RESUMEN
EphA4 receptor (EphA4) tyrosine kinase is an important regulator of central nervous system development and synaptic plasticity in the mature brain, but its relevance to the control of normal behavior remains largely unexplored. This study is the first attempt to obtain a behavioral profile of constitutive homozygous and heterozygous EphA4 knockout mice. A deficit in locomotor habituation in the open field, impairment in spatial recognition in the Y-maze and reduced probability of spatial spontaneous alternation in the T-maze were identified in homozygous EphA4(-/-) mice, while heterozygo us EphA4(+/-) mice appeared normal on these tests in comparison with wild-type (WT) controls. The multiple phenotypes observed in EphA4(-/-) mice might stem from an underlying deficit in habituation learning, reflecting an elementary form of nonassociative learning that is in contrast to Pavlovian associative learning, which appeared unaffected by EphA4 disruption. A deficit in motor coordination on the accelerating rotarod was also demonstrated only in EphA4(-/-) mice--a finding in keeping with the presence of abnormal gait in EphA4(-/-) mice--although they were able to improve performance over training. There was no evidence for substantial changes in major neurochemical markers in various brain regions rich in EphA4 as shown by post-mortem analysis. This excludes the possibility of major neurochemical compensation in the brain of EphA4(-/-) mice. In summary, we have demonstrated for the first time the behavioral significance of EphA4 disruption, supporting further investigation of EphA4 as a possible target for behavioral interventions where habituation deficits are prominent.
Asunto(s)
Habituación Psicofisiológica/genética , Aprendizaje por Laberinto/fisiología , Actividad Motora/genética , Desempeño Psicomotor/fisiología , Receptor EphA4/genética , Reconocimiento en Psicología/fisiología , Animales , Encéfalo/fisiología , Heterocigoto , Homocigoto , Masculino , Memoria a Corto Plazo/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Plasticidad Neuronal/genética , FenotipoRESUMEN
The neuromodulator adenosine maintains brain homeostasis and regulates complex behaviour via activation of inhibitory and excitatory adenosine receptors (ARs) in a brain region-specific manner. AR antagonists such as caffeine have been shown to ameliorate cognitive impairments in animal disease models but their effects on learning and memory in normal animals are equivocal. An alternative approach to reduce AR activation is to lower the extracellular tone of adenosine, which can be achieved by up-regulating adenosine kinase (ADK), the key enzyme of metabolic adenosine clearance. However, mice that globally over-express an Adk transgene ('Adk-tg' mice) were devoid of a caffeine-like pro-cognitive profile; they instead exhibited severe spatial memory deficits. This may be mechanistically linked to cortical/hippocampal N-methyl-d-aspartate receptor (NMDAR) hypofunction because the motor response to acute MK-801 was also potentiated in Adk-tg mice. Here, we evaluated the extent to which the behavioural phenotypes of Adk-tg mice might be modifiable by up-regulating adenosine levels in the cortex/hippocampus. To this end, we investigated mutant 'fb-Adk-def' mice in which ADK expression was specifically reduced in the telencephalon leading to a selective increase in cortical/hippocampal adenosine, while the rest of the brain remained as adenosine-deficient as in Adk-tg mice. The fb-Adk-def mice showed an even greater impairment in spatial working memory and a more pronounced motor response to NMDAR blockade than Adk-tg mice. These outcomes suggest that maintenance of cortical/hippocampal adenosine homeostasis is essential for effective spatial memory and deviation in either direction is detrimental with increased expression seemingly more disruptive than decreased expression.
Asunto(s)
Adenosina Quinasa/metabolismo , Adenosina/metabolismo , Encéfalo/metabolismo , Homeostasis/fisiología , Memoria a Corto Plazo/fisiología , Animales , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Mutantes , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
The Morris water maze (WM) is a common spatial memory test in rats. It has been adapted for evaluating genetic manipulations in mice. One major acknowledged problem of this cross-species translation is floating. We investigated here in mice the feasibility and practicality of an alternative paradigm-the cheeseboard (CB), which is a dry version of the WM, in a within-subject design allowing direct comparison with the conventional WM. Under identical task demands (reference or working memory), mice learned in the CB as efficiently as in the WM. Furthermore, individual differences in learning rate correlated between the two reference memory tests conducted separately in the two mazes. However, no such correlation was found with respect to reference memory retention or working memory performance. This study demonstrated that the CB is an effective alternative to the WM as spatial cognition test. Additional tests in the CB confirmed that the mice relied on extra maze cues in their spatial search. We would recommend the CB as a valuable addition to, rather than a replacement of the WM in phenotyping transgenic mice, because the two apparatus might diverge in the ability to detect individual differences in various domains of mnemonic functions.
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Adaptación Fisiológica/fisiología , Aprendizaje por Laberinto/fisiología , Memoria/fisiología , Conducta Espacial/fisiología , Agua , Animales , Conducta Animal , Señales (Psicología) , Discriminación en Psicología/fisiología , Privación de Alimentos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Estimulación Luminosa/métodos , Tiempo de Reacción/fisiologíaRESUMEN
Converging evidence from pharmacological and molecular studies has led to the suggestion that inhibition of glycine transporter 1 (GlyT1) constitutes an effective means to boost N-methyl-d-aspartate receptor (NMDAR) activity by increasing the extra-cellular concentration of glycine in the vicinity of glutamatergic synapses. However, the precise extent and limitation of this approach to alter cognitive function, and therefore its potential as a treatment strategy against psychiatric conditions marked by cognitive impairments, remain to be fully examined. Here, we generated mutant mice lacking GlyT1 in the entire forebrain including neurons and glia. This conditional knockout system allows a more precise examination of GlyT1 downregulation in the brain on behavior and cognition. The mutation was highly effective in attenuating the motor-stimulating effect of acute NMDAR blockade by phencyclidine, although no appreciable elevation in NMDAR-mediated excitatory postsynaptic currents (EPSC) was observed in the hippocampus. Enhanced cognitive performance was observed in spatial working memory and object recognition memory while spatial reference memory and associative learning remained unaltered. These findings provide further credence for the potential cognitive enhancing effects of brain GlyT1 inhibition. At the same time, they indicated potential phenotypic differences when compared with other constitutive and conditional GlyT1 knockout lines, and highlighted the possibility of a functional divergence between the neuronal and glia subpopulations of GlyT1 in the regulation of learning and memory processes. The relevance of this distinction to the design of future GlyT1 blockers as therapeutic tools in the treatment of cognitive disorders remains to be further investigated.
Asunto(s)
Proteínas de Transporte de Glicina en la Membrana Plasmática/genética , Memoria , Prosencéfalo/fisiología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Anfetamina/farmacología , Animales , Regulación hacia Abajo , Potenciales Postsinápticos Excitadores , Femenino , Glicina/metabolismo , Proteínas de Transporte de Glicina en la Membrana Plasmática/biosíntesis , Hipocampo/fisiología , Aprendizaje , Masculino , Ratones , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Mutación , Fenciclidina/farmacología , Prosencéfalo/efectos de los fármacos , Prosencéfalo/metabolismo , Desempeño Psicomotor , Receptores de N-Metil-D-Aspartato/biosíntesis , Reconocimiento en Psicología , Transmisión SinápticaRESUMEN
The membrane protein Nogo-A inhibits neurite outgrowth and regeneration in the injured central nervous system, primarily because of its expression in oligodendrocytes. Hence, deletion of Nogo-A enhances regeneration following spinal cord injury. Yet, the effects of Nogo-A deletion on general behavior and cognition have not been explored. The possibility of potential novel functions of Nogo-A beyond growth inhibition is strongly suggested by the presence of subpopulations of neurons also expressing Nogo-A - not only during development but also in adulthood. We evaluated here Nogo-A(-/-) mice in a series of general basic behavioral assays as well as functional analyses related to brain regions with notable expression levels of Nogo-A. The SHIRPA protocol did not show any major basic behavioral changes in Nogo-A(-/-) mice. Anxiety-related behavior, pain sensitivity, startle reactivity, spatial learning, and associative learning also appeared indistinguishable between Nogo-A(-/-) and control Nogo-A(+/+) mice. However, motor co-ordination and balance were enhanced in Nogo-A(-/-) mice. Spontaneous locomotor activity was also elevated in Nogo-A(-/-) mice, but this was specifically observed in the dark (active) phase of the circadian cycle. Enhanced locomotor reaction to systemic amphetamine in Nogo-A(-/-) mice further pointed to an altered dopaminergic tone in these mice. The present study is the first behavioral characterization of mice lacking Nogo-A and provides significant insights into the potential behavioral relevance of Nogo-A in the modulation of dopaminergic and motor functions.
Asunto(s)
Conducta Animal/fisiología , Proteínas de la Mielina/genética , Anfetamina/farmacología , Animales , Ansiedad/genética , Ansiedad/psicología , Aprendizaje por Asociación/fisiología , Reacción de Prevención/fisiología , Estimulantes del Sistema Nervioso Central/farmacología , Cerebelo/citología , Cerebelo/fisiología , Ritmo Circadiano/genética , Ritmo Circadiano/fisiología , Hipotálamo/citología , Hipotálamo/fisiología , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/genética , Actividad Motora/fisiología , Neuronas/fisiología , Proteínas Nogo , Dimensión del Dolor , Equilibrio Postural/fisiología , Desempeño Psicomotor/fisiología , Reflejo de Sobresalto/fisiología , Células Ganglionares de la Retina/fisiologíaRESUMEN
Maternal infections during pregnancy increase the risk for schizophrenia and related disorders of putative neurodevelopmental origin in the offspring. This association has been attributed to enhanced expression of pro-inflammatory cytokines in the fetal environment in response to maternal immunological stimulation. In contrast, the specific roles of anti-inflammatory cytokines are virtually unknown in this context. Here, we demonstrate that genetically enforced expression of the anti-inflammatory cytokine interleukin (IL)-10 by macrophages attenuates the long-term behavioral and pharmacological consequences of prenatal immune activation in a mouse model of prenatal viral-like infection by polyriboinosinic-polyribocytidilic acid (PolyI:C; 2 mg/kg, intravenously). In the absence of a discrete prenatal inflammatory stimulus, however, enhanced levels of IL-10 at the maternal-fetal interface by itself also precipitates specific behavioral abnormalities in the grown offspring. This highlights that in addition to the disruptive effects of excess pro-inflammatory molecules, a shift toward enhanced anti-inflammatory signaling in prenatal life can similarly affect cognitive and behavioral development. Hence, shifts of the balance between pro- and anti-inflammatory cytokine classes may be a critical determinant of the final impact on neurodevelopment following early life infection or innate immune imbalances.
Asunto(s)
Conducta Animal/fisiología , Citocinas/metabolismo , Interleucina-10/metabolismo , Efectos Tardíos de la Exposición Prenatal/patología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Animales , Animales Recién Nacidos , Aprendizaje por Asociación/fisiología , Conducta Animal/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Encéfalo/patología , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Inhibición Psicológica , Interleucina-10/genética , Interleucina-10/farmacología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Poli I-C/efectos adversos , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Transducción de Señal/fisiología , Factores de TiempoRESUMEN
Hippocampal GABA(A) receptors containing the alpha 5 subunit have been implicated in the modulation of hippocampal-dependent learning, presumably via their tonic inhibitory influence on hippocampal glutamatergic activity. Here, we examined the expression of latent inhibition (LI)--a form of selective learning that is sensitive to a number of manipulations targeted at the hippocampal formation, in alpha 5(H105R) mutant mice with reduced levels of hippocampal alpha 5-containing GABA(A) receptors. A single pre-exposure to the taste conditioned stimulus (CS) prior to the pairing of the same CS with LiCl-induced nausea was effective in reducing the conditioned aversion against the taste CS in wild-type mice--thus constituting the LI effect. LI was however distinctly absent in male alpha 5(H105R) mutant mice. Hence, a partial loss of hippocampal alpha 5 GABA(A) receptors is sufficient to alter one major form of selective learning, albeit this was not seen in the female. This observed phenotype suggests that specific activation of these extrasynaptic GABA(A) receptors may confer therapeutic potential against the failure to show selectivity in learning by human psychotic patients.
Asunto(s)
Hipocampo/metabolismo , Aprendizaje/fisiología , Inhibición Neural/fisiología , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Animales , Atención/fisiología , Condicionamiento Clásico/fisiología , Conducta de Ingestión de Líquido , Femenino , Ácido Glutámico/metabolismo , Masculino , Ratones , Ratones Mutantes , Fenotipo , Mutación Puntual/genética , AguaRESUMEN
The present study tested whether individual differences in anxiety- and fear-related behaviour are associated with between-subjects variation in postmortem brain levels of selected neurotrophic factors. Naïve C57BL6/J mice of both sexes were subjected either to an elevated plus maze test or to a Pavlovian fear conditioning paradigm. Two days after behavioural assays, the mice were sacrificed for postmortem quantification of the protein levels of brain derived neurotrophic factors (BDNF), nerve growth factor (NGF) and neurotrophin-3 (NT-3) in the hippocampus and amygdala. Significant correlations between behavioural measures and postmortem regional neurotrophic factor contents were revealed. The magnitude of anxiety-like behaviour in the elevated plus maze was positively related to dorsal hippocampal BDNF levels, but negatively related to NGF levels in dorsal hippocampus and in the amygdala. On the other hand, the expression of conditioned fear is positively related to amygdala BDNF and NGF levels, and to dorsal hippocampal NGF levels. Our results add to existing reports in human as well as in animals of correlation between anxiety trait and gross measures of hippocampal volume or activation levels. Moreover, a distinction between spontaneous and learned (or conditioned) anxiety/fear would be relevant to the identification of neurotrophin signalling mechanisms in the hippocampus and amygdala implicated in anxiety and related psychopathology.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Ansiedad/metabolismo , Miedo/fisiología , Hipocampo/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Amígdala del Cerebelo/química , Animales , Conducta Animal/fisiología , Ensayo de Inmunoadsorción Enzimática , Femenino , Hipocampo/química , Masculino , Ratones , Ratones Endogámicos C57BL , Factores de Crecimiento Nervioso/análisis , Factores SexualesRESUMEN
Prenatal exposures to a variety of infections have been associated with an increased incidence of schizophrenia. We have reported that a single injection of the synthetic cytokine releaser PolyI:C to pregnant mice produced offspring that exhibited multiple schizophrenia-related behavioral deficits in adulthood. Here, we characterized the effect of maternal inflammation during fetal brain development on adult limbic morphology and expression of GABAA-receptors. The PolyI:C treatment did not induce morphological abnormalities but resulted in a significant increase in GABAA receptor subunit alpha2 immunoreactivity (IR) in the ventral dentate gyrus and basolateral amygdala in adult treated compared to control subjects. Correlative analyses between the a2 subunit IR in the ventral dentate gyrus and the performance in the prepulse inhibition paradigm revealed a significant correlation in controls that was however absent in the pathological condition. These results suggest that prenatal immune activation-induced disturbances of early brain development result in profound alterations in the limbic expression of GABAA receptors that may underlie the schizophrenia-related behavioral deficits in the adult mice.
Asunto(s)
Sistema Límbico/metabolismo , Efectos Tardíos de la Exposición Prenatal/inmunología , Receptores de GABA-A/metabolismo , Esquizofrenia/patología , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Recuento de Células/métodos , Tamaño de la Célula/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica/métodos , Sistema Límbico/efectos de los fármacos , Sistema Límbico/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Poli I-C , Embarazo , Esquizofrenia/inducido químicamente , Esquizofrenia/metabolismo , Estadística como AsuntoRESUMEN
Schmajuk and Larrauri [Schmajuk NA, Larrauri JA. Neural network model of prepulse inhibition. Behav Neurosci 2005;119:1546-62.] introduced a real-time model of acoustic startle, prepulse inhibition (PPI) and facilitation (PPF) in animals and humans. The model assumes that (1) positive values of changes in noise level activate an excitatory and a facilitatory pathway, and (2) absolute values of changes in noise level activate an inhibitory pathway. The model describes many known properties of the phenomena and the effect of brain lesions on startle, PPI, and PPF. The purpose of the present study is to (a) establish the magnitude of startle and PPI as a function of pulse, prepulse, and background intensity, and (b) test the model predictions regarding an inverted-U function that relates startle to the intensity of the background noise.
Asunto(s)
Simulación por Computador , Modelos Biológicos , Inhibición Neural/fisiología , Ruido , Reflejo Acústico/fisiología , Reflejo de Sobresalto/fisiología , Estimulación Acústica/métodos , Animales , Conducta Animal , Relación Dosis-Respuesta en la Radiación , Femenino , Habituación Psicofisiológica , Masculino , Ratones , Ratas , Ratas Sprague-Dawley , Reflejo Acústico/efectos de la radiaciónRESUMEN
Latent inhibition is a form of negative priming in which repeated non-reinforced pre-exposures to a stimulus retard subsequent learning about the predictive significance of that stimulus. The nucleus accumbens shell and the anatomical projection it receives from the hippocampal formation have been attributed a pivotal role in the control or regulation of latent inhibition expression. A number of studies in rats have demonstrated the efficacy of selective shell lesions to disrupt latent inhibition in different associative learning paradigms, including conditioned active avoidance and conditioned emotional response. Here, we extended the test to the conditioned taste aversion paradigm, in which the effect of direct hippocampal damage on latent inhibition remains controversial. We demonstrated the expected effect of selective shell lesions on latent inhibition of conditioned emotional response and of conditioned active avoidance, before evaluating in a separate cohort of rats the effect of comparable selective lesions on latent inhibition of conditioned taste aversion: a null effect of the lesions was first obtained using parameters known to be sensitive to amphetamine treatment, then an enhancement of latent inhibition was revealed with a modified conditioned taste aversion procedure. Our results show that depending on the associative learning paradigm chosen, shell lesions can disrupt or enhance the expression of latent inhibition; and the pattern is reminiscent of that seen following hippocampal damage.
Asunto(s)
Condicionamiento Psicológico , Núcleo Accumbens/fisiología , Gusto , Animales , Mapeo Encefálico , Núcleo Accumbens/anatomía & histología , Núcleo Accumbens/patología , Ratas , Ratas WistarRESUMEN
Overactivity of the dopaminergic system in the brain is considered to be a contributing factor to the development and symptomatology of schizophrenia. Therefore, the GABAergic control of dopamine functions was assessed by disrupting the gene encoding the alpha3 subunit of the GABA(A) receptor. alpha3 knockout (alpha3KO) mice exhibited neither an obvious developmental defect nor apparent morphological brain abnormalities, and there was no evidence for compensatory up-regulation of other major GABA(A)-receptor subunits. Anxiety-related behavior in the elevated-plus-maze test was undisturbed, and the anxiolytic-like effect of diazepam, which is mediated by alpha2-containing GABA(A) receptors, was preserved. As a result of the loss of alpha3 GABA(A) receptors, the GABA-induced whole-cell current recorded from midbrain dopamine neurons was significantly reduced. Spontaneous locomotor activity was slightly elevated in alpha3KO mice. Most notably, prepulse inhibition of the acoustic startle reflex was markedly attenuated in the alpha3KO mice, pointing to a deficit in sensorimotor information processing. This deficit was completely normalized by treatment with the antipsychotic D2-receptor antagonist haloperidol. The amphetamine-induced hyperlocomotion was not altered in alpha3KO mice compared with WT mice. These results suggest that the absence of alpha3-subunit-containing GABA(A) receptors induces a hyperdopaminergic phenotype, including a severe deficit in sensorimotor gating, a common feature among psychiatric conditions, including schizophrenia. Hence, agonists acting at alpha3-containing GABA(A) receptors may constitute an avenue for an effective treatment of sensorimotor-gating deficits in various psychiatric conditions.
Asunto(s)
Dopamina/fisiología , Activación del Canal Iónico/genética , Actividad Motora/genética , Subunidades de Proteína/deficiencia , Receptores de GABA-A/deficiencia , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Anfetamina/farmacología , Animales , Ansiolíticos/farmacología , Diazepam/farmacología , Modelos Animales de Enfermedad , Electrofisiología , Moduladores del GABA/farmacología , Marcación de Gen , Haloperidol/farmacología , Inmunohistoquímica , Activación del Canal Iónico/fisiología , Ratones , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Subunidades de Proteína/genética , Subunidades de Proteína/fisiología , Receptores de GABA-A/genética , Receptores de GABA-A/fisiología , Esquizofrenia/tratamiento farmacológicoRESUMEN
Prepulse inhibition (PPI) refers to the phenomenon in which a low-intensity prepulse stimulus attenuates the reflexive response to a succeeding startle-eliciting pulse stimulus. The hippocampus, among other structures, is believed to play an important role in the modulation of PPI expression. In alpha5(H105R) mutant mice, the expression of the alpha5 subunit-containing GABA(A) receptors in the hippocampus is reduced. Here, we report that PPI was attenuated, and spontaneous locomotor activity was increased in alpha5(H105R) mutant mice. These effects were apparent in both genders. Thus, alpha5 subunit-containing GABA(A) receptors, which are located extrasynaptically and are thought to mediate tonic inhibition, are important regulators of the expression of PPI and locomotor exploration. Post-mortem analyses of schizophrenia brains have consistently revealed structural abnormalities of a developmental origin in the hippocampus. There may be a possibility that such abnormalities include disturbance of alpha5 GABA(A) receptor function or distribution, given that schizophrenia patients are known to exhibit a PPI deficit. Our data further highlight that the potential use of alpha5-selective inverse agonists to treat hippocampal-related mnemonic dysfunction needs to be considered against the possibility that such compounds may be adversely associated with deficient sensorimotor gating.
Asunto(s)
Hipocampo/metabolismo , Inhibición Neural/fisiología , Receptores de GABA-A/metabolismo , Reflejo de Sobresalto/fisiología , Esquizofrenia/fisiopatología , Estimulación Acústica , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Conducta Exploratoria/fisiología , Femenino , Hipocampo/citología , Activación del Canal Iónico/fisiología , Masculino , Ratones , Ratones Transgénicos , Actividad Motora/fisiología , Receptores de GABA-A/deficienciaRESUMEN
The amnestic effects of hippocampal lesions are well documented, leading to numerous memory-based theories of hippocampal function. It is debatable, however, whether any one of these theories can satisfactorily account for all the consequences of hippocampal damage: Hippocampal lesions also result in behavioural disinhibition and reduced anxiety. A growing number of studies now suggest that these diverse behavioural effects may be associated with different hippocampal subregions. There is evidence for at least two distinct functional domains, although recent neuroanatomical studies suggest this may be an underestimate. Selective lesion studies show that the hippocampus is functionally subdivided along the septotemporal axis into dorsal and ventral regions, each associated with a distinct set of behaviours. Dorsal hippocampus has a preferential role in certain forms of learning and memory, notably spatial learning, but ventral hippocampus may have a preferential role in brain processes associated with anxiety-related behaviours. The latter's role in emotional processing is also distinct from that of the amygdala, which is associated specifically with fear. Gray and McNaughton's theory can in principle incorporate these apparently distinct hippocampal functions, and provides a plausible unitary account for the multiple facets of hippocampal function.
Asunto(s)
Ansiedad/fisiopatología , Mapeo Encefálico , Miedo/fisiología , Hipocampo/fisiología , Memoria/fisiología , Animales , Hipocampo/anatomía & histología , Hipocampo/fisiopatología , HumanosRESUMEN
Repeated non-reinforced exposures of a neutral stimulus retard the development of a conditioned response to that stimulus when it is subsequently paired with a significant event. This stimulus pre-exposure effect is known as latent inhibition (LI). Early lesion studies have initially suggested an important role for the hippocampus in the normal development and expression of LI. This view has since been modified with the emergence of data derived from selective cell body lesions of the hippocampus and of the entorhinal cortex, with an abolition of LI only seen after lesions of the latter. This suggests that the significance of the hippocampus might have been overestimated in the past, possibly due to interruption of fibres en passage. However, intact behavioural expression of LI following hippocampal damage does not preclude the suggestion that the hippocampus participates in the control and regulation of LI expression in intact animals. The present study demonstrated that whilst cell body lesions of the ventral hippocampus spared LI (as expected), chemical activation of the ventral hippocampus by local N-methyl-D-aspartate infusion disrupted LI. These results parallel our earlier observations on prepulse inhibition (PPI) with similar manipulations [Neuroreport 10 (1999) 2533]. Thus, although the ventral hippocampus is itself not responsible for the behavioural manifestation of LI and PPI, it exerts at least a modulatory control over the form and/or magnitude of their expression. Our results should prompt a re-evaluation of the relative roles of the hippocampus and retrohippocampus in the development and expression of LI.
Asunto(s)
Agonistas de Aminoácidos Excitadores , Hipocampo/fisiopatología , N-Metilaspartato , Inhibición Neural/fisiología , Animales , Conducta Animal/fisiología , Condicionamiento Psicológico/fisiología , Desnervación , Hipocampo/patología , Masculino , Ratas , Ratas Endogámicas , Esquizofrenia/fisiopatologíaRESUMEN
RATIONALE: Prepulse inhibition (PPI) of startle refers to the phenomenon in which a weak prepulse attenuates the startle response to a succeeding intense stimulus. PPI can be disrupted by systemic apomorphine in animals, and reduced PPI has been consistently reported in schizophrenia patients. The ability of the atypical antipsychotic clozapine to reverse apomorphine-induced PPI deficit has been demonstrated in the rat, but has not yet been tested in the mouse. The present study was designed to fill this gap. OBJECTIVE AND RESULTS: We investigated the efficacy of clozapine in reversing apomorphine-induced (2.0 or 2.5 mg/kg, s.c.) PPI deficit in C57BL6 mice. Clozapine failed to restore PPI disruption in apomorphine-treated mice in two independent laboratories across two dose ranges (1-3 mg/kg, i.p., or 3-30 mg/kg, p.o.), whereas the typical antipsychotic haloperidol (1 mg/kg, i.p.) completely normalised PPI performance. CONCLUSIONS: Unlike the rat, apomorphine-induced PPI disruption in mice might be instrumental in distinguishing between typical and atypical antipsychotic drugs. This also lends further support to the suggestion that the neuropharmacology of PPI is not identical in the two rodent species.
Asunto(s)
Antiparkinsonianos/antagonistas & inhibidores , Antipsicóticos/farmacología , Apomorfina/antagonistas & inhibidores , Clozapina/farmacología , Haloperidol/farmacología , Reflejo de Sobresalto/efectos de los fármacos , Animales , Antiparkinsonianos/farmacología , Apomorfina/farmacología , Interacciones Farmacológicas , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Human presenilin-1 (PS1) mutations are associated with the incidence of familial Alzheimer's disease. The present study evaluated the behavioral and neurochemical effects of the L235P mutation (substitution of leucine by proline at codon 235) of the human PS1 gene, which has been linked to a form of early-onset Alzheimer's disease. Except for a significant increase in the production of beta-amyloid-42, the mutant mice did not show any overt signs of Alzheimer-like neuropathology in the form of plaque formation, changes in choline acetyltransferase activity, or somatostatin content in the brain. Cognitive assays indicated that the mutation did not affect the acquisition or reversal of a spatial reference memory task in the water maze or performance on a spatial working memory task. In contrast, L235P PS1 transgenic mice exhibited a significant impairment in a test of spontaneous object recognition. This dissociation is suggestive of a preferential impairment of the extrahippocampal memory system and is consistent with what has been reported in another pathological mutation (substitution of leucine by valine at codon 286) of the PS1 gene.
Asunto(s)
Enfermedad de Alzheimer/genética , Sustitución de Aminoácidos , Conducta Animal/fisiología , Proteínas de la Membrana/genética , Mutación , Péptidos beta-Amiloides/biosíntesis , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/metabolismo , Colina O-Acetiltransferasa/metabolismo , Expresión Génica , Humanos , Aprendizaje por Laberinto , Proteínas de la Membrana/biosíntesis , Memoria , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/biosíntesis , Presenilina-1 , Reconocimiento en Psicología , Somatostatina/metabolismoRESUMEN
This study with rats examined the effects of excitotoxic lesions to the entorhinal cortex (EC) and hippocampus (HPC) on using extramaze and intramaze cues to navigate to a hidden platform in a water maze. HPC lesions resulted in a disruption to the use of extramaze cues, but not intramaze cues, whereas EC lesions had no effect on the use of these cues when they were encountered for the first time. However, prior navigation training in which 1 type of cue was relevant disrupted navigation with the other type in rats with EC lesions. Results show that the EC contributes to the processing of spatial information, but that this contribution is most apparent when there is a conflict between 2 sources of navigational cues in the water maze.
Asunto(s)
Señales (Psicología) , Corteza Entorrinal/fisiología , Aprendizaje por Laberinto/fisiología , Animales , Ratas , Tiempo de Reacción/fisiología , Conducta Espacial/fisiologíaRESUMEN
Two experiments were carried out to evaluate the effects of amphetamine withdrawal in rats on spatial learning in the water maze. A schedule of repeated d-amphetamine administration lasting for 6 days, with three injections per day (1-5 mg/kg, i.p.), was employed. Experiment 1 demonstrated that amphetamine withdrawal did not impair the acquisition of the water maze task (third to fourth withdrawal days), but amphetamine-withdrawn rats made more target-zone visits and reached the former location of the platform quicker than controls during the probe test (fifth withdrawal day). In experiment 2, retention of the location of the escape platform was assessed in animals having been pre-trained on the water maze task before treatment. On the third withdrawal day, retention of the former platform location was assessed in a probe test. Retention was only clearly seen in the measure of target zone visits, and performance did not differ between groups. Next, the animals were trained to escape to a new location in the water maze on withdrawal days 4-5. A reversal effect could be discerned across the first four trials, as evident by the animals' tendency to search in the former target quadrant. This interfered with the new learning, but amphetamine-withdrawn animals appeared to overcome it more rapidly than saline-treated controls. This finding is consistent with the view that amphetamine withdrawal can enhance behavioural switching, which could be expressed as a reduction of proactive interference during learning; and, it is in line with our previous finding that latent inhibition is also attenuated during amphetamine withdrawal.
Asunto(s)
Anfetamina/efectos adversos , Estimulantes del Sistema Nervioso Central/efectos adversos , Aprendizaje por Laberinto/efectos de los fármacos , Conducta Espacial/efectos de los fármacos , Síndrome de Abstinencia a Sustancias , Síndrome de Abstinencia a Sustancias/fisiopatología , Anfetamina/farmacología , Animales , Estimulantes del Sistema Nervioso Central/farmacología , Esquema de Medicación , Reacción de Fuga/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Orientación , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Retención en Psicología , Síndrome de Abstinencia a Sustancias/psicología , Factores de TiempoRESUMEN
Rats with cytotoxic ventral hippocampal lesions which removed approximately 50% of the hippocampus (including dentate gyrus) starting from the temporal pole, displayed a reduction in freezing behaviour following the delivery of an unsignalled footshock in an operant chamber. This was more plausibly a result of reduced susceptibility to fear than a result of a lesion-induced increase in general motor activity. There was no consistent difference between sham and lesioned animals in spontaneous locomotor activity, or locomotion following acute or chronic treatment with amphetamine. In contrast, ventral hippocampal lesioned animals were quicker to pass from the black to the white box during a modified version of the light/dark exploration test, and were quicker to begin eating during tests of hyponeophagia. Furthermore, rats with ventral hippocampal lesions defecated less than their sham counterparts both during open field testing and in extinction sessions following contextual conditioning. In contrast to these clear lesion effects, there were no signs of any spatial learning impairment either in the watermaze or on the elevated T-maze. Taken together these results suggest that the ventral hippocampus may play a role in a brain system (or systems) associated with fear and/or anxiety, and provide further evidence for a distinct specialisation of function along the septotemporal axis of the hippocampus.