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1.
Int J Neuropsychopharmacol ; 21(10): 938-948, 2018 10 01.
Article in English | MEDLINE | ID: mdl-29860313

ABSTRACT

Background: Several currently available animal models reproduce select behavioral facets of human mania as well as the abnormal glutamatergic neurotransmission and dysregulation of glycogen synthase kinase 3ß that accompanies this disease. Methods: In this study, we addressed the therapeutic potential of ligands of sigma receptor type 1 (σ1R) in 2 putative models of mania: the "manic" Black Swiss outbred mice from Taconic farms (BStac) and mice with the 129 genetic background and histidine triad nucleotide-binding protein 1 (HINT1) deletion (HINT1-/- mice) that exhibit bipolar-like behaviors. Results: The activity of control mice, which do not exhibit manic-like behaviors in the forced swim test, was significantly enhanced by MK801, an inhibitor of glutamate N-methyl-D-aspartate receptor activity, an effect that was not or barely observed in manic-like mice. Typical mood stabilizers, such as glycogen synthase kinase 3ß inhibitors, but not σ1R ligands, reduced the N-methyl-D-aspartate receptor-mediated behaviors in control mice. Notably, σ1R antagonists S1RA, PD144418, BD1047, and BD1063, but not σ1R agonists PRE084 and PPCC, attenuated the manic-like behaviors of BStac and HINT1-/- mice by increasing antiactivity behaviors. The antimanic effects of a single administration of σ1R antagonists persisted for at least 24 hours, and these drugs did not alter the behavior of the "bipolar" HINT1-/- mice during pro-depressive episodes. Conclusions: σ1R antagonists exhibit a selective normalizing effect on specific behavioral domains of mania without altering control (normal) or depressive-like behaviors.


Subject(s)
Antimanic Agents/pharmacology , Mice, Knockout/psychology , Nerve Tissue Proteins/genetics , Receptors, sigma/antagonists & inhibitors , Animals , Animals, Outbred Strains/psychology , Cyclopropanes/pharmacology , Dizocilpine Maleate/pharmacology , Drug Interactions , Glycogen Synthase Kinase 3 beta/drug effects , Mice , Morpholines/pharmacology , Motor Activity/drug effects , Motor Activity/genetics , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Receptors, sigma/agonists
2.
Zh Vyssh Nerv Deiat Im I P Pavlova ; 67(1): 106-112, 2017 01.
Article in Russian | MEDLINE | ID: mdl-30695555

ABSTRACT

Receptor-like tyrosine kinase IRR (the insulin receptor-related receptor) can be activated by extra- cellular alkaline media. IRR is found in organs that come in contact with liquids of extremal pH, and also in specific cells of the nervous systems where its function is not known. In this study, we analyzed the phenotype of IRR knockout mice in a series of behavioral tests. In control experi- ments, null-mutation littermate mice were analyzed. In the "Social interaction" test, the knockout animals showed a reduced number of social contacts. No statistically significant differences in im- mobility time were revealed in the "Forced swim" test, yet the number of animals that showed pro- longed immobility time, was higher in the group of knockout mice. In the "Resident-intruder" test, wild-type mice demonstrated their typical aggressive behavior whereas 7 out of 16 knockout animals stayed inert and, in contrast, attacked by the intruder. The obtained data suggest that the IRR gene inactivation results in disturbances of the aggressive-defensive behavior typical of the parental mouse strain.


Subject(s)
Dominance-Subordination , Gene Deletion , Immobility Response, Tonic , Mice, Knockout/genetics , Receptor, Insulin/genetics , Aggression , Animals , Breeding , Female , Founder Effect , Grooming/physiology , Heterozygote , Homozygote , Hydrogen-Ion Concentration , Male , Mice , Mice, Inbred C57BL , Mice, Knockout/psychology , Phenotype , Receptor, Insulin/deficiency
3.
Nihon Rinsho ; 73(2): 341-9, 2015 Feb.
Article in Japanese | MEDLINE | ID: mdl-25764693

ABSTRACT

Wolfram syndrome(WFS: OMIM 222300) is a rare recessive neuro-endocrine degenerative disorder, known as DIDMOAD(Diabetes Insipidus, early-onset Diabetes Mellitus, Optic Atrophy and Deafness) syndrome. Most affected individuals carry recessive mutations in the Wolfram syndrome 1 gene(WFS1). The WFS1 protein is an endoplasmic reticulum(ER) embedded protein, which functions in ER calcium homeostasis and unfolded protein responses. Dysregulation of these cellular processes results in the development of ER stress, leading to apoptosis. In addition, abundantly present WFS1 protein in insulin secretory granules plays a role in the intra-granular acidification. However, the phenotypic pleiomorphism and molecular complexity of this disease limit the understanding of WFS. Here we review clinical features, molecular mechanisms and mutations of WFS1 gene that relate to this syndrome.


Subject(s)
Membrane Proteins/genetics , Wolfram Syndrome/genetics , Wolfram Syndrome/physiopathology , Animals , Diabetes Mellitus/etiology , Humans , Mice , Mice, Knockout/psychology , Mutation
4.
Behav Pharmacol ; 20(1): 18-32, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19179848

ABSTRACT

Several lines of knockout (KO) mice have been evaluated as models of depression-related behavioral and neurobiological changes, and used to investigate molecular and cellular mechanisms underlying the activity of antidepressant drugs. Adult neurogenesis and brain 5-hydroxytryptamine (5-HT)/neurotrophic factor interactions have recently attracted great interest in relation to the mechanism of action of antidepressant drugs. The present review focuses primarily on genetic manipulation of the serotoninergic (5-HT) system. Basal neurochemical and behavioral changes occurring in mice lacking the 5-HT transporter (SERT), which is the main target of antidepressant drugs, as well as in those lacking G protein-coupled serotonin receptors (e.g. 5-HT1B, 5-HT1A, and 5-HT4 receptors) are described and evaluated. The importance of KO mice for neurotrophic factors, particularly for brain-derived neurotrophic factor and its high-affinity receptor (R-TrkB), is also addressed. Constitutive KO, tissue specific, or inducible KO mice targeting both 5-HT and brain-derived neurotrophic factor systems may potentially make an important contribution to knowledge of the pathophysiology and treatment of depression.


Subject(s)
Antidepressive Agents/pharmacology , Brain-Derived Neurotrophic Factor/genetics , Depressive Disorder/drug therapy , Mice, Knockout/genetics , Models, Animal , Receptors, Serotonin/genetics , Serotonin/genetics , Adult , Animals , Antidepressive Agents/therapeutic use , Behavior, Animal/drug effects , Behavior, Animal/physiology , Brain-Derived Neurotrophic Factor/metabolism , Disease Models, Animal , Humans , Mice , Mice, Knockout/psychology , Polymorphism, Genetic/drug effects , Receptor, trkB/genetics , Receptor, trkB/metabolism , Receptors, Serotonin/drug effects , Receptors, Serotonin/metabolism , Receptors, Serotonin, 5-HT1/genetics , Receptors, Serotonin, 5-HT4/genetics , Serotonin/pharmacology , Serotonin Plasma Membrane Transport Proteins/drug effects , Serotonin Plasma Membrane Transport Proteins/genetics
5.
Physiol Behav ; 97(1): 131-4, 2009 Apr 20.
Article in English | MEDLINE | ID: mdl-19419666

ABSTRACT

It has been previously reported that vasopressin 1b receptor knockout (Avpr1b(-/-)) mice have reduced levels of aggressive behavior compared to wildtype littermates. However, as the background of the mice was always a mixture of 129/SvJ and C57BL/6, we wanted to determine if the phenotype persisted when our laboratory line was crossed with a wild-derived sub-species of house mice. To this end, we crossed our Avpr1b(-/-) mice with Mus musculus castaneus, one of the few sub-species that will breed with laboratory strains. Subsequent F(2) offspring were tested in a resident-intruder behavioral test to assess aggressive behavior. We found that even on this more "wild" background, Avpr1b(-/-) mice continued to demonstrate longer attack latencies and fewer attacks in a resident-intruder test than wildtype littermates. These findings are consistent with previous reports of reduced aggressive behavior in Avpr1b(-/-) mice and show that the deficit does persist on a different background strain. Further, these findings confirm the importance of the Avpr1b to normal displays of social forms of aggressive behavior.


Subject(s)
Aggression/physiology , Arginine Vasopressin/genetics , Mice, Inbred Strains/psychology , Mice, Knockout/psychology , Receptors, Vasopressin/genetics , Receptors, Vasopressin/physiology , Animals , Female , Hybridization, Genetic , Male , Mice , Mice, Inbred Strains/metabolism , Mice, Knockout/metabolism , Receptors, Vasopressin/metabolism
6.
Nat Biomed Eng ; 3(11): 930-942, 2019 11.
Article in English | MEDLINE | ID: mdl-31110290

ABSTRACT

Preclinical studies of psychiatric disorders use animal models to investigate the impact of environmental factors or genetic mutations on complex traits such as decision-making and social interactions. Here, we introduce a method for the real-time analysis of the behaviour of mice housed in groups of up to four over several days and in enriched environments. The method combines computer vision through a depth-sensing infrared camera, machine learning for animal and posture identification, and radio-frequency identification to monitor the quality of mouse tracking. It tracks multiple mice accurately, extracts a list of behavioural traits of both individuals and the groups of mice, and provides a phenotypic profile for each animal. We used the method to study the impact of Shank2 and Shank3 gene mutations-mutations that are associated with autism-on mouse behaviour. Characterization and integration of data from the behavioural profiles of Shank2 and Shank3 mutant female mice revealed their distinctive activity levels and involvement in complex social interactions.


Subject(s)
Autistic Disorder/genetics , Autistic Disorder/psychology , Behavior, Animal , Machine Learning , Nerve Tissue Proteins/genetics , Animals , Behavioral Research , Disease Models, Animal , Female , Male , Mice/genetics , Mice/psychology , Mice, Knockout/genetics , Mice, Knockout/psychology , Microfilament Proteins , Mutation , Phenotype , Social Behavior , Video Recording
7.
Transl Psychiatry ; 7(4): e1077, 2017 04 04.
Article in English | MEDLINE | ID: mdl-28375206

ABSTRACT

Anxious depression is a prevalent disease with devastating consequences and a poor prognosis. Nevertheless, the neurobiological mechanisms underlying this mood disorder remain poorly characterized. The LPA1 receptor is one of the six characterized G protein-coupled receptors (LPA1-6) through which lysophosphatidic acid acts as an intracellular signalling molecule. The loss of this receptor induces anxiety and several behavioural and neurobiological changes that have been strongly associated with depression. In this study, we sought to investigate the involvement of the LPA1 receptor in mood. We first examined hedonic and despair-like behaviours in wild-type and maLPA1 receptor null mice. Owing to the behavioural response exhibited by the maLPA1-null mice, the panic-like reaction was assessed. In addition, c-Fos expression was evaluated as a measure of the functional activity, followed by interregional correlation matrices to establish the brain map of functional activation. maLPA1-null mice exhibited anhedonia, agitation and increased stress reactivity, behaviours that are strongly associated with the psychopathological endophenotype of depression with anxiety features. Furthermore, the functional brain maps differed between the genotypes. The maLPA1-null mice showed increased limbic-system activation, similar to that observed in depressive patients. Antidepressant treatment induced behavioural improvements and functional brain normalisation. Finally, based on validity criteria, maLPA1-null mice are proposed as an animal model of anxious depression. Here, for we believe the first time, we have identified a possible relationship between the LPA1 receptor and anxious depression, shedding light on the unknown neurobiological basis of this subtype of depression and providing an opportunity to explore new therapeutic targets for the treatment of mood disorders, especially for the anxious subtype of depression.


Subject(s)
Anxiety/physiopathology , Depression/metabolism , Endophenotypes , Mice, Knockout/psychology , Receptors, Lysophosphatidic Acid/deficiency , Anhedonia/physiology , Animals , Anxiety/metabolism , Brain/metabolism , Genes, fos/genetics , Limbic System/metabolism , Lysophospholipids/metabolism , Male , Mice , Models, Animal , Receptors, Lysophosphatidic Acid/drug effects , Receptors, Lysophosphatidic Acid/metabolism , Stress, Psychological
8.
eNeuro ; 4(6)2017.
Article in English | MEDLINE | ID: mdl-29379874

ABSTRACT

Interleukin (IL)-33 is a member of the IL-1 family of cytokines. IL-33 is expressed in nuclei and secreted as alarmin upon cellular damage to deliver a danger signal to the surrounding cells. Previous studies showed that IL-33 is expressed in the brain and that it is involved in neuroinflammatory and neurodegenerative processes in both humans and rodents. Nevertheless, the role of IL-33 in physiological brain function and behavior remains unclear. Here, we have investigated the behaviors of mice lacking IL-33 (Il33-/- mice). IL-33 is constitutively expressed throughout the adult mouse brain, mainly in oligodendrocyte-lineage cells and astrocytes. Notably, Il33-/- mice exhibited reduced anxiety-like behaviors in the elevated plus maze (EPM) and the open field test (OFT), as well as deficits in social novelty recognition, despite their intact sociability, in the three-chamber social interaction test. The immunoreactivity of c-Fos proteins, an indicator of neuronal activity, was altered in several brain regions implicated in anxiety-related behaviors, such as the medial prefrontal cortex (mPFC), amygdala, and piriform cortex (PCX), in Il33-/- mice after the EPM. Altered c-Fos immunoreactivity in Il33-/- mice was not correlated with IL-33 expression in wild-type (WT) mice nor was IL-33 expression affected by the EPM in WT mice. Thus, our study has revealed that Il33-/- mice exhibit multiple behavioral deficits, such as reduced anxiety and impaired social recognition. Our findings also indicate that IL-33 may regulate the development and/or maturation of neuronal circuits, rather than control neuronal activities in adult brains.


Subject(s)
Behavior, Animal/physiology , Interleukin-33/deficiency , Mice, Knockout/psychology , Animals , Anxiety/metabolism , Astrocytes/metabolism , Astrocytes/pathology , Brain/metabolism , Brain/pathology , Interleukin-33/genetics , Male , Mice, Inbred C57BL , Mice, Knockout/metabolism , Neurons/metabolism , Neurons/pathology , Oligodendroglia/metabolism , Oligodendroglia/pathology , Proto-Oncogene Proteins c-fos/metabolism , Recognition, Psychology/physiology
9.
Curr Opin Neurobiol ; 4(5): 687-92, 1994 Oct.
Article in English | MEDLINE | ID: mdl-7849524

ABSTRACT

Gene targeting is revealing new molecular functions by creating very specific developmental, physiological and behavioral perturbations, and providing new insights into biochemical pathways underlying synaptic plasticity. Recent studies of mice carrying mutations in genes thought to be involved in modulating synaptic transmission have been subject to integrated biochemical, physiological and behavioral analyses.


Subject(s)
Gene Targeting , Neuronal Plasticity , Synapses/physiology , Animals , Behavior, Animal/physiology , Humans , Learning/physiology , Mice , Mice, Knockout/psychology , Models, Neurological , Mutation , Nerve Tissue Proteins/physiology , Neurons/physiology , Protein Kinases/genetics , Receptors, N-Methyl-D-Aspartate/genetics , Second Messenger Systems , Synaptic Vesicles/metabolism
10.
ILAR J ; 47(2): 124-31, 2006.
Article in English | MEDLINE | ID: mdl-16547369

ABSTRACT

New technologies in molecular genetics have dramatically increased the number of targeted gene mutations available to the biomedical research community. Many mutant mouse lines have been generated to provide animal models for human genetic disorders, offering insights into anatomical, neurochemical, and behavioral effects of aberrant gene expression. A variety of assays have been developed to identify and characterize phenotypic changes. In the behavioral domain, our phenotyping strategy involves a comprehensive standardized methodological approach that assesses general health, reflexes, sensory abilities, and motor functions. This assessment is followed by a series of complementary tasks in the specific behavioral domain(s) hypothesized to reveal the function(s) of the gene. Our multitiered approach minimizes intersubject variability by standardizing the experimental history for all animals, improves interlaboratory reliability by providing a clearly defined experimental protocol, and minimizes artifactual interpretations of behavioral data by careful preliminary assessments of basic behaviors, followed by multiple tests within the behavioral domain of interest. Despite meticulous attention to experimental protocol, attention to environmental factors is essential. Differences in noise, light, home cage environment, handling, and diet can dramatically alter behavior. Baseline differences in the behaviors of inbred strains used to generate targeted mutant mouse lines can directly influence the behavioral phenotype of the mutant line. Strategies aimed at minimizing environmental variability and contributions of background genes will enhance the robustness of mouse behavioral phenotyping assays.


Subject(s)
Behavior, Animal/physiology , Mice, Knockout/physiology , Animal Husbandry , Animals , Female , Housing, Animal , Male , Mice , Mice, Knockout/genetics , Mice, Knockout/psychology , Phenotype
11.
Neurosci Biobehav Rev ; 22(3): 453-62, 1998 May.
Article in English | MEDLINE | ID: mdl-9579332

ABSTRACT

The use of mice with targeted deletion, or knockout, of specific genes provides a relatively new approach to establish the molecular bases of behavior. As with all ablation studies, the interpretation of behavioral data may be limited by the technique. For example, indirect effects of the missing gene may affect behavior, rather than the missing gene per se. Also, because the missing gene might affect many developmental processes throughout ontogeny and because up-regulation or compensatory mechanisms may be activated in knockouts, behavioral data from mice with targeted gene deletions should be interpreted with caution. The development of conditional knockouts, in which a specific gene can be inactivated any time during ontogeny, should allow investigators to avoid these conceptual shortcomings associated with behavioral data from knockouts in the near future. The behavioral alterations reported in knockout mice are reviewed here. Many dramatic changes in complex motivated behaviors including aggression, sexual, ingestive, and parental behaviors, have been reported for knockouts. There have also been many reports of alterations in sensorimotor abilities and spontaneous activity, as well as impairments in balance, coordination, and gait. Impaired learning and memory have also been reported for mice with targeted disruption of specific genes. Taken together, the use of knockouts will provide an important new tool to understand the mechanisms underlying behavior.


Subject(s)
Behavior, Animal/physiology , Genetics, Behavioral , Mice, Knockout/genetics , Mice, Knockout/psychology , Animals , Mice
12.
Neurosci Biobehav Rev ; 25(2): 143-58, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11323079

ABSTRACT

Feeding behavior results from complex interactions arising between numerous neuromediators, including classical neurotransmitters and neuropeptides present in hypothalamic networks. One way to unravel these complex mechanisms is to examine animal models with a deletion of genes coding for the different neuropeptides involved in the regulation of feeding. The aim of this review is to focus on feeding and body weight regulation in mice lacking neuropeptide Y (NPY), melanocortins (POMC), corticotropin-releasing hormone, melanin-concentrating hormone, or bombesin-like peptides respectively. The phenotypes, which relate to the deletion of gene coding for the peptides, rarely include changes in body weight and food intake, indicating therefore the existence of redundant mechanisms to compensate for the loss of the peptide. The phenotype is much more marked when the gene deletion is targeted towards the functioning of the peptidergic machinery, e.g. the receptors and especially the POMC and NPY receptors, as well as one subtype of bombesin receptor (BRS-3). These knockout models are also interesting when examining the role of environmental and social factors in the determination of feeding behavior. They have granted us better knowledge of all these integrated and complex mechanisms. Moreover, they are also valuable tools for pharmacological studies when specific antagonists are lacking. From the information obtained by the study of knockouts, it is possible to determine certain targets for selective drugs that could be efficient for the pharmacological treatment of obesity. However, at the present state of our knowledge, it seems necessary to target several peptides in order to get good results with weight loss. It will also be imperative to associate these multitherapies with changes in eating and behavioral habits, in order to obtain complete effectiveness and long-lasting results.


Subject(s)
Feeding Behavior/physiology , Mice, Knockout/psychology , Neuropeptides/physiology , Animals , Humans , Mice , Mice, Knockout/physiology
13.
Neurosci Biobehav Rev ; 25(3): 261-73, 2001 May.
Article in English | MEDLINE | ID: mdl-11378180

ABSTRACT

Studying the behavioral phenotypes of transgenic and gene knockout mice is a powerful means to better understand the pathophysiology of neuropsychiatric disorders and ultimately improve their treatment. This paper provides an overview of the methods and findings of studies that have tested for anxiety-related behavioral phenotypes in gene mutant mice. In the context of improving the side effect burden of benzodiazepines, gene targeting has been valuable for dissociating the functional roles (i.e., anxiolytic, sedative, amnestic) of individual GABA(A) receptor subunits. Supporting the link between abnormalities in CRH function and anxiety, CRH overexpressing transgenic mice and CRH-R2 receptor knockout mutants have displayed significantly increased anxiety-like behavior, while CRH-R1 receptor knockout mice have shown an anxiolytic-like phenotype. Consistent with an important role for the serotonergic system in anxiety, 5-HT1(A) receptor deficient mice have consistently exhibited heightened anxiety-like behavior, while the evidence from 5-HT1(B) and 5-HT2(C) deficient mice remains somewhat equivocal. Mutant mice lacking either of the monoamine degrading enzymes, MAOA or COMT, have shown a number of behavioral and neurological effects, including alterations in anxiety-like behavior. With enhanced spatial and temporal control over gene mutations, in combination with an improved battery of behavioral tests, gene mutant mice will provide an increasingly valuable tool for understanding the neural substrates of anxiety.


Subject(s)
Anxiety/genetics , Mice/psychology , Mutation/genetics , Animals , Behavior, Animal/physiology , Mice, Knockout/psychology
14.
Neuroscience ; 85(1): 93-110, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9607706

ABSTRACT

Using apolipoprotein E knockout mice derived from the Maeda source [Piedrahita J. A. et al. (1992) Proc. natn. Acad Sci. US.A. 89, 4471 4475], we have studied the influence of apolipoprotein E gene deletion on normal CNS function by neurological tests and water maze learning, hippocampal ultrastructure assessed by quantitative immunocytochemistry and electron microscopy, CNS plasticity, i.e. hippocampal long-term potentiation and amygdaloid kindling, and CNS repair, i.e. synaptic recovery in the hippocampus following deafferentation. In each study there was little difference between the apolipoprotein E knockout mice and wild-type controls of similar age and genetic background. Apolipoprotein E knockout mice aged eight months demonstrated accurate spatial learning and normal neurological function. Synaptophysin and microtubule-associated protein 2 immunohistochemistry and electron microscopic analysis of these animals revealed that the hippocampal synaptic and dendritic densities were similar between genotypes. The induction and maintenance of kindled seizures and hippocampal long-term potentiation were indistinguishable between groups. Finally, unilateral entorhinal cortex lesions produced a marked loss of hippocampal synaptophysin immunoreactivity in both groups and a marked up-regulation of apolipoprotein E in the wild-type group. Both apolipoprotein E knockout and wild-type groups showed immunohistochemical evidence of reactive synaptogenesis, although the apolipoprotein E knockout group may have initially shown greater synaptic loss. It is suggested that either apolipoprotein E is of no importance in the maintenance of synaptic integrity and in processes of CNS plasticity and repair, or more likely, alternative (apolipo)proteins may compensate for the loss of apolipoprotein E in the knockout animals.


Subject(s)
Apolipoproteins E/genetics , Behavior, Animal/physiology , Mice, Knockout/physiology , Mice, Knockout/psychology , Animals , Apolipoproteins E/metabolism , Dentate Gyrus/cytology , Dentate Gyrus/ultrastructure , Electrophysiology , Entorhinal Cortex/physiology , GAP-43 Protein/metabolism , Hippocampus/cytology , Hippocampus/metabolism , Immunohistochemistry , Kindling, Neurologic/physiology , Mice , Mice, Knockout/anatomy & histology , Microtubule-Associated Proteins/metabolism , Neurons/cytology , Synapses/ultrastructure , Synaptophysin/metabolism
15.
Behav Brain Res ; 144(1-2): 111-7, 2003 Sep 15.
Article in English | MEDLINE | ID: mdl-12946601

ABSTRACT

Nociceptin/orphanin FQ (N/OFQ) is a newly discovered neuropeptide that has been implicated in the neurobiological regulation of the behavioral responses to stress and fear. To investigate the role of this peptide in the expression of stress/anxiety-related behaviors in mice, a gene targeting approach to disrupt N/OFQ in the pre-proN/OFQ gene was used. The impact of environmental housing conditions (single and social housing) was assessed on N/OFQ-knockout male and female mice in different experimental paradigms known to trigger distinctive types of stress and anxiety states. Neurological examination of homozygous mutant adult animals indicated that basic neurological functions (vision, audition, olfaction, tactile and pain sensitivity, motor performances) were normal. When housed individually, N/OFQ-knockout animals displayed responses similar to control animals in behavioral tests of emotional reactivity (behavioral despair, locomotor activity, light-dark preference, and acoustic startle tests). In contrast, increased emotional responses were detected when individually housed mice were crowded together (five per cage) under conditions of competitive access to food, water, space, and social contacts. Under those conditions, male mice deficient for N/OFQ developed greater home-cage aggression and increased fear/anxiety-like behaviors in the light-dark and acoustic startle tests, when compared to their wild-type littermates. Group-housed female mutants also showed higher level of anxiety in the acoustic startle test, but needed additional restrain stress to express detectable levels of anxiety in the light-dark test. These data indicate a clear environment-induced rise in fear reactions of N/OFQ-knockout mice. They further suggest that N/OFQ system is essential for development of adequate coping strategies to acute and chronic stress.


Subject(s)
Emotions/physiology , Environment , Gene Deletion , Opioid Peptides/genetics , Analysis of Variance , Animals , Behavior, Animal , Exploratory Behavior/physiology , Light , Mice , Mice, Inbred C57BL , Mice, Knockout/physiology , Mice, Knockout/psychology , Mutation , Neurologic Examination/methods , Opioid Peptides/deficiency , Psychomotor Performance/physiology , Rats , Reflex, Acoustic , Reflex, Startle , Restraint, Physical/methods , Sex , Swimming , Time Factors , Nociceptin
16.
Behav Brain Res ; 148(1-2): 185-98, 2004 Jan 05.
Article in English | MEDLINE | ID: mdl-14684259

ABSTRACT

The dopamine (DA) transporter (DAT) controls the temporal and spatial resolution of dopaminergic neurotransmission. Disruption of the Dat1 gene in mice leads to increased extracellular DA concentrations and reduced expression of D1- and D2-like receptors in striatum. The mutants are hyperactive in the open field and they display deficits in learning and memory. In humans, dopaminergic dysfunction has been associated with a number of different psychiatric disorders and some of these conditions are accompanied by abnormal social responses. To determine whether social responses were also impaired in DAT knockout (KO) mice, behaviors of group- and isolation-housed animals were compared. All group-housed animals readily established hierarchies. However, the social organizations of the mutants were changed over time. Under both group- and isolation-housed conditions, mutants exhibited increased rates of reactivity and aggression following mild social contact. In isolation, exposure to a novel environment exacerbated these abnormal responses. Regardless of housing context, stereotyped and perseverative patterns of social responses were a common feature of the KO repertoire. In fact, many abnormal behaviors were due to the emergence and predominance of these inflexible behaviors. These data suggest that KO mice may serve as a useful animal model for understanding not only how DA dysfunction contributes to social abnormalities, but also how behavioral inflexibility distorts their social responses.


Subject(s)
Interpersonal Relations , Membrane Glycoproteins , Membrane Transport Proteins/metabolism , Mice, Knockout/psychology , Nerve Tissue Proteins , Stereotyped Behavior , Aggression/physiology , Analysis of Variance , Animals , Behavior, Animal , Discrimination, Psychological/physiology , Dopamine Plasma Membrane Transport Proteins , Female , Genotype , Hierarchy, Social , Male , Membrane Transport Proteins/genetics , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Knockout/genetics , Regression Analysis , Smell/physiology , Social Environment , Stress, Psychological , Time Factors
17.
Brain Res ; 752(1-2): 189-96, 1997 Mar 28.
Article in English | MEDLINE | ID: mdl-9106456

ABSTRACT

Recent studies on apolipoprotein E (apoE) have stressed the importance of this protein in neuronal viability, especially in the hippocampal area. In the present study, we used the Morris water maze to assess spatial learning and memory in 6-month-old homozygous apoE-deficient and heterozygous control mice. The apoE status was checked by genotyping and immunocytochemistry. ApoE-knockout mice were not able to learn the task at all, developed neither spatial nor other strategies to locate the platform, but rather an unusual repetitive behavioral pattern of 'wall bumping'. Heterozygous control mice did not experience any difficulty with the task. Swimming ability and general locomotor activity of both groups were comparable. These results indicate that absence of apoE in these animals might be critical for spatial learning and memory abilities.


Subject(s)
Apolipoproteins E/genetics , Learning Disabilities/genetics , Maze Learning/physiology , Mice, Knockout/psychology , Animals , Male , Mice , Motor Activity/physiology , Reference Values , Swimming
18.
Physiol Behav ; 107(5): 641-8, 2012 Dec 05.
Article in English | MEDLINE | ID: mdl-22406388

ABSTRACT

The development of tasks measuring behaviors specific to the three major symptom categories for autism makes it possible to differentiate mouse models of autism spectrum disorders (ASD) in terms of changes in these specific categories. Prior studies indicate that BTBR T+tf/J mice, the strain that has been evaluated most extensively, show autism-relevant changes in all three symptom categories; reciprocal social interactions; communication; and repetitive, ritualized behaviors. This report reviews the behaviors of oxytocin receptor (Oxtr) and Mecp2(308/Y) wild-type (WT) and knockout (KO) mice, in a number of tests specifically designed to provide information on behaviors that may show functional parallels to the core symptoms of ASD. Oxtr KO mice show robust decreases in reciprocal social interactions, and reduced levels of communication, but no changes in repetitive, ritualized behaviors; whereas Mecp2(308/Y) KO mice show a slight but consistent enhancement of social behavior and communication, and no changes in repetitive, ritualized behaviors. This data base, although small, strongly indicates that mouse models can sort the diagnostic symptoms of autism, and suggests that biological and physiological analyses of these strains may be capable of providing differential information on the brain systems involved in particular symptoms of this disorder. Profiles of behavioral changes in other mouse models of ASD should provide additional specificity in the search for biomarkers associated with particular ASD symptoms and symptom clusters.


Subject(s)
Autistic Disorder/genetics , Methyl-CpG-Binding Protein 2/physiology , Receptors, Oxytocin/physiology , Social Behavior , Animal Communication , Animals , Disease Models, Animal , Methyl-CpG-Binding Protein 2/genetics , Mice , Mice, Knockout/genetics , Mice, Knockout/psychology , Receptors, Oxytocin/genetics , Stereotypic Movement Disorder/genetics , Stereotypic Movement Disorder/physiopathology
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