RESEARCH SOLUTIONS IN NEUROSCIENCE
Sylics offers innovative research solutions for preclinical neuroscience. We specialize in developing and employing customized mouse models, and in behavioral tests to evaluate compound effects on and disease mechanisms of neurological and psychiatric diseases, with a strong focus on neurodegeneration (cognitive impairment, Alzheimer’s disease, Parkinson’s disease, ALS) and Schizophrenia.
Highly efficient, sensitive and reproducible automated screening for behavioral deficits is supported by our automated behavioral screening platform and proprietary analysis software AHCODA™ (available for licensing).
Over the last 10 years, we successfully characterized hundreds of novel mouse models, and determined compound efficacy and side effects in numerous projects for academia, biotech, pharma and food industry clients.
Mouse models of Alzheimer’s disease (AD) are widely used to study amyloid-beta (Aβ) oligomerization, amyloid plaque formation and their consequences, such as Aβ-induced pathology and cognitive decline.
Alzheimer’s disease pathology
AD is a progressive, highly debilitating disease that is associated with cognitive decline. An early event in the pathology of AD is the oligomerization of Aβ and the formation of amyloid plaques. These protein aggregates, whose formation is due to an imbalance between the production of Aβ from APP, and clearance of Aβ, are thought to underlie downstream pathology, including synaptic toxicity, neurodegeneration and inflammation.
Mouse models and behavioural readouts of AD
Mouse models of AD carry human mutations that cause early-onset familial AD. These mutations lead to increased production of Aβ and a shift towards the production of Aβ42, the most toxic Aβ species. These mouse models develop amyloid plaques and severe cognitive impairments by 6 months of age (i.e. Morris Water Maze, T-maze). However, recent studies by us and others show that cognitive impairments can already be detected before plaque onset (i.e. CognitionWall™ Discrimination learning, Fear conditioning, Nesting test)1.
Various treatment options can be tested in AD mouse models. For instance, acute treatment with a BACE1 inhibitor, an enzyme critically involved in the generation of toxic Aβ species, effectively reduces the amount of Aβ42 in brain tissue a few hours after treatment. In addition to the analysis of Aβ levels in the brain, cerebrospinal fluid, and blood using ELISA, the number and size of amyloid plaques can be quantified after immunohistochemical staining of brain slices of mouse models of AD.
We routinely perform s.c., i.p., iv., and intracranial (single time stereotaxic, or repeated using cannula) infusions, as well as administration through subcutaneous Alzet osmotic minipumps.
Brain region-specific expression using viral vectors
Current projects focus on expressing light-sensitive receptors (optogenetics) as well as designer receptors that can be activated by designer drugs (DREADD technology)
On a fee-for-service basis, Sylics Contract Research offers:
Disease indications include: Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis (ALS), White matter disorders, Schizophrenia, Cognitive impairment, Mental retardation, Nutrient deficiency
Testing domains include: Sensory and motor function, Anxiety and depression, Learning and memory, Cognition, Executive function, Social behavior, Drug addiction, and Spontaneous behavior (activity, habituation, circadian rhythm, eating, drinking)
Selection of behavioral tests for mice and rats: Morris Water Maze, 5-choice serial reaction time task, 8-arm radial maze, T-maze, Fear conditioning, Passive avoidance, Novel object recognition, Barnes maze, Dark-light box, Elevated plus maze, Open field, Grip strength test, Rotarod, Acoustic startle response, Prepulse inhibition, Three chamber sociability test, Conditioned place preference, Drug self-administration, Automated home-cage tests (spontaneous behavior, discrimination learning, anxiety)
Mouse models of amyotrophic lateral sclerosis (ALS) carry human mutations that cause ALS in patients, typically mutations in the SOD1 gene.
Amyotrophic lateral sclerosis pathology
amyotrophic-lateral-sclerosisALS is a progressive neurodegenerative disorder characterized by degeneration of motor neurons, and is associated with both motor and cognitive symptoms. Pathological mechanisms thought to be involved in the disease include protein aggregation and oxidative stress. Superoxide dismutase 1 (SOD1) was the first gene found to be associated with ALS, and subsequently evidence has been provided for the presence of SOD1 protein aggregates and increased oxidative stress as a result of mutations in the SOD1 gene, which codes for an antioxidant protein.
Behavioural readouts for ALS mouse models
Mouse models of ALS develop significant motor problems in our tests of motor function (e.g. Activity in an automated home-cage, Grip strength, Rotarod).
PD pathology and the MPTP model
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive motor symptoms that result from a loss of dopaminergic neurons in the substantia nigra of the brain. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin that is highly toxic to dopaminergic neurons in the substantia nigra. Since the discovery that MPTP induces PD symptoms in humans, MPTP-induced neurotoxicity has been one of the most widely used rodent models of PD.
Behavioural readouts for PD mouse models
The effect of MPTP treatment on motor function can be assessed in our automated home cages, as well as other tests of motor function.
Sylics operates a 1000 square meter animal facility where well-separated rooms are permanently equipped with specific behavioural setups for conventional and automated screening. Together with our fully standardized operating procedures, this ensures the highest level of reproducibility.
Standardized and customized tests
We offer a continuously increasing number of behavioural tests that evaluate a range of locomotor, cognitive and anxiety phenotypes. In case your project requires an adapted form of a conventional behavioural test, or no test with the required readout is currently available, our scientists are keen to think along with you to develop customized behavioural tests. Contact us if you have any questions about customized tests.
Automated behavioural screening
Sylics is the leading provider of automated home-cage-based screening. Automated home-cages have the potential to increase the efficiency, sensitivity, and reproducibility of behavioural testing, because tests are executed in a familiar environment and without human intervention. We are continuously developing novel tests to add to our automated test repertoire. We have implemented our established automated tests for motor function, activity/anxiety and cognition in our standard screening services.
CognitionWall Discrimination learning
Evaluation of discrimination learning
Using the CognitionWall™, we developed a one-night automated test to efficiently identify discrimination learning impairments in mice, without time-consuming handling of mice. The CognitionWall is a wall with three entrances that is placed in front of a food dispenser in the automated home-cage. Mice are rewarded with a food reward when they choose to pass through one of the three entrances. The rate at which a mouse gains a relative preference for the rewarded entrance is used as a measure of discrimination learning.
Screening of cognitive impairments in MK-801-induced and AD mouse models
Acute induction of cognitive impairments with NMDA receptor antagonist MK-801 significantly increases the number of entries required for reaching the discrimination learning criterion. Mouse models for Alzheimer’s disease also consistently display impaired discrimination learning in this test compared with wild-type littermates. Automated discrimination learning can be used to efficiently screen for cognitive enhancers and potential therapeutics for AD in these models.
Comprehensive automated phenotyping
Especially when observations of discrimination learning are combined with several other tests in the same cage, targeting different behavioural domains, a highly detailed profile of a novel mouse mutant can be generated in a matter of a few days.
CognitionWall Reversal learning (Behavioural flexibility)
Evaluation of cognitive flexibility
Using the CognitionWall™, we developed a four-night automated test to efficiently identify reversal learning impairments in mice, without time-consuming handling of mice. The CognitionWall is a wall with three entrances that is placed in front of a food dispenser in the automated home-cage. Mice are rewarded with a food reward when they choose to pass through one of the three entrances. After an initial discrimination learning phase, the rewarded entrance is switched to another entrance (reversal). The rate at which a mouse gains a relative preference for the newly rewarded entrance is used as a measure of reversal learning.
Comprehensive automated phenotyping
Especially when observations of reversal learning are combined with several other tests in the same cage, targeting different behavioural domains, a highly detailed profile of a novel mouse mutant can be generated in a matter of a few days.
Evaluation of spatial memory
The Morris Water Maze is a test for spatial learning and memory. It is the standard test for hippocampal impairment in mouse models for Alzheimer’s disease, mutagenesis studies of neural plasticity-related genes and other impairments of long-term spatial memory. The test is similar to the Barnes Maze, with the important difference that this test requires swimming. As such, in most strains of mice, this leads to a higher motivation to learn to navigate to the target compared to the Barnes Maze.
The Morris Water Maze consists of a circular pool filled with water, with an escape platform just below the water surface. After multiple training trials, mice learn to locate the submerged platform using the visual cues around the maze. In a probe trial, in which the escape platform is not present, the spatial memory of its location is tested.
In subsequent reversal trials the escape platform is placed opposite to its previous location and the acquisition of a new memory is tested. Cued trials can be performed in which the location of the escape platform is marked by a flag, to determine whether mice that do not acquire the task are unable to detect visual cues mounted on the walls.
MWM performance is affected in AD models
We routinely test mouse models of Alzheimer’s disease in the Morris Water Maze. These mice show deficits in learning (multiday acquisition curve), resulting in deficits in memory of the platform location during a probe trial.
Broad analysis of motor function
Mice display a variety of spontaneous behaviours in our automated home-cages, which are tracked at high resolution with video cameras. The cages are equipped with a shelter compartment, on which mice climb during bouts of activity during the dark phase1,2. Mouse mutants with known motor function deficits, such as the SOD1 model of amyotrophic lateral sclerosis (ALS), show reduced or absent shelter climbing, an early detection of motor function deficits.
Comprehensive automated phenotyping
Especially when observations of spontaneous behaviour are combined with several other tests in the same cage, targeting different behavioural domains, a highly detailed profile of a novel mouse mutant can be generated in a matter of a few days.
Evaluation of motor function
Motor performance and motor learning can be assessed by placing mice on a rotating rod and increasing the rotating speed. Motor performance is measured by the maximal RPM (rounds per minute) at which mice are able to keep up with the rotating rod. Motor learning can be assessed by training mice on the rod for several trials.
NMJ dysfunction affects Rotarod performance
The neuromuscular junction (NMJ) connects efferent nerves of the peripheral nervous system to muscle cells. In collaboration with our partners, we previously reported that Tomosyn-2 null mice display impaired motor performance on the rotarod without a deficit in motor learning, in line with the essential role of Tomosyn-2 in neurotransmission at the neuromuscular junction.
Evaluation of neuromuscular function
Neuromuscular function is measured by the peak force a mouse can apply by grasping a bar connected to a force meter. Five trials with front paws are followed by five trials with front and hind paws combined. The median of these five trials is used as measure of grip strength.
NMJ dysfunction affects grip strength
The neuromuscular junction (NMJ) connects efferent nerves of the peripheral nervous system to muscle cells. In collaboration with our partners, we previously reported that Tomosyn-2 null mice display impaired performance in the grip strength test, in line with the essential role of Tomosyn-2 in neurotransmission at the neuromuscular junction.
Evaluation of activity and anxiety
This commonly used test is an efficient method to measure a change in activity/anxiety-related behaviour due to genetic mutations or interventions. Due to the novelty of the open white plastic arena mice will explore the arena. Activity is tracked by overhead video tracking. Gross changes in motor function may be detected by changes in the total distance moved or velocity. Alterations in emotionality may be detected by changes in the time spent in the center area of the arena.
Genetic background affects open field behaviour
Common inbred strains of mice differ in activity and anxiety-related behaviour. In collaboration with our partners, we studied the behaviour of a panel of these commonly used inbred strains of mice in a battery of activity/anxiety tests
Evaluation of anxiety-like behaviour
Mice are introduced into the elevated plus maze, which contains two open and two enclosed arms. The time spent on the open arms is a measure of anxiety-related behaviour.
Genetic background affects anxiolytic response
Common inbred strains of mice differ in activity and anxiety-related behaviour. In collaboration with our partners, we studied the behaviour of a panel of these commonly used inbred strains of mice in a battery of activity/anxiety tests.
Evaluation of social approach behaviour
Alterations in social behaviour are symptoms of several neuropsychiatric and neurological diseases. The three‐chamber test is a commonly used method to measure social approach behaviour in mice. After adaptation to the thee-chamber arena, a mouse is released into the middle chamber and allowed to explore the other compartments. In the adjacent ‘mouse’ compartment a docile stimulus mouse is situated in a mesh-wire container, while in the other adjacent compartment a similar container is located without stimulus mouse (object compartment). The tendency to approach or avoid the compartment with the stimulus mouse provides a measure of sociability.
Mice prefer social interaction
Wild-type mice have a tendency to socialize; they spend more time in the mouse compartment in comparison to the object compartment.
Evaluation of sensorimotor gating
A startle reflex in response to an intense acoustic stimulus is inhibited when a barely detectable pulse precedes the startle stimulus by 30-500 milliseconds. It has been theorized that this phenomenon, named prepulse inhibition (PPI) of a startle response, is an automatic early-stage gating process contributing to the ability to focus attention. Patients with schizophrenia spectrum disorders show deficits in PPI.
Autism-related gene affects prepulse inhibition
Pcdh9 is a cell adhesion gene that is associated with autism spectrum disorder. In collaboration with our partners, we detected sensorimotor gating deficits in a Pcdh9 knockout mutant, in line with structural changes in deep layers of sensory cortices, where Pcdh9 is selectively expressed.
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