ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Knowledge of the genetic and molecular events underlying the neuroendocrine and behavioural sequelae of the response to stress has advanced rapidly over recent years. The response of an individual to a stressful experience is a polygenic trait, but also involves non‐genetic sources of variance. Using a combination of top‐down (quantitative trait locus [QTL] and microarray analysis) and bottom‐up (gene targeting, transgenesis, antisense technology and random mutagenesis) strategies, we are beginning to dissect the molecular players in the mediation of the stress response. Given the wealth of the data obtained from mouse mutants, this review will primarily focus on the contributions made by transgenesis and knockout studies, but the relative contribution of QTL studies and microarray studies will also be briefly addressed. From these studies it is evident that several neuroendocrine and behavioural alterations induced by stress can be modelled in mouse mutants with alterations in hypothalamic–pituitary–adrenal axis activity or other, extrahypothalamic, neurotransmitter systems known to be involved in the stress response. The relative contribution of these models to understanding the stress response and their limitations will be discussed.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The serotonin1A(5‐HT1A) receptor has been under intense investigation, mostly due to its putative role in both the etiology and therapeutic treatments of depression and anxiety‐related behaviors. However, the exact contribution of this receptor to normal brain physiology and disease processes remains poorly understood, due to a complex expression pattern and multiple functions. Recent development in genetic and genomic approaches allows not only for more refined functional dissection, but also for probing large gene databases for unknown gene product interactions. Here, we describe an experimental approach that is based on a combination of regional and temporal genetic manipulations of the 5‐HT1Areceptor with large‐scale gene expression profiling to attempt to untangle the distinct roles for this receptor in particular brain regions, as well as to identify molecular partners that mediate its function. In turn, new leads for understanding mechanisms of anxiety, depression and their pharmacological treatments may be generated.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The 5‐HT1Areceptor has been implicated in the modulation of anxiety processes, mainly via pharmacological experiments. The recent production, in three independent research groups, of 5‐HT1Areceptor knockout (R KO) mice in three different genetic backgrounds (C57BL/6J, 129/Sv, Swiss–Webster) led to the intriguing finding that all mice, independent from the genetic background strain from which the null mutants were made, showed an ‘anxious’ phenotype compared to corresponding wild‐type mice. The present paper reviews the behavioral findings in these three KO lines and focuses on new findings in the 129/Sv‐KO mice. These mice were more anxious or stress‐prone only under specific conditions (high stress) and not as broadly as suggested from the initial studies. The 5‐HT1AR KO made in the Swiss–Webster background displays disturbances in the GABAA–benzodiazepine (BZ) receptor system in the brain, including downregulation of GABAAα1and α2subunits in the amygdala. In contrast, the GABAA‐BZ receptor system seems to function normally in the 5‐HT1AR KO in the 129/Sv background suggesting that changes in the GABAA‐BZ receptor system may not be a prerequisite for anxiety but rather could have a modifying effect on this phenotype. It can be concluded that the constitutive absence of the 5‐HT1Areceptor gene and receptor leads to a more ‘anxious’ mouse, dependent on the stress level but independent from the strain. Depending on the genetic background, this null mutation may be associated with changes in GABAA‐ergic neurotransmission. It is as yet unclear which mechanisms are involved in this intriguing differentiation.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Anxiolytic drugs exert their pharmacological actions by binding to molecular targets, such as benzodiazepine receptors or 5‐hydroxytryptamine (5‐HT) receptors. Specific genes encode these receptors, or the subunits of which they are formed. Therefore, genetic factors may influence strongly the ability of anti‐anxiety agents to produce their behavioural effects. The literature on this subject is reviewed here, with emphasis on data derived from studies with rodents. We present in a critical way the animal models used in the studies aimed at investigating the genetic basis of the action of anxiolytic compounds, including inbred mice, selected lines, linkage strains or mice generated by targeted mutation. Data show that increased anxiety‐like behaviour is not a predictive factor for increased sensitivity to anxiolytic treatment, and it is possible that gene deletion might not be isomorphic to pharmacological antagonism. It is suggested that the strain differences in anxiety‐like behaviour may be used as a tool in assaying anxiolytic activity of new drugs.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Fibroblast growth factor receptor‐3 (FGFR‐3) regulates aspects of bone development. Mutations in the FGFR‐3 gene (Fgfr3) in humans and mice produce vertebral abnormalities and bone deformities. The present study evaluated the behavioural concomitants of theFgfr3−/− mutation.Fgfr3−/− null mutant mice displayed severe impairments of motor abilities as detected on the rotarod, wire hang and open field tests. Absence of prepulse inhibition of acoustic startle was seen at prepulse levels from 74 to 86 dB. The motor deficits appear to be a direct and predicted consequence of the skeletal kyphosis, scoliosis and long bone overgrowth previously reported inFgfr3null mutant mice. The behavioural phenotype displayed by these mutant mice complements their anatomical, physiological and biochemical phenotypes, to complete the characterization of the functional outcome of a single gene mutation. Simple, robust behavioural symptoms, such as poor rotorod performance inFgfr3knockout mice, can provide useful surrogate markers to evaluate pharmacological treatments and gene therapies for human genetic diseases.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Plasminogen activators are serine proteases induced in the brain by electrical activity leading to synaptic remodelling. They are classified into two distinct subtypes, tissue plasminogen activating factor and urokinase plasminogen activating factor (tPA and uPA, respectively), which are both expressed in brain areas thought to be important in learning and memory. Plasminogen activator inhibitor‐1 (PAI‐1) is the primary inhibitor of tPA and uPA activity, and is expressed in corresponding brain areas. Mice lacking tPA show a deficit in the acquisition of a 15 s differential reinforcement of low rate of responding (DRL15″) task relative to their wild types (WTs) under certain conditions. The current set of experiments were designed to investigate further the role of tPA and to extend our knowledge to uPA and PAI‐1, using mice with the respective genes deleted (uPA−/− andPAI‐1−/− mice) in the DRL15″ task.uPA−/− mice showed no disruption of DRL acquisition, butPAI‐1−/− mice showed a deficit similar to that seen intPA−/− mice. In an attempt to compensate for this deficit, experiments using a fixed number of reinforcers or a signalled‐DRL15″ schedule, similar to that used in rat lesion studies of DRL, were performed.tPA−/− mice were able to complete the signalled‐DRL task as well as their WTs, and, similarly,PAI‐1−/− mice were able to learn the fixed‐number‐of‐reinforcers‐DRL15″ schedule and the signalled‐DRL schedule. These data indicate thatuPAdeletion does not affect performance of a standard DRL15″ task, whereas deletion ofPAI‐1has the same behavioural consequences in these tasks as deletion oftPA. Deficits of both genotypes can be attenuated by providing either external information on completion of the delay or by equalizing the number of reinforcers obtained.

ISSN:0955-8810    

出版商:OVID    

年代:2001

数据来源: OVID