RESUMO
BACKGROUND: The ability to filter sensory information into relevant versus irrelevant stimuli is a fundamental, conserved property of the central nervous system and is accomplished in part through habituation learning. Synaptic plasticity that underlies habituation learning has been described at the cellular level, yet the genetic regulators of this plasticity remain poorly understood, as do circuits that mediate sensory filtering. METHODS: To identify genes critical for plasticity, a forward genetic screen for zebrafish genes that mediate habituation learning was performed, which identified a mutant allele, doryp177, that caused reduced habituation of the acoustic startle response. In this study, we combine whole-genome sequencing with behavioral analyses to characterize and identify the gene affected in doryp177 mutants. RESULTS: Whole-genome sequencing identified the calcium voltage-gated channel auxiliary subunit alpha-2/delta-3 (cacna2d3) as a candidate gene affected in doryp177 mutants. Behavioral characterization of larvae homozygous for two additional, independently derived mutant alleles of cacna2d3, together with failure of these alleles to complement doryp177, confirmed a critical role for cacna2d3 in habituation learning. Notably, detailed analyses of the acoustic response in mutant larvae also revealed increased startle sensitivity to acoustic stimuli, suggesting a broader role for cacna2d3 in controlling innate response thresholds to acoustic stimuli. CONCLUSIONS: Taken together, our data demonstrate a critical role for cacna2d3 in sensory filtering, a process that is disrupted in human CNS disorders, e.g. ADHD, schizophrenia, and autism.
Assuntos
Canais de Cálcio , Habituação Psicofisiológica , Reflexo de Sobressalto , Peixe-Zebra , Estimulação Acústica , Animais , Canais de Cálcio/genética , Habituação Psicofisiológica/genética , Larva/genética , Aprendizagem/fisiologia , Reflexo de Sobressalto/genética , Peixe-Zebra/genéticaRESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that results in cognitive decline and a number of other neuropsychiatric symptoms. One area that is often affected by neuropsychiatric disease is the response to sudden, loud noises, as measured by the acoustic startle response (ASR), and prepulse inhibition (PPI), which indicates sensory-gating abilities. Evidence suggests AD patients, even early in the disease, show alteration in ASR. Studies have also shown changes in this measure in transgenic mouse models of AD. To assess the homology of 5xFAD mice to AD patients, the current study analyzed several aspects of the startle response in these mice using a protocol with fewer trials than previous studies. It was found that the 5xFAD mice had a delayed startle response, similar to what has been observed in AD sufferers. These results suggest the ASR may be a useful tool in assessing the efficacy of potential therapeutics, and that a simplified protocol may be more sensitive to between-groups differences for this task.
Assuntos
Doença de Alzheimer/fisiopatologia , Inibição Pré-Pulso/genética , Tempo de Reação/genética , Estimulação Acústica , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Modelos Animais de Doenças , Comportamento Exploratório , Habituação Psicofisiológica/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Presenilina-1/genética , Reflexo de Sobressalto/genética , Estatísticas não ParamétricasRESUMO
Toll-like receptors (TLRs) mediate the induction of the innate immune system in response to pathogens, injury and disease. However, they also play non-immune roles and are expressed in the central nervous system (CNS) during prenatal and postnatal stages including adulthood. Little is known about their roles in the CNS in the absence of pathology. Several members of the TLR family have been implicated in the development of neural and cognitive function although the contribution of TLR9 to these processes has not been well defined. The current studies were undertaken to determine whether developmental TLR9 deficiency affects motor, sensory or cognitive functions. We report that TLR9 deficient (TLR9(-/-)) mice show a hyper-responsive sensory and motor phenotype compared to wild type (TLR9(+/+)) controls. This is indicated by hypersensitivity to thermal stimuli in the hot plate paw withdrawal test, enhanced motor-responsivity under anxious conditions in the open field test and greater sensorimotor reactivity in the acoustic startle response. Prepulse inhibition (PPI) of the acoustic startle response was also enhanced, which indicates abnormal sensorimotor gating. In addition, subtle, but significant, gait abnormalities were noted in the TLR9(-/-) mice on the horizontal balance beam test with higher foot slip numbers than TLR9(+/+) controls. In contrast, spatial learning and memory, assessed by the Morris water maze, was similar in the TLR9(-/-) and TLR9(+/+) mice. These findings support the notion that TLR9 is important for the appropriate development of sensory and motor behaviors.
Assuntos
Comportamento Animal/fisiologia , Atividade Motora/genética , Atividade Motora/fisiologia , Sensação/genética , Sensação/fisiologia , Receptor Toll-Like 9/deficiência , Receptor Toll-Like 9/fisiologia , Estimulação Acústica , Animais , Ansiedade/genética , Ansiedade/psicologia , Feminino , Habituação Psicofisiológica/genética , Habituação Psicofisiológica/fisiologia , Força da Mão/fisiologia , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/psicologia , Dor/genética , Dor/psicologia , Fenótipo , Equilíbrio Postural/genética , Equilíbrio Postural/fisiologia , Reflexo de Sobressalto/genética , Reflexo de Sobressalto/fisiologia , Receptor Toll-Like 9/genéticaRESUMO
Quantitative trait locus mapping of chemical/inflammatory pain in the mouse identified the Avpr1a gene, which encodes the vasopressin-1A receptor (V1AR), as being responsible for strain-dependent pain sensitivity to formalin and capsaicin. A genetic association study in humans revealed the influence of a single nucleotide polymorphism (rs10877969) in AVPR1A on capsaicin pain levels, but only in male subjects reporting stress at the time of testing. The analgesic efficacy of the vasopressin analog desmopressin revealed a similar interaction between the drug and acute stress, as desmopressin inhibition of capsaicin pain was only observed in nonstressed subjects. Additional experiments in mice confirmed the male-specific interaction of V1AR and stress, leading to the conclusion that vasopressin activates endogenous analgesia mechanisms unless they have already been activated by stress. These findings represent, to the best of our knowledge, the first explicit demonstration of analgesic efficacy depending on the emotional state of the recipient, and illustrate the heuristic power of a bench-to-bedside-to-bench translational strategy.
Assuntos
Analgésicos/uso terapêutico , Limiar da Dor/efeitos dos fármacos , Dor/tratamento farmacológico , Dor/genética , Dor/fisiopatologia , Vasopressinas/uso terapêutico , Animais , Animais Recém-Nascidos , Capsaicina/efeitos adversos , Desamino Arginina Vasopressina/uso terapêutico , Modelos Animais de Doenças , Feminino , Estudos de Associação Genética , Habituação Psicofisiológica/efeitos dos fármacos , Habituação Psicofisiológica/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Peso Molecular , Dor/induzido quimicamente , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Limiar da Dor/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas , Receptores de Vasopressinas/deficiência , Receptores de Vasopressinas/genética , Fatores Sexuais , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologiaRESUMO
Evidence suggests that the heterozygous transmembrane domain mutant mouse model for the schizophrenia candidate gene neuregulin 1 (Nrg1 HET) exhibits a deficit in prepulse inhibition (PPI). However, not all mouse models for Nrg1 exhibit PPI deficits. Thus, our study intended to clarify the severity of the initially described PPI deficit in Nrg1 HET mice. For this, Nrg1 mutant mice and wild type-like littermates of one breeding colony were tested for PPI in four different phenotyping facilities in Australia employing a variety of different PPI protocols with fixed and variable interstimulus intervals (ISIs). Testing mutant and wild type-like mice in three Australian phenotyping facilities using PPI protocols with variable ISIs revealed no effect of mutant transmembrane domain Nrg1 on sensorimotor gating. Changes to the startle response and startle response habituation were site/protocol-specific. The employment of two different PPI protocols at the same phenotyping facility revealed a protocol-dependent and site-specific facilitation of PPI in Nrg1 mutant mice compared to wild type-like mice. In conclusion, the often-noted PPI phenotype of the transmembrane domain Nrg1 mutant mouse model is highly PPI protocol-specific and appears sensitive to the particular conditions of the test laboratory. Our study describes wild type-like PPI under most test conditions and across three different laboratories. The research suggests that analysing one of the alleged hallmarks of animal models for schizophrenia must be done carefully: to obtain reliable PPI data it seems necessary to use more than one particular PPI protocol.
Assuntos
Mutação/fisiologia , Neuregulina-1/genética , Neuregulina-1/fisiologia , Filtro Sensorial/genética , Filtro Sensorial/fisiologia , Estimulação Acústica , Animais , Modelos Animais de Doenças , Habituação Psicofisiológica/genética , Habituação Psicofisiológica/fisiologia , Masculino , Potenciais da Membrana/fisiologia , Camundongos , Reflexo de Sobressalto/fisiologia , EsquizofreniaRESUMO
The neurotransmitter acetylcholine (ACh) plays a crucial role in both the central and peripheral nervous system. Central cholinergic transmission is important for cognitive functions and cholinergic disruptions have been associated with different neural disorders. We here tested the role of cholinergic transmission in basic cognitive functions, i.e. in prepulse inhibition (PPI) and short-term habituation (STH) as well as long-term habituation (LTH) of startle using mice with a 65% knockdown (KD) of the vesicular ACh transporter (VAChT). These mice are slow in refilling cholinergic synaptic transmitter vesicles, leading to a reduced cholinergic tone. Prepulse inhibition has been assumed to be mediated by cholinergic projections from the midbrain to the reticular formation. Surprisingly, PPI and STH were normal in these mice, whereas LTH was disrupted. This disruption could be rescued by pre-testing injections of the ACh esterase inhibitor galantamine, but not by post-testing injections. The lack of a PPI deficit might be because of the fact that VAChT KD mice show disruptions mainly in prolonged cholinergic activity, therefore the transient activation by prepulse processing might not be sufficient to deplete synaptic vesicles. The disruption of LTH indicates that the latter depends on a tonic cholinergic inhibition. Future experiments will address which cholinergic cell group is responsible for this effect.
Assuntos
Acetilcolina/metabolismo , Habituação Psicofisiológica/genética , Filtro Sensorial/genética , Proteínas Vesiculares de Transporte de Acetilcolina/genética , Estimulação Acústica , Animais , Camundongos , Camundongos Knockout , Reflexo de Sobressalto/genética , Transmissão Sináptica/genética , Vesículas Sinápticas/genética , Vesículas Sinápticas/metabolismo , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismoRESUMO
Inhibition of glycine transporter 1 (GlyT1) augments N-methyl-D-aspartate receptor (NMDAR)-mediated transmission and represents a potential antipsychotic drug target according to the NMDAR hypofunction hypothesis of schizophrenia. Preclinical evaluation of GlyT1 inhibiting drugs using the prepulse inhibition (PPI) test, however, has yielded mixed outcomes. Here, we tested for the first time the impact of two conditional knockouts of GlyT1 on PPI expression. Complete deletion of GlyT1 in the cerebral cortices confers resistance to PPI disruption induced by the NMDAR blocker MK-801 (0.2mg/kg, i.p.) without affecting PPI expression in unchallenged conditions. In contrast, restricting GlyT1 deletion to neurons in forebrain including the striatum significantly attenuated PPI, and the animals remained sensitive to the PPI-disruptive effect of MK-801 at the same dose. These results demonstrate in mice that depending on the regional and/or cell-type specificity, deletion of the GlyT1 gene could yield divergent effects on PPI.
Assuntos
Deleção de Genes , Proteínas da Membrana Plasmática de Transporte de Glicina/genética , Inibição Psicológica , Prosencéfalo/metabolismo , Filtro Sensorial/genética , Estimulação Acústica , Análise de Variância , Animais , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/fisiologia , Feminino , Habituação Psicofisiológica/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/genética , Reflexo de Sobressalto/genéticaRESUMO
Stress exacerbates several physical and psychological disorders. Voluntary exercise can reduce susceptibility to many of these stress-associated disorders. In rodents, voluntary exercise can reduce hypothalamic-pituitary-adrenocortical (HPA) axis activity in response to various stressors as well as upregulate several brain neurotrophins. An important issue regarding voluntary exercise is whether its effect on the reduction of HPA axis activation in response to stress is due to the physical activity itself or simply the enhanced environmental complexity provided by the running wheels. The present study compared the effects of physical activity and environmental complexity (that did not increase physical activity) on HPA axis habituation to repeated stress and modulation of brain neurotrophin mRNA expression. For six weeks, male rats were given free access to running wheels (exercise group), given 4 objects that were repeatedly exchanged (increased environmental complexity group), or housed in standard cages. On week 7, animals were exposed to 11 consecutive daily 30-min sessions of 98-dBA noise. Plasma corticosterone and adrenocorticotropic hormone were measured from blood collected directly after noise exposures. Tissue, including brains, thymi, and adrenal glands was collected on Day 11. Although rats in both the exercise and enhanced environmental complexity groups expressed higher levels of BDNF and NGF mRNA in several brain regions, only exercise animals showed quicker glucocorticoid habituation to repeated audiogenic stress. These results suggest that voluntary exercise, independent from other environmental manipulations, accounts for the reduction in susceptibility to stress.
Assuntos
Estimulação Acústica/efeitos adversos , Habituação Psicofisiológica/genética , Sistema Hipotálamo-Hipofisário/fisiopatologia , Fatores de Crescimento Neural/genética , Condicionamento Físico Animal/métodos , Sistema Hipófise-Suprarrenal/fisiopatologia , RNA Mensageiro/metabolismo , Estresse Psicológico/genética , Estimulação Acústica/métodos , Animais , Modelos Animais de Doenças , Ambiente Controlado , Masculino , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologiaRESUMO
Prepulse inhibition (PPI) of the startle response is a measure of sensorimotor gating, a process that filters out extraneous sensory, motor and cognitive information. Humans with neurological and psychiatric disorders, including schizophrenia, obsessive-compulsive disorder and Huntington's disease, exhibit a reduction in PPI. Habituation of the startle response is also disrupted in schizophrenic patients. In order to elucidate the genes involved in sensorimotor gating, we phenotyped 472 mice from an F(2) cross between LG/J × SM/J for PPI and genotyped these mice genome-wide using 162 single nucleotide polymorphism (SNP) markers. We used prepulse intensity levels that were 3, 6 and 12 dB above background (PPI3, PPI6 and PPI12, respectively). We identified a significant quantitative trait locus (QTL) on chromosome 12 for all three prepulse intensities as well as a significant QTL for both PPI6 and PPI12 on chromosome 11. We identified QTLs on chromosomes 7 and 17 for the startle response when sex was included as an interactive covariate and found a QTL for habituation of the startle response on chromosome 4. We also phenotyped 135 mice from an F(34) advanced intercross line (AIL) between LG/J × SM/J for PPI and genotyped them at more than 3000 SNP markers. Inclusions of data from the AIL mice reduced the size of several of these QTLs to less than 5 cM. These results will be useful for identifying genes that influence sensorimotor gaiting and show the power of AIL for fine mapping of QTLs.
Assuntos
Locos de Características Quantitativas/genética , Reflexo de Sobressalto/genética , Reflexo de Sobressalto/fisiologia , Filtro Sensorial/genética , Filtro Sensorial/fisiologia , Estimulação Acústica , Análise de Variância , Animais , Mapeamento Cromossômico , Cruzamentos Genéticos , Feminino , Marcadores Genéticos , Genótipo , Habituação Psicofisiológica/genética , Escore Lod , Masculino , Camundongos , Camundongos Endogâmicos , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Caracteres Sexuais , Especificidade da EspécieRESUMO
Acoustic startle response and its plasticity, e.g., habituation and prepulse inhibition (PPI), have been extensively investigated, being altered in several neuropsychiatric disorders. Yet, little is known about the expression of startle-related behaviors during adolescence, a critical phase in the development of a variety of major neuropsychiatric pathologies. The present study investigated for the first time startle behaviors across adolescence in male mice of the inbred strains C57BL/6J and DBA/2J. Pre-pubertal (4 weeks of age) mice displayed reduced startle reactivity and altered PPI compared to adult animals (8 weeks of age), but these effects were observed only in the C57BL/6J strain. Strain differences were also clearly detected for startle response, habituation, and PPI. All effects were modulated by the intensity of the pulse stimulus and were not confounded by differences in anxiety levels. Our data demonstrate that genetic factors and the early adolescent phase are critically important considerations in the design of mouse models of neuropsychiatric disturbances.
Assuntos
Genótipo , Habituação Psicofisiológica/genética , Inibição Psicológica , Reflexo de Sobressalto/genética , Estimulação Acústica , Fatores Etários , Animais , Nível de Alerta/genética , Medo , Masculino , Camundongos , Camundongos Endogâmicos C57BL/genética , Camundongos Endogâmicos DBA/genética , Fenótipo , Especificidade da EspécieRESUMO
Recent studies on the phosphoprotein synapsin II have revealed reduced expression in postmortem medial prefrontal cortex tissues from subjects with schizophrenia, and chronic antipsychotic drug treatment has resulted in concurrent increases in synapsin II mRNA and protein levels. Collectively, this research suggests a role of synapsin II in the pathophysiology of schizophrenia; however, whether synapsin II plays a causal role in this disease process still remains unclear. Therefore, the goal of this investigation was to examine whether synapsin II knockout mice display behavioral abnormalities commonly expressed in preclinical animal models of schizophrenia, namely deficits in prepulse inhibition (PPI), decreased social behavior, and locomotor hyperactivity. Results indicate that mice with knockout of the synapsin II gene demonstrate deficits in PPI at three prepulse intensities (67, 70, and 73 dB), along with deficits in habituation to startle to a 110 dB acoustic pulse. Knockout animals also expressed decreased social behavior and increased locomotor activity when compared to wildtype and heterozygous populations. Complete knockout of the synapsin II gene was confirmed in postmortem brain tissues via immunoblotting. In conclusion, these results confirm that synapsin II knockout mice display behavioral endophenotypes similar to established preclinical animal models of schizophrenia, and lend support to the notion that abnormalities in synapsin II expression may play a causal role in the underlying pathophysiological mechanisms of schizophrenia.
Assuntos
Modelos Animais de Doenças , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Sinapsinas/deficiência , Estimulação Acústica/métodos , Análise de Variância , Animais , Comportamento Animal/fisiologia , Feminino , Regulação da Expressão Gênica/genética , Genótipo , Habituação Psicofisiológica/genética , Relações Interpessoais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/genética , Inibição Neural/genética , Psicoacústica , Reflexo de Sobressalto/genética , Sinapsinas/metabolismoRESUMO
Arginine vasopressin and the arginine vasopressin 1a (AVPR1a) gene contribute to a range of social behaviors both in lower vertebrates and in humans. Human promoter-region microsatellite repeat regions (RS1 and RS3) in the AVPR1a gene region have been associated with autism spectrum disorders, prosocial behavior and social cognition. Prepulse inhibition (PPI) of the startle response to auditory stimuli is a largely autonomic response that resonates with social cognition in both animal models and humans. Reduced PPI has been observed in disorders including schizophrenia that are distinguished by deficits in social skills. In the current investigation association was examined between PPI and the AVPR1a RS1 and RS repeat regions and PPI in a group of 113 nonclinical subjects. Using a robust family-based strategy, association was observed between AVPR1a promoter-region repeat length, especially RS3) and PPI (30 ms: global p=0.04; 60 ms p=0.006; 120 ms p=0.008). Notably, longer RS3 alleles were associated with greater levels of prepulse inhibition. Using a short/long classification scheme for the repeat regions, significant association was also observed between all three PPI intervals (30, 60 and 120 ms) and both RS1 and RS3 polymorphisms (PBAT: FBAT-PC(2) statistic p=0.047). Tests of within-subject effects (SPSS GLM) showed significant sexxRS3 interactions at 30 ms (p=0.045) and 60 ms (p=0.01). Longer alleles, especially in male subjects, are associated with significantly higher PPI response, consistent with a role for the promoter repeat region in partially molding social behavior in both animals and humans. This is the first report in humans demonstrating a role of the AVPR1a gene in contributing to the PPI response to auditory stimuli.
Assuntos
Habituação Psicofisiológica/genética , Inibição Neural/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Receptores de Vasopressinas/genética , Reflexo de Sobressalto/genética , Estimulação Acústica , Adolescente , Adulto , Feminino , Frequência do Gene , Humanos , Masculino , Regiões Promotoras Genéticas/genética , Caracteres Sexuais , Adulto JovemRESUMO
Initial playback of recorded birdsong triggers a number of responses in zebra finches, including overt listening behavior and ERK pathway-dependent activation of zenk gene transcription in the auditory lobule of the forebrain. Repetition of one song stimulus leads to persistent habituation of these responses, as measured by subsequent presentations 1 day later. In this study, we examined the causal relationships between behavioral and molecular (ERK/zenk) habituation. In a within-subject comparison, we found a strong correlation with the level of prior training for both responses (duration of behavioral listening and magnitude of zenk expression), but little correlation between these responses for birds within the same treatment group. We then tested the hypothesis that ERK/zenk activation during training is necessary for the development of habituation measured 1 day later. Cannula-directed infusion of a pharmacological inhibitor of ERK activation (U0126) immediately before training blocked the development of habituation of the zenk gene response. However, measurement of the effect on behavioral habituation was confounded because birds that were infused with a non-active drug analogue (U0124) showed a decreased response 1 day later, even to novel songs. We conclude that the behavioral response to song stimulation is strongly influenced by factors other than song familiarity, whereas the zenk response in the forebrain may be a more accurate indicator of actual experience hearing a particular song.
Assuntos
Tentilhões/fisiologia , Habituação Psicofisiológica/genética , Habituação Psicofisiológica/fisiologia , Vocalização Animal/fisiologia , Estimulação Acústica , Animais , Western Blotting , Butadienos/farmacologia , Proteína 1 de Resposta de Crescimento Precoce/genética , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Hibridização In Situ , Masculino , Microinjeções , Nitrilas/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Prepulse inhibition (PPI) of startle is an operational measure of sensorimotor gating that is reduced in some neuropsychiatric disorders (e.g. schizophrenia). Animal models have revealed insight into the neuronal and pharmacological underpinnings of PPI-deficits. Recent work has shown that a PPI-deficit can be selectively bred in Wistar rats and is already stable in the second filial generation. We here report on developmental and parametric characteristics of sensorimotor gating deficits in the 4th and 6th filial generation of male rats selectively bred for low PPI (low PPI) compared to rats with normal levels of PPI (high PPI). Low PPI rats showed significantly reduced PPI and variable startle magnitude (in pulse alone trials) along with reduced short-term habituation of startle as adults. Reduced PPI in the low PPI rats was found throughout development (tested on postnatal days 21, 35, 49, 70). PPI-deficits in the low PPI rats were evident at prepulse intensities ranging from 62-86 dB and for interstimulus intervals ranging between 30-1000 ms. These behavioral data add to a growing body of knowledge about the genetic basis of sensorimotor gating deficits and suggest that low PPI rats have potential use as an intermediate phenotype in schizophrenia research. The stable phenotype of breeding-induced PPI-deficits and reduced startle habituation indicates that PPI has strong genetic determinants and that selectively bred rats can be used for future neurophysiological, anatomical, pharmacological, and genomic analyses.
Assuntos
Habituação Psicofisiológica/genética , Reflexo de Sobressalto/genética , Estimulação Acústica , Envelhecimento , Animais , Animais Recém-Nascidos , Modelos Animais , Fenômenos Fisiológicos do Sistema Nervoso , Ratos , Ratos WistarRESUMO
Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating, a process critical to normal cognitive function. Researchers (D. Feifel & K. Priebe, 2001) have identified PPI deficits in the Brattleboro rat, a genetically vasopressin-deficient strain that is derived from the Long Evans rat. The absence of vasopressin, a neuropeptide involved in affiliative behaviors, may adversely affect the rearing of offspring by Brattleboro dams, perhaps accounting for their attenuated PPI. Cross-fostering of Long Evans and Brattleboro pups did not alter the PPI deficits in Brattleboro rats. However, the magnitude and habituation of the startle response, which normally differs between Brattleboro and Long Evans rats, was not different in cross-fostered rats. The authors' results indicated that abnormal rearing by Brattleboro dams may contribute to the startle magnitude and habituation abnormalities in Brattleboro Rats but not to their PPI deficits, suggesting that their sensorimotor gating deficits result from their genetic deviation from Long Evans rats.
Assuntos
Arginina Vasopressina/fisiologia , Comportamento Materno/fisiologia , Reflexo de Sobressalto/fisiologia , Meio Social , Estimulação Acústica , Animais , Animais Recém-Nascidos , Arginina Vasopressina/genética , Feminino , Genótipo , Habituação Psicofisiológica/genética , Habituação Psicofisiológica/fisiologia , Masculino , Fenótipo , Ratos , Ratos Brattleboro , Ratos Long-Evans , Reflexo de Sobressalto/genéticaRESUMO
The neural cell adhesion molecule (NCAM) plays important roles in development of the nervous system and in synaptic plasticity and memory formation in the adult. The present study sought to further investigate the role of NCAM in learning by testing habituation and footshock sensitization learning of the startle response (SR) in NCAM null mutant (NCAM-/-) and wildtype littermate (NCAM+/+) mice. Whereas habituation is a form of non-associative learning, footshock sensitization is induced by rapid contextual fear conditioning. Habituation was tested by repetitive presentation of acoustic and tactile startle stimuli. Although NCAM-/- mice showed differences in sensitivity in both stimulus modalities, habituation learning was intact in NCAM-/- mice, suggesting that NCAM does not play a role in the mechanisms underlying synaptic plasticity in the startle pathway. Footshock sensitization was elicited by presentation of electric footshocks between two series of acoustic stimuli. In contrast to habituation, footshock sensitization learning was attenuated in NCAM-/- mice: the acoustic SR increase after the footshocks was lower in the mutant than in wildtype mice, indicating that NCAM plays an important role in the relevant brain areas, such as amygdala and/or the hippocampus.
Assuntos
Aprendizagem por Associação/fisiologia , Habituação Psicofisiológica/fisiologia , Moléculas de Adesão de Célula Nervosa/fisiologia , Reflexo de Sobressalto/fisiologia , Estimulação Acústica , Animais , Limiar Auditivo/fisiologia , Condicionamento Operante/fisiologia , Feminino , Habituação Psicofisiológica/genética , Audição/genética , Audição/fisiologia , Camundongos , Camundongos Knockout , Moléculas de Adesão de Célula Nervosa/genética , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Reflexo de Sobressalto/genética , Tato/genética , Tato/fisiologiaRESUMO
One of the characteristic manifestations in several neurodegenarative diseases is the loss of voluntary motor control and the development of involuntary movements. In order to determine the suitability of six mouse strains as transgenic background strains we investigated performance on a variety of tasks designed to identify subtle changes in motor control. On both the accelerating and the staggered speed rotarod all six mouse strains performed well. However, latency to fall from the rod was sensitive to both rotarod speed and repeated exposure to the apparatus. Performance of the DBA/2 mouse strain was highly variable across the time points used. On the acoustic startle test CBA mice showed the greatest degree of reactivity to the acoustic startle stimuli with both the C57 and DBA showing the least. Complex strain differences were also identified on measures of habituation to the startle stimuli and variations in the prepulse noise level, and prepulse/startle delay. Gait analysis using the footprint test did not reveal strain differences on measures of base width, overlap or stride length but the 129S2/Sv strain took significantly longer to traverse the runway than the other mouse strains. Finally, the swim tank test detected complex strain differences in swim speed, and the number of fore- and hindpaw paddles required to swim the length of the tank. These data taken together suggest that choice of background strain is a crucial consideration for the repeated behavioural assessment of motor deficits in transgenic mouse models of disease.
Assuntos
Inibição Neural/fisiologia , Desempenho Psicomotor/fisiologia , Reflexo de Sobressalto/fisiologia , Estimulação Acústica , Análise de Variância , Animais , Nível de Alerta/fisiologia , Marcha/genética , Marcha/fisiologia , Engenharia Genética , Habituação Psicofisiológica/genética , Habituação Psicofisiológica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Camundongos Endogâmicos , Camundongos Transgênicos , Modelos Animais , Inibição Neural/genética , Tempo de Reação , Reflexo de Sobressalto/genética , Teste de Desempenho do Rota-Rod , Especificidade da EspécieRESUMO
Adenosine and dopamine receptors interact in the CNS to modulate behaviour, including sensorimotor gating. Prepulse inhibition (PPI) has been suggested to be an operational measure of sensorimotor gating. PPI and startle habituation are disrupted in patients with schizophrenia. In experimental animals, both parameters are modulated by dopaminergic and adenosine receptor agonists and antagonists. In the present study, we measured PPI and startle habituation in mice that lack functional adenosine A(2A) receptors. Startle amplitudes, startle habituation and PPI were significantly reduced in mice homozygous null for the adenosine A(2A) receptor (A(2A)(-/-)). In addition, differential effects of amphetamine and MK-801 on startle amplitude, startle habituation and PPI were observed between A(2A)(-/-) and wildtype controls. These data support the involvement of adenosine A(2A) receptors in regulation of PPI and startle habituation.
Assuntos
Habituação Psicofisiológica/fisiologia , Inibição Neural/fisiologia , Receptores Purinérgicos P1/fisiologia , Reflexo de Sobressalto/fisiologia , Limiar Sensorial/fisiologia , Estimulação Acústica , Anfetamina/farmacologia , Animais , Maleato de Dizocilpina/farmacologia , Dopaminérgicos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Habituação Psicofisiológica/efeitos dos fármacos , Habituação Psicofisiológica/genética , Masculino , Camundongos , Camundongos Knockout , Inibição Neural/efeitos dos fármacos , Inibição Neural/genética , Receptor A2A de Adenosina , Receptores Purinérgicos P1/deficiência , Receptores Purinérgicos P1/genética , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/genética , Limiar Sensorial/efeitos dos fármacosRESUMO
The pathogenic mechanisms of gene-environment interactions determining variability of human neurodevelopmental disorders remain unclear. In the two consecutive papers, we used the neonatal Borna disease virus (BDV) infection rat model of neurodevelopmental damage to evaluate brain pathology, monoamine alterations, behavioral deficits, and responses to pharmacological treatments in two inbred rat strains, Lewis and Fisher344. The first paper reports that despite comparable virus replication and distribution in the brain of both rat strains, neonatal BDV infection produced significantly greater thinning of the neocortex in BDV-infected Fisher344 rats compared to BDV-infected Lewis rats, while no strain-related differences were found in BDV-induced granule cell loss in the dentate gyrus of the hippocampus and cerebellar hypoplasia. Unlike BDV-infected Lewis rats, more severe BDV-induced brain pathology in Fisher344 rats was associated with (1) greater locomotor activity to novelty and (2) impairment of habituation and prepulse inhibition of the acoustic startle response. The present data demonstrate that the same environmental insult can produce differential neuroanatomical and behavioral abnormalities in genetically different inbred rat strains.
Assuntos
Doença de Borna/genética , Encéfalo/virologia , Predisposição Genética para Doença/genética , Degeneração Neural/genética , Neurônios/virologia , Estimulação Acústica , Animais , Animais Recém-Nascidos , Peso Corporal/genética , Doença de Borna/virologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Feminino , Genótipo , Habituação Psicofisiológica/genética , Degeneração Neural/fisiopatologia , Degeneração Neural/virologia , Inibição Neural/genética , Neurônios/patologia , Gravidez , Agitação Psicomotora/genética , Agitação Psicomotora/fisiopatologia , Agitação Psicomotora/virologia , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Reflexo de Sobressalto/genética , Carga ViralRESUMO
BACKGROUND: Corticotropin-releasing hormone (CRH) hyperactivity in transgenic mice overexpressing CRH in the brain (CRH-OE(2122)) appears to be associated with chronic stress-like alterations, including increased CRH content in the hypothalamus, changes in hypothalamus-pituitary-adrenal axis regulation, and increased heart rate and body temperature. In the present study, we investigated if sensory information processing of startling auditory stimuli was affected in CRH-OE(2122) mice. METHODS: CRH-OE(2122) mice (on C57BL/6J background) were subjected to a number of procedures probing sensory information processing mechanisms, including the acoustic startle response, habituation, and prepulse inhibition of startle. RESULTS: CRH-OE(2122) mice displayed reduced acoustic startle reactivity and increased motor activity during startle testing compared to wild-type mice. Furthermore, transgenic mice did not show habituation of the startle response after repeated exposure to the auditory stimulus, or habituation across procedures. CRH-OE(2122) mice exhibited robust impairments of prepulse inhibition in two different paradigms. CONCLUSIONS: The results in CRH-OE(2122) mice indicate that chronic CRH hyperactivity is associated with reductions in startle reactivity, habituation, and prepulse inhibition. The latter two abnormalities are also observed in schizophrenia patients. We conclude that chronic CRH excess may reduce behavioral reactivity to environmental stimuli and impair information processing mechanisms.