scholarly journals Baseline Depression-Like Behaviors in Wild-Type Adolescent Mice Are Strain and Age but Not Sex Dependent

2021 ◽  
Vol 15 ◽  
Author(s):  
Ahmed Eltokhi ◽  
Barbara Kurpiers ◽  
Claudia Pitzer
Keyword(s):  
Sex Differences ◽  
Mouse Models ◽  
Public Health Problem ◽  
Neuropsychiatric Disorders ◽  
Sensitive Period ◽  
Strong Impact ◽  
Rodent Models ◽  
Wild Type ◽  
Behavioral Experiments ◽  
Behavioral Outcome

Depression is a major neuropsychiatric disorder, decreasing the ability of hundreds of millions of individuals worldwide to function in social, academic, and employment settings. Beyond the alarming public health problem, depression leads to morbidity across the entire age including adolescence and adulthood. Modeling depression in rodents has been used to understand the pathophysiological mechanisms behind this disorder and create new therapeutics. Although women are two times more likely to be diagnosed with depression compared to men, behavioral experiments on rodent models of depression are mainly performed in males based on the assumption that the estrous cycles in females may affect the behavioral outcome and cause an increase in the intrinsic variability compared to males. Still, the inclusion of female rodents in the behavioral analysis is mandatory to establish the origin of sex bias in depression. Here, we investigated the baseline depression-like behaviors in male and female mice of three adolescent wild-type inbred strains, C57BL/6N, DBA/2, and FVB/N, that are typically used as background strains for mouse models of neuropsychiatric disorders. Our experiments, performed at two different developmental stages during adolescence (P22–P26 and P32–P36), revealed strain but no sex differences in a set of depression-related tests, including tail suspension, sucrose preference and forced swim tests. Additionally, the 10-day interval during this sensitive period uncovered a strong impact on the behavioral outcome of C57BL/6N and FVB/N mice, highlighting a significant effect of maturation on behavioral patterns. Since anxiety-related behavioral tests are often performed together with depression tests in mouse models of neuropsychiatric disorders, we extended our study and included hyponeophagia as an anxiety test. Consistent with a previous study revealing sex differences in other anxiety tests in adolescent mice, male and females mice behaved differently in the hyponeophagia test at P27. Our study gives insight into the behavioral experiments assessing depression and stresses the importance of considering strain, age and sex when evaluating neuropsychiatric-like traits in rodent models.

scholarly journals Comprehensive characterization of motor and coordination functions in three adolescent wild-type mouse strains

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ahmed Eltokhi ◽  
Barbara Kurpiers ◽  
Claudia Pitzer
Keyword(s):  
Developmental Stages ◽  
Wild Type Mouse ◽  
Neuropsychiatric Disorders ◽  
Autism Spectrum ◽  
Face Validity ◽  
Mouse Strains ◽  
Behavioral Tests ◽  
Wild Type ◽  
Behavioral Experiments ◽  
Behavioral Studies

AbstractNeuropsychiatric disorders are often associated with motor and coordination abnormalities that have important implications on the etiology, pathophysiology, and management of these disorders. Although the onset of many neuropsychiatric disorders including autism spectrum disorder, schizophrenia, and attention-deficit hyperactivity disorder emerges mainly during infancy and adolescence, most of the behavioral studies in mice modeling neuropsychiatric phenotypes are performed in adult animals, possibly missing valuable phenotypic information related to the effect of synaptic maturation during development. Here, we examined which behavioral tests assessing both motor and coordination functions can be performed in mice at two different adolescent stages. As strain and sex affect mouse behavior, our experiments covered both male and female mice of three inbred wild-type strains, C57BL/6N, DBA/2, and FVB/N. Adolescent mice of both postnatal days (P)22–30 and P32–40 developmental stages were capable of mastering common motor and coordination tests. However, results differed significantly between strains and sexes. Moreover, the 10-day interval between the two tested cohorts uncovered a strong difference in the behavioral results, confirming the significant impact of maturation on behavioral patterns. Interestingly, the results of distinct behavioral experiments were directly correlated with the weight of mice, which may explain the lack of reproducibility of some behavioral results in genetically-modified mice. Our study paves the way for better reproducibility of behavioral tests by addressing the effect of the developmental stage, strain, sex, and weight of mice on achieving the face validity of neuropsychiatric disorder-associated motor dysfunctions.

scholarly journals Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders

2021 ◽  
Author(s):  
Ahmed Eltokhi ◽  
Miguel A. Gonzalez-Lozano ◽  
Lars-Lennart Oettl ◽  
Andrey Rozov ◽  
Claudia Pitzer ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Social Interaction ◽  
Social Behavior ◽  
Ampa Receptors ◽  
Signal To Noise Ratio ◽  
Signal Transmission ◽  
Neuropsychiatric Disorders ◽  
Autism Spectrum ◽  
Strong Impact ◽  
Odor Processing

AbstractMutations in SHANK genes play an undisputed role in neuropsychiatric disorders. Until now, research has focused on the postsynaptic function of SHANKs, and prominent postsynaptic alterations in glutamatergic signal transmission have been reported in Shank KO mouse models. Recent studies have also suggested a possible presynaptic function of SHANK proteins, but these remain poorly defined. In this study, we examined how SHANK2 can mediate electrophysiological, molecular, and behavioral effects by conditionally overexpressing either wild-type SHANK2A or the extrasynaptic SHANK2A(R462X) variant. SHANK2A overexpression affected pre- and postsynaptic targets and revealed a reversible, development-dependent autism spectrum disorder-like behavior. SHANK2A also mediated redistribution of Ca2+-permeable AMPA receptors between apical and basal hippocampal CA1 dendrites, leading to impaired synaptic plasticity in the basal dendrites. Moreover, SHANK2A overexpression reduced social interaction and increased the excitatory noise in the olfactory cortex during odor processing. In contrast, overexpression of the extrasynaptic SHANK2A(R462X) variant did not impair hippocampal synaptic plasticity, but still altered the expression of presynaptic/axonal signaling proteins. We also observed an attention-deficit/hyperactivity-like behavior and improved social interaction along with enhanced signal-to-noise ratio in cortical odor processing. Our results suggest that the disruption of pre- and postsynaptic SHANK2 functions caused by SHANK2 mutations has a strong impact on social behavior. These findings indicate that pre- and postsynaptic SHANK2 actions cooperate for normal neuronal function, and that an imbalance between these functions may lead to different neuropsychiatric disorders.

scholarly journals Mouse models of human cancer and the need for more translational research

2008 ◽  
Author(s):  
Martin Fenner
Keyword(s):  
Mouse Model ◽  
Translational Research ◽  
Synovial Sarcoma ◽  
Mouse Models ◽  
Human Disease ◽  
Human Cancer ◽  
Neuropsychiatric Disorders ◽  
International Congress

One of the opening lectures this Saturday of the International Congress of Genetics was held by Mario Capecchi. His talked was entitled Modeling human disease in the mouse: from cancer to neuropsychiatric disorders. In the first half he described his mouse model of synovial sarcoma. ...

scholarly journals Social Factors Influence Behavior in the Novel Object Recognition Task in a Mouse Model of Down Syndrome

2021 ◽  
Vol 15 ◽  
Author(s):  
Cesar Sierra ◽  
Ilario De Toma ◽  
Lorenzo Lo Cascio ◽  
Esteban Vegas ◽  
Mara Dierssen
Keyword(s):  
Down Syndrome ◽  
Object Recognition ◽  
Environmental Factors ◽  
Mouse Models ◽  
Recognition Task ◽  
Novel Object Recognition ◽  
The Novel ◽  
Wild Type ◽  
Male And Female ◽  
Novel Object

The use of mouse models has revolutionized the field of Down syndrome (DS), increasing our knowledge about neuropathology and helping to propose new therapies for cognitive impairment. However, concerns about the reproducibility of results in mice and their translatability to humans have become a major issue, and controlling for moderators of behavior is essential. Social and environmental factors, the experience of the researcher, and the sex and strain of the animals can all have effects on behavior, and their impact on DS mouse models has not been explored. Here we analyzed the influence of a number of social and environmental factors, usually not taken into consideration, on the behavior of male and female wild-type and trisomic mice (the Ts65Dn model) in one of the most used tests for proving drug effects on memory, the novel object recognition (NOR) test. Using principal component analysis and correlation matrices, we show that the ratio of trisomic mice in the cage, the experience of the experimenter, and the timing of the test have a differential impact on male and female and on wild-type and trisomic behavior. We conclude that although the NOR test is quite robust and less susceptible to environmental influences than expected, to obtain useful results, the phenotype expression must be contrasted against the influences of social and environmental factors.

scholarly journals In vivo multi-parametric manganese-enhanced MRI for detecting senile plaques in rodent models of Alzheimer’s disease

2021 ◽  
Author(s):  
Eugene Kim ◽  
Davide Di Censo ◽  
Mattia Baraldo ◽  
Camilla Simmons ◽  
Ilaria Rosa ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
High Resolution ◽  
Senile Plaques ◽  
Rodent Models ◽  
Wild Type ◽  
Enhanced Mri ◽  
Manganese Uptake ◽  
5Xfad Mice ◽  
Manganese Enhanced Mri

AbstractSenile plaques are a hallmark of Alzheimer’s disease (AD) that develop in its earliest stages. Thus, non-invasive detection of these plaques would be invaluable for diagnosis and the development and monitoring of treatments, but this remains a challenge due to their small size. Here, we investigated the utility of manganese-enhanced MRI (MEMRI) for visualizing plaques in transgenic rodent models of AD across two species: 5xFAD mice and TgF344-AD rats.Fourteen mice (eight transgenic, six wild-type) and eight rats (four transgenic, four wild-type) were given subcutaneous injections of MnCl2 and imaged in vivo using a 9.4T Bruker scanner. Susceptibility-weighted images, transverse relaxation rate (R2*) maps, and quantitative susceptibility maps were derived from high-resolution 3D multi-gradient-echo (MGE) data to directly visualize plaques. Longitudinal relaxation rate (R1) maps were derived from MP2RAGE data to measure regional manganese uptake. After scanning, the brains were processed for histology and stained for beta-amyloid (4G8 antibody), iron (Perl’s), and calcium/manganese (Alizarin Red).MnCl2 improved signal-to-noise ratio (1.55±0.39-fold increase in MGE images) as expected, although this was not necessary for detection of plaques in the high-resolution images. Plaques were visible in susceptibility-weighted images, R2* maps, and quantitative susceptibility maps, with increased R2* and more positive magnetic susceptibility compared to surrounding tissue.In the 5xFAD mice, most MR-visible plaques were in the hippocampus, though histology confirmed plaques in the cortex and thalamus as well. In the TgF344-AD rats, many more plaques were MR-visible throughout the hippocampus and cortex. Beta-amyloid and iron staining indicate that, in both models, MR visibility was driven by plaque size and iron load.Voxel-wise comparison of R1 maps revealed increased manganese uptake in brain regions of high plaque burden in transgenic animals compared to their wild-type littermates. Interestingly, in contrast to plaque visibility in the high-resolution images, the increased manganese uptake was limited to the rhinencephalon in the TgF344-AD rats (family-wise error (FWE)-corrected p < 0.05) while it was most significantly increased in the cortex of the 5xFAD mice (FWE-corrected p < 0.3). Alizarin Red staining suggests that manganese bound to plaques in 5xFAD mice but not in TgF344-AD rats.Multi-parametric MEMRI is a simple, viable method for detecting senile plaques in rodent models of AD. Manganese-induced signal enhancement can enable higher-resolution imaging, which is key to visualizing these small amyloid deposits. We also present in vivo evidence of manganese as a potential targeted contrast agent for imaging plaques in the 5xFAD model of AD.HighlightsThis is the first study to use manganese-enhanced MRI (MEMRI) for direct visualization of senile plaques in rodent models of Alzheimer’s disease, in vivo.Manganese enhancement is not necessary to detect plaques but improves image contrast and signal-to-noise ratio.Manganese binds to plaques in 5xFAD mice but not in TgF344-AD rats, demonstrating potential as a targeted contrast agent for imaging plaques in certain models of AD.

scholarly journals Whole exome sequencing of radiation-induced thymic lymphoma in mouse models identifies Notch1 activation as a driver of p53 wild-type lymphoma

2021 ◽  
pp. canres.2823.2020
Author(s):  
Chang-Lung Lee ◽  
Kennedy D. Brock ◽  
Stephanie Hasapis ◽  
Dadong Zhang ◽  
Alexander B. Sibley ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Mouse Models ◽  
Wild Type ◽  
Thymic Lymphoma ◽  
Whole Exome ◽  
Radiation Induced

scholarly journals Daily oscillation of the excitation/inhibition ratio is disrupted in two mouse models of autism

2021 ◽  
Author(s):  
Michelle Bridi ◽  
Nancy Luo ◽  
Grace Kim ◽  
Caroline O'Ferrall ◽  
Ruchit Oatel ◽  
...  
Keyword(s):  
Mouse Models ◽  
Sensory Processing ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Behavioral State ◽  
Wild Type ◽  
Inhibitory Synaptic Transmission ◽  
Sleep Timing ◽  
Per Se ◽  
Daily Oscillation

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder involving sensory processing abnormalities. Alterations to the balance between excitation and inhibition (E/I ratio) are postulated to underlie behavioral phenotypes in ASD patients and mouse models. However, in primary visual cortex (V1) of wild type mice, the E/I ratio is not a fixed value, but rather oscillates across the 24h day. Therefore, we hypothesized that the E/I oscillation, rather than the overall E/I ratio, may be disrupted in ASD mouse models. To this end, we measured the E/I ratio in Fmr1 KO and BTBR mice, models of syndromic and idiopathic ASD, respectively. We found that the E/I ratio is dysregulated in both models, but in different ways: the oscillation is flattened in Fmr1 KO and phase-shifted in BTBR mice. These phenotypes cannot be explained by altered sleep timing, which was largely normal in both lines. Furthermore, we found that E/I dysregulation occurs due to alterations in both excitatory and inhibitory synaptic transmission in both models. These findings provide a crucial perspective on the E/I ratio in ASD, suggesting that ASD phenotypes may be produced by a mismatch of E/I to the appropriate behavioral state, rather than alterations to overall E/I levels per se.

Abstract 5501: Reduced Coronary Reserve as a Mechanism in Beta-Adrenergic Receptor Mediated Cardiomyopathy and its Rescue by Adenylyl Cyclase Type 5 Knockout

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Shumin Gao ◽  
Lin Yan ◽  
Chull Hong ◽  
Xin Zhao ◽  
Li Chen ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
Mouse Models ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Potential Mechanism ◽  
Wild Type ◽  
Coronary Reserve ◽  
Small Heart ◽  
Cardinal Feature ◽  
Adenylyl Cyclase Type 5

Reduced coronary reserve (CR) is a cardinal feature of human cardiomyopathy, but it has not been studied extensively in mouse models of cardiomyopathy, potentially because of difficulties inherent to measuring CR in such a small heart. The first goal of this study was to determine if reduced CR is a potential mechanism involved in a transgenic (Tg) mouse model of cardiomyopathy, induced by cardiac overexpression of beta 2 -adrenergic receptors (beta 2 -AR Tg). Older beta 2 -AR Tg mice (16–17 months, n=7) developed cardiomyopathy, as reflected by decreased LV ejection fraction (LVEF, 50±7%), and increased fibrosis (5.2±0.4%) and apoptosis (3.8±0.6%). CR was obtained by measuring LV coronary blood flow at baseline and with adenosine (160 microg/kg/min) induced hyperemia using high resolution ultrasound (Vevo 770). CR was significantly decreased in beta 2 -AR Tg (1.8±0.2) compared with wild type (WT) (3.0±0.3, n=6). The next goal was to determine if the rescue of the beta 2 -AR Tg cardiomyopathy resulted in a rescue of reduced CR. Since adenylyl cyclase type 5 knockout (AC5 KO) mice are protected against catecholamine stress and the development of heart failure (HF), and exhibit enhanced CR (3.7±0.4, n=5), we hypothesized that mating these mice with beta 2 -AR Tg might rescue the cardiomyopathy. Older (16–17 months, n=4) bigenic mice (beta 2 -AR Tg x AC5 KO) demonstrated a rescue of cardiomyopathy, as reflected by normalized LVEF (71±1%) and levels of apoptosis (0.11±0.01%) and fibrosis (1.09±0.33%), similar to WT. In these mice, CR was also normalized (3.4±0.6). Reduced CR in beta 2 -AR Tg cardiomyopathy is similar to that observed in large mammalian models, and in patients with cardiomyopathy. Thus, this mechanism is important to consider in mouse models of cardiomyopathy, in general, and also in particular for the mechanism of the rescue of the beta 2 -AR Tg cardiomyopathy by AC5 KO.

Mouse Models of Schizophrenia and Bipolar Disorder

2013 ◽  
pp. 287-300
Author(s):  
Mikhail V. Pletnikov ◽  
Christopher A. Ross
Keyword(s):  
Bipolar Disorder ◽  
Animal Models ◽  
Mouse Models ◽  
Recent Progress ◽  
Neuropsychiatric Disorders ◽  
Environmental Interventions ◽  
The Future ◽  
Underlying Mechanisms ◽  
Insight Into ◽  
Genetic Mouse Models

Despite the recent advances in research into schizophrenia and bipolar disorder, the neurobiology of these maladies remains poorly understood. Animal models can be instrumental in elucidating the underlying mechanisms of neuropsychiatric disorders. Early animal models of schizophrenia and bipolar disorder used lesion methods, pharmacologic challenges or environmental interventions to mimic pathogenic features of the diseases. The recent progress in genetics has stimulated the development of etiological models that have begun to provide insight into pathogenesis. In this review, we evaluate the strengths and weaknesses of the existing genetic mouse models of schizophrenia and discuss potential developments for the future.

Quantitative Untersuchungen über die Ommochromvorstufen in den Malpighischen Gefäßen verschiedener Drosophila-Mutanten

1968 ◽  
Vol 23 (4) ◽  
pp. 547-554 ◽  
Author(s):  
Dieter Eichelberg
Keyword(s):  
Sex Differences ◽  
Drosophila Melanogaster ◽  
Quantitative Determination ◽  
Paper Chromatography ◽  
Type A ◽  
Individual Development ◽  
Wild Type ◽  
Strong Reduction ◽  
The Individual

This paper concerns with the quantitative determination of ommochrome precursors in the Malpighian tubes of Drosophila melanogaster during the individual development. After separation by paper chromatography the amounts of tryptophane, kynurenine and 3-hydroxykynurenine have been estimated by a spectrophotometer. The concentrations of these three substances obtained from wild-type Malpighian tubes have been compared with the quantities of the mutants brown (bw) and red Malpighian tubes (red). During development there are significant variabilities in contents of tryptophane, kynurenine and 3-hydroxykynurenine in the Malpighian tubes. In the larval tubes large quantities of ommochrome precursors are accumulated. With the beginning of metamorphosis there is a distinct decrease in these substances. After hatching the amount increases steadily until reaching a constant level. In the Malpighian tubes there are also sex differences: in females the concentration of kynurenine and 3-hydroxykynurenine is higher than in males. The results obtained from the mutants brown and red Malpighian tubes are on principle the same as those obtained from wild-type. A strong reduction of kynurenine contents is found in the mutant red Malpighian tubes. Perhaps in this mutant the kynurenine-hydroxilase-activity is lower than in wild-type. The amounts of ommochrome precursors, accumulated in the larval Malpighian tubes, do not correspond in all cases to the contents of xanthommatine formed in the eyes of the adults.

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