Wisket rat model of schizophrenia : Impaired motivation and, altered brain structure, but no anhedonia

It is well-known that the poor cognition in schizophrenia is strongly linked to negative symptoms, including motivational deficit, which due to, at least partially, anhedonia. The goal of this study was to explore whether the schizophrenia-like Wisket animals with impaired motivation (obtained in the reward-based hole-board test), also show decreased hedonic behavior (investigated with the sucrose preference test). While neurochemical alterations of different neurotransmitter systems have been detected in the Wisket rats, no research has been performed on structural changes. Therefore, our additional aim was to reveal potential neuroanatomical and structural alterations in different brain regions in these rats. The rats showed decreased general motor activity (locomotion, rearing and exploration) and impaired task performance in the hole-board test compared to the controls, whereas no significant difference was observed in the sucrose preference test between the groups. The Wisket rats exhibited a significant decrease in the frontal cortical thickness and the hippocampal area, and moderate increases in the lateral ventricles and cell disarray in the CA3 subfield of hippocampus. To our knowledge, this is the first study to investigate the hedonic behavior and neuroanatomical alterations in a multi-hit animal model of schizophrenia. The results obtained in the sucrose preference test suggest that anhedonic behavior might not be involved in the impaired motivation obtained in the hole-board test. The neuropathological changes agree with findings obtained in patients with schizophrenia, which refine the high face validity of the Wisket model

Automating, Analyzing and Improving Pupillometry with Machine Learning Algorithms

The investigation of the pupillary light reflex (PLR) is a well-known method to provide information about the functionality of the autonomic nervous system. Pupillometry, a non-invasive technique, was applied to study the PLR alterations in a new, schizophrenia-like rat substrain, named WISKET. The pupil responses to light impulses were recorded with an infrared camera; the videos were automatically processed and features were extracted from the pupillograms. Besides the classical statistical analysis (ANOVA), feature selection and classification were applied to reveal the significant differences in the PLR parameters between the control and WISKET animals. Based on these results, the disadvantages of this method were analyzed and the measurement setup was redesigned and improved. The pupil segmentation method has also been adapted to the new videos. 2564 images were annotated manually and used to train a fully-convolutional neural network to produce pupil mask images. The method was evaluated on 329 test images and achieved 4% median relative error. With the new setup, the pupil detection became reliable and the new data acquisition offers robustness to the experiments

Neurobehavioral impairments in ciprofloxacin-treated osteoarthritic adult rats

Background and purpose – Ciprofloxacin (CIP) is a broad-spectrum antibiotic widely used in clinical practice to treat musculoskeletal infections. Fluoroquinoloneinduced neurotoxic adverse events have been reported in a few case reports, all the preclinical studies on its neuropsychiatric side effects involved only healthy animals. This study firstly investigated the behavioral effects of CIP in an osteoarthritis rat model with joint destruction and pain, which can simulate inflammation-associated musculoskeletal pain. Furthermore, effects of CIP on regional brain-derived neurotrophic factor (BDNF) expression were examined given its major contributions to the neuromodulation and plasticity underlying behavior and cognition. Methods – Fourteen days after induction of chronic osteoarthritis, animals were administered vehicle, 33 mg/kg or 100 mg/kg CIP for five days intraperitoneally. Motor activity, behavioral motivation, and psychomotor learning were examined in a reward-based behavioral test (Ambitus) on Day 4 and sensorimotor gating by the prepulse inhibition test on Day 5. Thereafter, the prolonged BDNF mRNA and protein expression levels were measured in the hippocampus and the prefrontal cortex. Results – CIP dose-dependently reduced both locomotion and reward-motivated exploratory activity, accompanied with impaired learning ability. In contrast, there were no significant differences in startle reflex and sensory gating among treatment groups; however, CIP treatment reduced motor activity of the animals in this test, too. These alterations were associated with reduced BDNF mRNA and protein expression levels in the hippocampus but not the prefrontal cortex. Conclusion – This study revealed the detrimental effects of CIP treatment on locomotor activity and motivation/learning ability during osteoarthritic condition, which might be due to, at least partially, deficient hippocampal BDNF expression and ensuing impairments in neural and synaptic plasticity

Caffeine-Induced Acute and Delayed Responses in Cerebral Metabolism of Control and Schizophrenia-like Wisket Rats

Recently, morphological impairments have been detected in the brain of a triple-hit rat schizophrenia model (Wisket), and delayed depressive effects of caffeine treatment in both control and Wisket animals have also been shown. The aims of this study were to determine the basal and caffeine-induced acute (30 min) and delayed (24 h) changes in the cerebral (18)fluorodeoxyglucose (F-18-FDG) uptake by positron emission tomography (PET) in control and Wisket rats. No significant differences were identified in the basal whole-brain metabolism between the two groups, and the metabolism was not modified acutely by a single intraperitoneal caffeine (20 mg/kg) injection in either group. However, one day after caffeine administration, significantly enhanced F-18-FDG uptake was detected in the whole brain and the investigated areas (hippocampus, striatum, thalamus, and hypothalamus) in the control group. Although the Wisket animals showed only moderate enhancements in the F-18-FDG uptake, significantly lower brain metabolism was observed in this group than in the caffeine-treated control group. This study highlights that the basal brain metabolism of Wisket animals was similar to control rats, and that was not influenced acutely by single caffeine treatment at the whole-brain level. Nevertheless, the distinct delayed responsiveness to this psychostimulant in Wisket model rats suggests impaired control of the cerebral metabolism

Feature extraction and classification for pupillary images of rats

The investigation of the pupillary light reflex (PLR) is a well-known method to provide information about the functionality of the autonomic nervous system. Pupillometry, a non-invasive technique, was applied in our lab to study the schizophrenia-related PLR alterations in a new selectively bred rat substrain, named WISKET. The pupil responses to light impulses were recorded with an infrared camera; the videos were automatically processed and features were extracted. Besides the classical statistical analysis (ANOVA), feature selection and classification were applied to reveal the significant differences in the PLR parameters between the control and WISKET animals

Automating, analyzing and improving pupillometry with machine learning algorithms

The investigation of the pupillary light reflex (PLR) is a well-known method to provide information about the functionality of the autonomic nervous system. Pupillometry, a non-invasive technique, was applied to study the PLR alterations in a new, schizophrenia-like rat substrain, named WISKET. The pupil responses to light impulses were recorded with an infrared camera; the videos were automatically processed and features were extracted from the pupillograms. Besides the classical statistical analysis (ANOVA), feature selection and classification were applied to reveal the significant differences in the PLR parameters between the control and WISKET animals. Based on these results, the disadvantages of this method were analyzed and the measurement setup was redesigned and improved. The pupil segmentation method has also been adapted to the new videos. 2564 images were annotated manually and used to train a fully-convolutional neural network to produce pupil mask images. The method was evaluated on 329 test images and achieved 4% median relative error. With the new setup, the pupil detection became reliable and the new data acquisition offers robustness to the experiments

Cognitive training improves the disturbed behavioral architecture of schizophrenia-like rats, "Wisket"

Translational schizophrenia research depends on the relevance of animal models supported by reliable tests. Human data suggest that the intensive cognitive training in schizophrenia improves the memory impairments and decreases the chance of acute psychiatric remission. Here we examined the effects of a 10-day long training session in the behavioral architecture of a new schizophrenia-like rat substrain (Wisket) in a narrow square corridor with food rewards (AMBITUS). The instrument was designed to model the natural environment of rats and enable the simultaneous recording of multiple behavioral parameters. For the compact visualization of differences between the Wisket and control animals in several parameters (behavioromics), color-coded grid plots were applied. The Wisket animals exhibited an altered pattern and/or amount of locomotion, exploratory and food collecting activity at the first few days, revealing impaired motivation, attention, anxiety and learning ability (face validity). Most of the parameters normalized with training, except for the decreased exploratory activity. This resembles the effects of cognitive behavioral therapy in human schizophrenics providing a significant support for the predictive validity of this substrain as an animal model of schizophrenia. This study also highlights the importance of behavior tests that investigate the egocentric learning ability during reward-based tasks