nm. Fish opsin repertoire affected the perception of red light. By contrast, the copy number of long-wavelength-sensitive ( LWS ) genes did not necessarily improve red-light sensitivity. While the duplication of LWS and other cone opsin genes that has occurred extensively during fish evolution might not aid increasing spectral sensitivity, it may provide some other advantageous ophthalmic function, such as enhanced spectral discrimination.

Tauroursodeoxycholic Acid Protects Retinal and Visual Function in a Mouse Model of Type 1 Diabetes

Purpose: Previous studies demonstrated that systemic treatment with tauroursodeoxycholic acid (TUDCA) is protective in in vivo mouse models of retinal degeneration and in culture models of hyperglycemia. This study tested the hypothesis that TUDCA will preserve visual and retinal function in a mouse model of early diabetic retinopathy (DR). Methods: Adult C57BL/6J mice were treated with streptozotocin (STZ) and made diabetic at 8–10 weeks of age. Control and diabetic mice were treated with vehicle or TUDCA starting 1 or 3 weeks after induction of diabetes, and were assessed bimonthly for visual function via an optomotor response and monthly for retinal function via scotopic electroretinograms. Results: Diabetic mice showed significantly reduced spatial frequency and contrast sensitivity thresholds compared to control mice, while diabetic mice treated early with TUDCA showed preservation at all timepoints. A-wave, b-wave, and oscillatory potential 2 (OP2) amplitudes decreased in diabetic mice. Diabetic mice also exhibited delays in a-wave and OP2-implicit times. Early TUDCA treatment ameliorated a-wave, b-wave, and OP2 deficits. Late TUDCA treatment showed reduced preservation effects compared to early treatment. Conclusions: Early TUDCA treatment preserved visual function in an STZ-mouse model of Type I diabetes. These data add to a growing body of preclinical research that may support testing whether TUDCA may be an effective early clinical intervention against declining visual function caused by diabetic retinopathy.

Circuit Organization Underlying Optic Flow Processing in Zebrafish

Animals’ self-motion generates a drifting movement of the visual scene in the entire field of view called optic flow. Animals use the sensation of optic flow to estimate their own movements and accordingly adjust their body posture and position and stabilize the direction of gaze. In zebrafish and other vertebrates, optic flow typically drives the optokinetic response (OKR) and optomotor response (OMR). Recent functional imaging studies in larval zebrafish have identified the pretectum as a primary center for optic flow processing. In contrast to the view that the pretectum acts as a relay station of direction-selective retinal inputs, pretectal neurons respond to much more complex visual features relevant to behavior, such as spatially and temporally integrated optic flow information. Furthermore, optic flow signals, as well as motor signals, are represented in the cerebellum in a region-specific manner. Here we review recent findings on the circuit organization that underlies the optic flow processing driving OKR and OMR.

The evaluation of zebrafish cardiovascular and behavioral functions through microfluidics

This study proposed a new experimental approach for the vascular and phenotype evaluation of the non-anesthetized zebrafish with representative imaging orientations for heart, pectoral fin beating, and vasculature views by means of the designed microfluidic device through inducing the optomotor response and hydrodynamic pressure control. In order to provide the visual cues for better positioning of zebrafish, computer-animated moving grids were generated by an in-house control interface which was powered by the larval optomotor response, in conjunction with the pressure suction control. The presented platform provided a comprehensive evaluation of internal circulation and the linked external behaviors of zebrafish in response to the cardiovascular parameter changes. The insights from these imaging sections was extended to identify the linkage between the cardiac parameters and behavioral endpoints. In addition, selected chemicals such as ethanol and caffeine were employed for the treatment of zebrafish. The obtained findings can be applicable for future investigation in behavioral drug screening serving as the forefront in psychopharmacological and cognition research.

Visual dysfunction in a mouse model of chemotherapy-related neurotoxicity.

e24059 Background: Chemotherapy-related neurotoxicity (CRNT) poses challenges to long-term outcomes of cancer survivors. Visual function remains relatively unexplored in CRNT. Preliminary clinical work from our group suggests contrast sensitivity may be impaired in patients receiving chemotherapy. Here, we sought to isolate effects of chemotherapy on visual dysfunction in a mouse model. Methods: 10-week old C57BL/6J mice received either 4, 7, or 10 weekly intraperitoneal injections of chemotherapy (CTX group; n=15) or physiologic saline (SAL group; n=12). CTX mice received cyclophosphamide (50 mg/kg) and doxorubicin (2 mg/kg). Contrast sensitivity was assessed using an optomotor response (OMR) chamber. Psychometric functions were fitted to OMR contrast response functions to derive measures of contrast sensitivity (K), stimulus responsivity (Rmax), and stimulus selectivity (n). Electroretinography (ERG) waveforms, which measure light-evoked retinal neural activity, were recorded under scotopic (rod-driven) conditions and decomposed to isolate photoreceptor (a-wave), bipolar cell (b-wave), and interneuron amacrine cell (oscillatory potentials [OP]) activity. OMR and ERG were measured prior to and following treatment. Dependent- and independent-sample t-tests assessed within- and between-group changes, respectively, in outcome measures. Results: Outcome measures are reported in Table 1. SAL relative to CTX mice showed greater weight gain (p=0.004). OMR revealed increases in Rmax (pCTX=0.002; pSAL=0.11) and K (pCTX=0.80; pSAL=0.06) parameters in SAL but not CTX mice. ERG results revealed significant declines in OP peak frequency in CTX relative to SAL mice (p=0.006). Other OMR and ERG measures showed no within- or between-group differences (p>0.10). Decreases in weight were associated with decreases in Rmax (R2=0.25, p=.008) and OP peak frequency (R2=0.20, p=.02). Conclusions: Our animal model showed chemotherapy-related visual dysfunction. Mice receiving chemotherapy showed relative declines in contrast sensitivity, stimulus responsivity, and oscillatory neural activity, suggestive of disrupted neuronal circuits within the visual pathway. Future studies will focus on understanding neuronal mechanisms of visual pathway dysfunction and translating findings to clinical studies. [Table: see text]

Adaptable internal representations drive cerebellum-mediated predictive control of an innate behavior

The brain uses internal models to estimate future states of the environment based on current inputs and to predict consequences of planned actions. Neural mechanisms that underlie the acquisition and use of these predictive models are poorly understood. Using a novel experimental paradigm, we show clear evidence for predictive processing in the larval zebrafish brain. We find that when presented with repetitive optic flow stimuli, larval zebrafish modulate their optomotor response by quickly acquiring internal representations of the optic flow pattern. Distinct subcircuits in the cerebellum are involved in the predictive representation of stimulus timing and in using them for motor planning. Evidence for such predictive internal representations appears quickly within two trials, lasts over minute timescales even after optic flow is stopped and quickly adapts to changes in the pattern. These results point to an entrainment-based mechanism that allows the cerebellum to rapidly generate predictive neural signals ultimately leading to faster response times.

Zebrafish Optomotor Response and Morphology Are Altered by Transient, Developmental Exposure to Bisphenol-A

Estrogen-specific endocrine disrupting compounds (EDCs) are potent modulators of neural and visual development and common environmental contaminants. Using zebrafish, we examined the long-term impact of abnormal estrogenic signaling by testing the effects of acute, early exposure to bisphenol-A (BPA), a weak estrogen agonist, on later visually guided behaviors. Zebrafish aged 24 h postfertilization (hpf), 72 hpf, and 7 days postfertilization (dpf) were exposed to 0.001 μM or 0.1 μM BPA for 24 h, and then allowed to recover for 1 or 2 weeks. Morphology and optomotor responses (OMRs) were assessed after 1 and 2 weeks of recovery for 24 hpf and 72 hpf exposure groups; 7 dpf exposure groups were additionally assessed immediately after exposure. Increased notochord length was seen in 0.001 μM exposed larvae and decreased in 0.1 μM exposed larvae across all age groups. Positive OMR was significantly increased at 1 and 2 weeks post-exposure in larvae exposed to 0.1 μM BPA when they were 72 hpf or 7 dpf, while positive OMR was increased after 2 weeks of recovery in larvae exposed to 0.001 μM BPA at 72 hpf. A time-delayed increase in eye diameter occurred in both BPA treatment groups at 72 hpf exposure; while a transient increase occurred in 7 dpf larvae exposed to 0.1 μM BPA. Overall, short-term developmental exposure to environmentally relevant BPA levels caused concentration- and age-dependent effects on zebrafish visual anatomy and function.

Using a variant of the optomotor response as a visual defect detection assay in zebrafish

We describe a visual stimulus that can be used with both larval and adult zebrafish (Danio rerio). This protocol is a modification of a standard visual behavior analysis, the optomotor response (OMR). The OMR is often used to determine the spatial response or to detect directional visuomotor deficiencies. An OMR can be generated using a high contrast grated pattern, typically vertical bars. The spatial sensitivity is measured by detection and response to a change in grating bar width and is reported in cycles per degree (CPD). This test has been used extensively with zebrafish larvae and adults to identify visual- and/or motor-based mutations. Historically, when tested in adults, the grated pattern was presented from a vertical perspective, using a rotating cylinder around a holding tank, allowing the grating to be seen solely from the sides and front of the organism. In contrast, OMRs in zebrafish larvae are elicited using a stimulus projected below the fish. This difference in methodology means that two different experimental set-ups are required: one for adults and one for larvae. Our visual stimulus modifies the stimulation format so that a single OMR stimulus, suitable for use with both adults and larvae, is being presented underneath the fish. Analysis of visuomotor responses using this method does not require costly behavioral tracking software and, using a single behavioral paradigm, allows the observer to rapidly determine visual spatial response in both zebrafish larvae and adults.