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Biomedical subjects

Valerie J Bolivar

Publications and source records attributed to Valerie J Bolivar.

11 recordsLinked to original sources
PubMed2006

Antibody induction of lupus-like neuropsychiatric manifestations.

Although systemic lupus erythematosus (SLE) is usually evaluated with regard to autoimmune reactivity toward the kidney, there are multiple psychiatric abnormalities associated with this autoimmune disease. Lupus-prone male NZM88 mice, derived from NZB/NZW F1 mice, develop early neuropsychiatric manifestations without any signs of nephritis. In addition to the usual repertoire of antibody specificities, including autoantibodies to dsDNA and renal antigens, mice of this inbred strain express autoantibodies to numerous brain antigens. Here, we show that autoantibodies to brain antigens, assessed by Western analysis, are as individually varied as are the diverse neuropsychiatric manifestations observed in SLE patients. Additionally, a monoclonal antibody derived from the spleen of an untreated NZM88 male when injected into healthy BALB/cByJ, but not C57BL/6J, mice induced behaviors similar to those of lupus-prone NZM88 mice. This monoclonal antibody, which is specific to dynamin-1, binds preferentially in BALB/cByJ cortex and induces substantial expression of cytokines mainly in the hypothalamus. Thus, an antibody to just one brain antigen can induce multiple behavioral changes, and multiple autoantibodies to different brain antigens exist in lupus-prone mice; however, susceptibility to the induction of neurobehavioral deficits is dependent on host genetics.

Animals↗
PubMed2006

Assessing autism-like behavior in mice: variations in social interactions among inbred strains.

Autism is a pervasive developmental disorder, with characteristics including impairments in reciprocal social interaction, impaired communication, and repetitive/stereotyped behaviors. Despite decades of research, the etiology of autism remains elusive. Thus, it is important that we pursue all avenues, in attempting to understand this complicated disorder. One such avenue is the development of animal models. While autism may be uniquely human, there are behavioral characteristics of the disorder that can be established in animal models. Evidence supports a genetic component for this disorder, and over the past few decades the mouse has been a highly valuable tool for the elucidation of pathways involved in many human disorders (e.g., Huntington's disease). As a first step toward establishing a mouse model of autism, we studied same-sex social behavior in a number of inbred mouse strains. In Study 1, we examined intra-strain social behavior of male pairs after one mouse had 15 min prior exposure to the testing chamber. In Study 2, we evaluated intra-strain and inter-strain social behavior when both mice were naive to the testing chamber. The amount and type of social behavior seen differed between these studies, but overall there were general inbred strain differences in social behavior. Some strains were highly social, e.g., FVB/NJ, while others displayed low levels of social behavior (e.g., A/J, BTBR T+tf/J). These strains may be useful in future genetic studies to determine specific genes involved in mouse social behavior, the findings of which should in turn help us to determine some of the genes involved in human social behavior and its disorders (e.g., autism).

Animals↗
PubMed2006

Habituation in rodents: a review of behavior, neurobiology, and genetics.

Habituation to a novel environment in rodents is commonly defined as a change in exploratory or locomotor activity over time (intrasession) or with repeated exposures (intersession). While numerous neuroactive substances are known to influence habituation, neurotransmitters that play particularly important roles are serotonin, acetylcholine, dopamine and glutamate. Although habituation is a complex process, studies over the past two decades have demonstrated that there is a genetic component. At present, although researchers are still attempting to isolate key genes that control habituation, findings in mutant mice have begun to highlight some of the genes that could play a role. The challenge will be in deciphering what genes are directly involved in the process of habituation, what genes indirectly influence habituation through a secondary mechanism, and what genes have no role in habituation but are only affected as part of the downstream cascade.

Animals↗
PubMed2006

Two new behavioral QTLs, Emo4 and Reb1, map to mouse Chromosome 1: Congenic strains and candidate gene identification studies.

By use of newly developed subcongenic strains of mice from a parental B6.129-Il10-/- knockout/congenic strain, we have narrowed the critical region for a new behavioral QTL, called Emo4, for open-field activity to a segment of Chromosome 1 between Erbb4 (68.4Mb) and B3gnt7 (86.2 Mb). We have also uncovered an additional QTL governing repetitive beam breaks in the open field. This QTL, called Reb1, maps to the interval between Asb1 (91.4 Mb) and NM_172851 (100.0 Mb) and is one of the first QTLs mapped for this type of behavior. Genome-wide microarray expression analyses were then undertaken to help to identify candidate genes that may be the cause of these genetic differences in open-field performance. In this effort, we analyzed global gene expression differences in the amygdalae by use of Affymetrix GeneChips between B6, B6.129-Il10-/-, and B6.129R4. Several probe sets representing target Chr 1 genes were found that showed significantly differential expression in the subcongenic and congenic strains. Several candidate genes have been identified. One of these regions coincides with an homologous region in humans that has been associated with autism, a disease whose symptoms include repetitive actions. This study illustrates that the use of congenic strains combined with global gene expression analyses can produce a list of viable candidates. It further shows that caution should be observed when analyzing the effects of knockout/congenic strains because many of the gene expression differences in these comparisons could not be attributable to the ablated Il10 gene but rather to passenger gene effects.

Amygdala↗
PubMed2005

Behavioral differences among fourteen inbred mouse strains commonly used as disease models.

We compared the behavior of 14 inbred mouse strains and an F1 hybrid commonly used in transgenic and knockout production. These strains were 129P3/J, 129S1/SvImJ, 129S6/SvEvTac, 129T2/SvEmsJ, 129X1/SvJ (formerly 129/J, 129/Sv-p+Tyr+Kitl+/J, 129/SvEvTac, 129SvEmsJ, and 129/SvJ, respectively), A/JCrTac, BALB/cAnNTac, C3H/HeNTac, C57BL/6J, C57BL/6NTac, DBA/2NTac, FVB/NTac, NOD/MrkTac, SJL/JCrNTac, and the hybrid B6129S6F1Tac. Performance in three behavioral tests (rotorod, open-field activity-habituation, and contextual and cued fear conditioning) was determined. On the rotorod assay, SJL/JCrNTac mice had the shortest latencies to fall on the first day of testing, and DBA/2NTac mice showed impaired motor learning. Open-field behavior was analyzed using the parameters total distance, center distance, velocity, and vertical activity. 129T2/EvEmsJ and A/JCrTac were least active in the open field, whereas NOD/MrkTac mice were most active. Contrary to earlier studies, we found that all strains habituated to the open field in at least one of these parameters. In contextual and cued fear conditioning, all strains displayed activity suppression. However, FVB/NTac mice reacted less strongly to both context and cue than did most of the other strains. There were no significant behavioral differences between C57BL/6J and C57BL/6NTac, except for higher open-field activity in C57BL/6J female mice. These findings illustrate the importance of the appropriate selection of background strain for transgenic, gene targeting, or drug research.

Animals↗
PubMed2004

Early exploratory behavior abnormalities in R6/1 Huntington's disease transgenic mice.

The Huntington's disease (HD) R6/1 transgenic mouse model, containing a human huntington gene exon-1 with approximately 115 CAG repeats, has multiple biochemical and neuroanatomical abnormalities. Overt neurological symptoms have a relatively late onset (15-21 weeks of age). In this paper, we report exploratory behavior abnormalities that appear well before the onset of obvious pathology. The first differences in exploratory behaviors were evident by 4 weeks of age, when R6/1 mice were hyperactive relative to wild-type controls. However, by 6-7 weeks of age, R6/1 mice were less active than controls. R6/1 mice traveled less in the activity monitor, engaged in fewer stereotypic movements, spent more time resting, and traveled less distance per movement than did wild-type controls. R6/1 mice also displayed intersession habituation abnormalities over the 3 days of testing. These behavioral abnormalities precede the earliest neurochemical and molecular changes reported in the literature to date, and thus indicate subtle early pathology that has not yet been documented. These behavioral abnormalities also occur prior to weight loss in the transgenic mice. Since we were able to detect an abnormal phenotype at an early age in R6/1 mice, this assay may be a useful tool for evaluating therapeutic agents.

Animals↗
PubMed2004

Genetic control of novel food preference in mice.

In food preference studies, mammals are often categorized as being either neophilic or neophobic, i.e., preferring or disliking a novel-tasting food. To date, the genetic factors influencing novel food preference have not been elucidated. To understand this phenomenon, we investigated the genetics of food preference in eight inbred strains of mice. We gave them plain-, cinnamon-, or cocoa-flavored powdered food on day 0 for 45 min and then a choice of cinnamon- or cocoa-flavored food 14 days later. We determined their preference for novel versus already-experienced flavored food and found that some inbred strains chose the food that they had been given previously, while others chose a different food. In particular, the DBA/2 strain chose more cinnamon-flavored food after it was pre-exposed to cinnamon, while the B6 strain chose less cinnamon-flavored food after this initial exposure. The BXD recombinant inbred (RI) strain set was then used to map quantitative trait loci (QTLs) that influence this novel food preference. One of these QTLs was found to map to the distal end of Chromosome (Chr) 8.

Animals↗
PubMed2003

Exploratory activity and fear conditioning abnormalities develop early in R6/2 Huntington's disease transgenic mice.

The Huntington's disease R6/2 transgenic mouse model, containing exon 1 of the human huntingtin gene with a greatly increased CAG repeat length, shows multiple effects of the altered polyglutamine in the resultant protein. The authors report that exploratory and fear conditioning behavioral changes appear well before the onset of obvious pathology. The first differences in exploratory and fear conditioning behavior emerge by 4 and 5 weeks of age, respectively. These behaviors correlate with the earliest neurochemical and molecular changes previously reported and provide insight into functional mechanisms by which cellular and subcellular disease changes may mediate neurological symptoms. These studies provide behavioral protocols suitable for high-throughput screening of therapeutic agents.

Age Factors↗
PubMed2002

The development of behavioral abnormalities in the motor neuron degeneration (mnd) mouse.

The motor neuron degeneration (mnd) mouse, which has widespread abnormal accumulating lipoprotein and neuronal degeneration, has a mutation in CLN8, the gene for human progressive epilepsy with mental retardation (EPMR). EPMR is one of the neuronal ceroid lipofuscinoses (NCLs), a group of neurological disorders characterized by autofluorescent lipopigment accumulation, blindness, seizures, motor deterioration, and dementia. The human phenotype of EPMR suggests that, in addition to the motor symptoms previously categorized, various types of progressive behavioral abnormalities would be expected in mnd mice. We have therefore examined exploratory behavior, fear conditioning, and aggression in 2-3 month and 4-5 month old male mnd mice and age-matched C57BL/6 (B6) controls. The mnd mice displayed increased activity with decreased habituation in the activity monitor, poor contextual and cued memory, and heightened aggression relative to B6 controls. These behavioral deficits were most prominent at 4-5 months of age, which is prior to the onset of gross motor symptoms at 6 months. Our results provide a link from the mutation via pathology to a quantifiable multidimensional behavioral phenotype of this naturally occurring mouse model of NCL.

Aggression↗
PubMed2002

Behavioral differences among 129 substrains: implications for knockout and transgenic mice.

Most knockout (KO) mice are produced with embryonic stem cells derived from a 129 strain. Because most KO strains are backcrossed to B6 yet retain a portion of their genome from 129, especially around the ablated target locus, phenotypes previously attributed to the ablated locus may be due to passenger 129 genes. Thus, the authors decided to test several 129 substrains for their behavioral characteristics. Seven 129 substrains were put through a battery of tasks to determine their behavioral profiles. Differences were found in anxiety-related behaviors in the zero-maze, habituation to the open field, and cued fear conditioning. All strains successfully performed the rotorod task. The behavioral differences observed may have important implications for the interpretation of data and show divergence of behavioral performance in these 129 substrains.

Animals↗