RESUMEN
It has been suggested that a functional deficit in NMDA-receptors (NMDARs) on parvalbumin (PV)-positive interneurons (PV-NMDARs) is central to the pathophysiology of schizophrenia. Supportive evidence come from examination of genetically modified mice where the obligatory NMDAR-subunit GluN1 (also known as NR1) has been deleted from PV interneurons by Cre-mediated knockout of the corresponding gene Grin1 (Grin1(ΔPV) mice). Notably, such PV-specific GluN1 ablation has been reported to blunt the induction of hyperlocomotion (a surrogate for psychosis) by pharmacological NMDAR blockade with the non-competitive antagonist MK-801. This suggests PV-NMDARs as the site of the psychosis-inducing action of MK-801. In contrast to this hypothesis, we show here that Grin1(ΔPV) mice are not protected against the effects of MK-801, but are in fact sensitized to many of them. Compared with control animals, Grin1(ΔPV)mice injected with MK-801 show increased stereotypy and pronounced catalepsy, which confound the locomotor readout. Furthermore, in Grin1(ΔPV)mice, MK-801 induced medial-prefrontal delta (4 Hz) oscillations, and impaired performance on tests of motor coordination, working memory and sucrose preference, even at lower doses than in wild-type controls. We also found that untreated Grin1(ΔPV)mice are largely normal across a wide range of cognitive functions, including attention, cognitive flexibility and various forms of short-term memory. Taken together these results argue against PV-specific NMDAR hypofunction as a key starting point of schizophrenia pathophysiology, but support a model where NMDAR hypofunction in multiple cell types contribute to the disease.
Asunto(s)
Maleato de Dizocilpina , Interneuronas/metabolismo , Parvalbúminas/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Esquizofrenia/fisiopatología , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Noqueados , Esquizofrenia/inducido químicamenteRESUMEN
Hippocampal pathology is likely to contribute to cognitive disability in Down syndrome, yet the neural network basis of this pathology and its contributions to different facets of cognitive impairment remain unclear. Here we report dysfunctional connectivity between dentate gyrus and CA3 networks in the transchromosomic Tc1 mouse model of Down syndrome, demonstrating that ultrastructural abnormalities and impaired short-term plasticity at dentate gyrus-CA3 excitatory synapses culminate in impaired coding of new spatial information in CA3 and CA1 and disrupted behavior in vivo. These results highlight the vulnerability of dentate gyrus-CA3 networks to aberrant human chromosome 21 gene expression and delineate hippocampal circuit abnormalities likely to contribute to distinct cognitive phenotypes in Down syndrome.
Asunto(s)
Región CA3 Hipocampal/fisiopatología , Cromosomas Humanos Par 21 , Giro Dentado/fisiopatología , Modelos Animales de Enfermedad , Síndrome de Down/fisiopatología , Red Nerviosa/fisiopatología , Animales , Región CA3 Hipocampal/patología , Cromosomas Humanos Par 21/genética , Giro Dentado/patología , Síndrome de Down/genética , Síndrome de Down/patología , Humanos , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Red Nerviosa/patología , Técnicas de Cultivo de Órganos , Trisomía/genéticaRESUMEN
The long allele variant of the serotonin transporter (SERT, 5-HTT) gene-linked polymorphic region (5-HTTLPR) is associated with higher levels of 5-HTT expression and reduced risk of developing affective disorders. However, little is known about the mechanisms underlying this protective effect. One hypothesis is that 5-HTT expression influences aversive information processing, with reduced negative cognitive bias present in those with higher 5-HTT expression. Here we investigated this hypothesis using genetically-modified mice and a novel aversive learning paradigm. Mice with high levels of 5-HTT expression (5-HTT over-expressing, 5-HTTOE mice) and wild-type mice were trained to discriminate between three distinct auditory cues: one cue predicted footshock on all trials (CS+); a second cue predicted the absence of footshock (CS-); and a third cue predicted footshock on 20% of trials (CS20%), and was therefore ambiguous. Wild-type mice exhibited equivalently high levels of fear to the CS+ and CS20% and minimal fear to the CS-. In contrast, 5-HTTOE mice exhibited high levels of fear to the CS+ but minimal fear to the CS- and the CS20%. This selective reduction in fear to ambiguous aversive cues suggests that increased 5-HTT expression reduces negative cognitive bias for stimuli with uncertain outcomes.
Asunto(s)
Condicionamiento Clásico , Señales (Psicología) , Discriminación en Psicología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Animales , Miedo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismoRESUMEN
The GRIA1 locus, encoding the GluA1 (also known as GluRA or GluR1) AMPA glutamate receptor subunit, shows genome-wide association to schizophrenia. As well as extending the evidence that glutamatergic abnormalities have a key role in the disorder, this finding draws attention to the behavioural phenotype of Gria1 knockout mice. These mice show deficits in short-term habituation. Importantly, under some conditions the attention being paid to a recently presented neutral stimulus can actually increase rather than decrease (sensitization). We propose that this mouse phenotype represents a cause of aberrant salience and, in turn, that aberrant salience (and the resulting positive symptoms) in schizophrenia may arise, at least in part, from a glutamatergic genetic predisposition and a deficit in short-term habituation. This proposal links an established risk gene with a psychological process central to psychosis and is supported by findings of comparable deficits in short-term habituation in mice lacking the NMDAR receptor subunit Grin2a (which also shows association to schizophrenia). As aberrant salience is primarily a dopaminergic phenomenon, the model supports the view that the dopaminergic abnormalities can be downstream of a glutamatergic aetiology. Finally, we suggest that, as illustrated here, the real value of genetically modified mice is not as 'models of schizophrenia' but as experimental tools that can link genomic discoveries with psychological processes and help elucidate the underlying neural mechanisms.
Asunto(s)
Habituación Psicofisiológica/fisiología , Receptores AMPA/metabolismo , Esquizofrenia/fisiopatología , Animales , Encéfalo/fisiopatología , Dopamina/metabolismo , Humanos , Ratones Noqueados , Receptores AMPA/genética , Psicología del EsquizofrénicoRESUMEN
The idea that an NMDA receptor (NMDAR)-dependent long-term potentiation-like process in the hippocampus is the neural substrate for associative spatial learning and memory has proved to be extremely popular and influential. However, we recently reported that mice lacking NMDARs in dentate gyrus and CA1 hippocampal subfields (GluN1(ΔDGCA1) mice) acquired the open field, spatial reference memory watermaze task as well as controls, a result that directly challenges this view. Here, we show that GluN1(ΔDGCA1) mice were not impaired during acquisition of a spatial discrimination watermaze task, during which mice had to choose between two visually identical beacons, based on extramaze spatial cues, when all trials started at locations equidistant between the two beacons. They were subsequently impaired on test trials starting from close to the decoy beacon, conducted post-acquisition. GluN1(ΔDGCA1) mice were also impaired during reversal of this spatial discrimination. Thus, contrary to the widely held belief, hippocampal NMDARs are not required for encoding associative, long-term spatial memories. Instead, hippocampal NMDARs, particularly in CA1, act as part of a comparator system to detect and resolve conflicts arising when two competing, behavioural response options are evoked concurrently, through activation of a behavioural inhibition system. These results have important implications for current theories of hippocampal function.
Asunto(s)
Aprendizaje Discriminativo/fisiología , Hipocampo/metabolismo , Potenciación a Largo Plazo/fisiología , Memoria/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Conducta Espacial/fisiología , Animales , Hipocampo/citología , Hipocampo/fisiología , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones MutantesRESUMEN
Catechol-O-methyltransferase (COMT) catabolises the catecholamine neurotransmitters and influences cognitive function. COMT modulates dopamine levels in the prefrontal cortex and its action in this region is generally invoked to explain its effects on cognition. However, its role in other brain regions important for cognitive function remains largely unexplored. Here, we investigated COMT's impact on dopamine metabolism in the hippocampus and hippocampal-dependent behaviour. We examined the acute effects of a centrally-acting COMT inhibitor, tolcapone (30 mg/kg i.p.), on dopamine metabolism in the rat dorsal hippocampus, assessed both in tissue homogenates and extracellularly, using in vivo microdialysis. Additionally, we investigated the effect of tolcapone on delayed-rewarded alternation and spatial novelty preference, behavioural tasks which are dependent on the dorsal hippocampus. Tolcapone significantly modulated dopamine metabolism in the dorsal hippocampus, as indexed by the depletion of extracellular homovanillic acid (HVA) and the accumulation of dihydroxyphenylacetic acid (DOPAC). Tolcapone also improved performance on the delayed-rewarded alternation and spatial novelty preference tasks, compared to vehicle-treated rats. Our findings suggest that COMT regulates dorsal hippocampal neurochemistry and modulates hippocampus-dependent behaviours. These findings support the therapeutic candidacy of COMT inhibition as a cognitive enhancer, and suggest that, in addition to the prefrontal cortex, the hippocampus might be a key region for mediating these effects.
Asunto(s)
Benzofenonas/farmacología , Inhibidores de Catecol O-Metiltransferasa , Cognición/efectos de los fármacos , Dopamina/metabolismo , Nitrofenoles/farmacología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Catecol O-Metiltransferasa/metabolismo , Inhibidores Enzimáticos/farmacología , Espacio Extracelular/metabolismo , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ácido Hidroxiindolacético/metabolismo , Masculino , Microdiálisis , Ratas , Recompensa , TolcaponaRESUMEN
The psychotomimetic effects of N-methyl-d-aspartate receptor (NMDA) antagonists such as ketamine and phencyclidine suggest a role for reduced NMDA receptor-mediated neurotransmission in schizophrenia. GluN1 'hypomorph' (GluN1(hypo) ) mice exhibit reduced NMDA receptor expression and have been suggested as a mouse model of schizophrenia. However, NMDA receptors are ubiquitous and are implicated in many physiological and pathological processes. The GluN1(hypo) mice have a global reduction of NMDA receptors and the consequences of such a global manipulation are likely to be wide-ranging. We therefore assessed GluN1(hypo) mice on a battery of behavioral tests, including tests of naturalistic behaviors, anxiety and cognition. GluN1(hypo) mice exhibited impairments on all tests of cognition that we employed, as well as reduced engagement in naturalistic behaviors, including nesting and burrowing. Behavioral deficits were present in both spatial and non-spatial domains, and included deficits on both short- and long-term memory tasks. Results from anxiety tests did not give a clear overall picture. This may be the result of confounds such as the profound hyperactivity seen in GluN1(hypo) mice, although hyperactivity cannot account for all of the results obtained. When viewed against this background of far-reaching behavioral abnormalities, the specificity of any one behavioral deficit is inevitably called into question. Indeed, the present data from GluN1(hypo) mice are indicative of a global impairment rather than any specific disease. The deficits seen go beyond what one would expect from a mouse model of schizophrenia, thus questioning their utility as a selective model of this disease.
Asunto(s)
Receptores de N-Metil-D-Aspartato/deficiencia , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Psicología del Esquizofrénico , Animales , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Femenino , Hipercinesia/genética , Hipercinesia/metabolismo , Hipercinesia/fisiopatología , Masculino , Trastornos Mentales/genética , Trastornos Mentales/metabolismo , Trastornos Mentales/fisiopatología , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de N-Metil-D-Aspartato/genética , Esquizofrenia/metabolismoRESUMEN
Impairments in executive function and cognitive control are a common feature of neuropsychiatric and neurodegenerative disorders. A promising behavioral paradigm for elucidating the neural mechanisms of executive function is extradimensional/intradimensional (ED/ID) shifting, which places demands on executive function by requiring the adjustment of behavioral responses based on affective or attentional information. To augment the understanding of the brain systems required for these aspects of executive function, we examined the induction of Fos protein in rats tested in the ED/ID paradigm. We found increased Fos-like immunoreactivity (Fos-LI) in several cortical areas, including medial and orbital frontal cortex (OFC), in rats performing affective or attentional shifts relative to rats performing control discriminations. However, increased Fos-LI was also present in rats that performed a yoked number of additional control discrimination trials, without affective or attentional shifting. These observations suggest that cortical networks required for affective and attentional shifting are also activated during comparable discrimination tasks that do not require shifting, consistent with a role for these networks in monitoring ongoing behavior even in situations in which adaptation to changing behavioral demands is not required.
Asunto(s)
Atención , Encéfalo/metabolismo , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Animales , Discriminación en Psicología , Corteza Entorrinal/metabolismo , Inmunohistoquímica , Masculino , Lóbulo Parietal/metabolismo , Corteza Prefrontal/metabolismo , Ratas , Aprendizaje Inverso , Disposición en PsicologíaRESUMEN
Orbitofrontal cortical (OFC) and hippocampal (HPC) lesions in primates and rodents have been associated with impulsive behaviour. We showed previously that OFC- or HPC-lesioned rats chose the immediate low-reward (LR) option in preference to the delayed high-reward (HR) option, where LR and HR were associated with different spatial responses in a uniform grey T-maze. We now report that on a novel nonspatial T-maze task in which the HR and LR options are associated with patterned goal arms (black-and-white stripes vs. gray), OFC-lesioned rats did not show impulsive behaviour, choosing the delayed HR option, and were indistinguishable from controls. In contrast, HPC-lesioned rats exhibited impulsive choice in the nonspatial decision-making task, although they chose the HR option on the majority of trials when there was a 10-s delay associated with both goal arms. The previously reported impairment in OFC-lesioned rats on the spatial version of the intertemporal choice task is unlikely to reflect a general problem with spatial learning, because OFC lesions were without effect on acquisition of the standard reference memory water-maze task and spatial working memory performance (nonmatching-to-place) on the T-maze. The differential effect of OFC lesions on the two versions of the intertemporal choice task may be explained instead in terms of the putative role of OFC in using associative information to represent expected outcomes and generate predictions. The impulsivity in HPC-lesioned rats may reflect impaired temporal information processing, and emphasizes a role for the hippocampus beyond the spatial domain.
Asunto(s)
Conducta de Elección/fisiología , Toma de Decisiones/fisiología , Lóbulo Frontal/fisiología , Hipocampo/fisiología , Conducta Impulsiva/fisiopatología , Animales , Masculino , Aprendizaje por Laberinto/fisiología , RatasRESUMEN
Damage to the ventromedial frontal cortex (VMFC) in humans is associated with deficits in decision making. Decision making, however, often happens while people are interacting with others, where it is important to take the social consequences of a course of action into account. It is well known that VMFC lesions also lead to marked alterations in patients' emotions and ability to interact socially; however, it has not been clear which parts of the VMFC are critical for these changes. Recently, there has been considerable interest in the role of the VMFC in choice behavior during interpersonal exchanges. Here, we highlight recent research that suggests that two areas within or adjacent to the VMFC, the orbitofrontal cortex (OFC) and the anterior cingulate cortex (ACC), may play distinct but complementary roles in mediating normal patterns of emotion and social behavior. Converging lines of evidence from human, macaque, and rat studies now suggest that the OFC may be more specialized for simple emotional responses, such as fear and aggression, through its role in representing primary reinforcement or punishment. By contrast, the ACC may play a distinct role in more complex aspects of emotion, such as social interaction, by virtue of its connections with the discrete parts of the temporal lobe and subcortical structures that control autonomic responses.
Asunto(s)
Toma de Decisiones/fisiología , Emociones/fisiología , Lóbulo Frontal/fisiología , Conducta Social , Animales , Conducta Animal/fisiología , Conducta de Elección/fisiología , Lóbulo Frontal/fisiopatología , Giro del Cíngulo/fisiología , Humanos , Relaciones Interpersonales , Macaca , Motivación , Vías Nerviosas/fisiología , RatasRESUMEN
RATIONALE: The 5-HT transporter (5-HTT) is implicated in the regulation of appetite. Expression of the 5-HTT varies in the human population, and this variation may determine both individual differences in feeding and abnormal feeding behaviours such as eating disorders. OBJECTIVES: The effects of 5-HTT expression on feeding and satiety were examined in a transgenic mouse model of 5-HTT overexpression. MATERIALS AND METHODS: We measured free-feeding food intake and observed the behavioural satiety sequence (BSS) after food deprivation in mice at baseline and after administration of the anorectic drug fenfluramine. RESULTS: 5-HTT overexpressing mice were both lighter and shorter than their wildtype littermates. Despite this size difference, food intake by transgenic and wildtype mice did not differ. There was no effect of genotype on the BSS or on food intake during the test at baseline. Increasing doses of fenfluramine reduced food intake in a similar manner in both transgenic and wildtype mice. After 0.3 and 1 mg/kg fenfluramine, the temporal pattern of the BSS was the same for both groups, whereas 3 and 10 mg/kg fenfluramine disrupted the BSS. In transgenic mice, this disruption was evident at the 3 mg/kg dose, while in wildtypes, it emerged only at the 10-mg/kg dose. CONCLUSION: These data suggest that overexpression of the 5-HTT does not lead to alterations in feeding or satiety in food-deprived mice but does increase the occurrence of other non-feeding behaviours in response to the 5-HT releasing agent fenfluramine.
Asunto(s)
Conducta Alimentaria/efectos de los fármacos , Fenfluramina/farmacología , Serotoninérgicos/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Animales , Peso Corporal , Relación Dosis-Respuesta a Droga , Fenfluramina/administración & dosificación , Expresión Génica , Genotipo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Respuesta de Saciedad/efectos de los fármacos , Serotoninérgicos/administración & dosificación , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genéticaRESUMEN
It is widely believed that synaptic plasticity may provide the neural mechanism that underlies certain kinds of learning and memory in the mammalian brain. The expression of long-term potentiation (LTP) in the hippocampus, an experimental model of synaptic plasticity, requires the GluR-A subunit of the AMPA subtype of glutamate receptor. Genetically modified mice lacking the GluR-A subunit show normal acquisition of the standard, fixed-location, hidden-platform watermaze task, a spatial reference memory task that requires the hippocampus. In contrast, these mice are dramatically impaired on hippocampus-dependent, spatial working memory tasks, in which the spatial response of the animal is dependent on information in short-term memory. Taken together, these results argue for two distinct and independent spatial information processing mechanisms: (i) a GluR-A-independent associative learning mechanism through which a particular spatial response is gradually or incrementally strengthened, and which presumably underlies the acquisition of the classic watermaze paradigm and (ii) a GluR-A-dependent, non-associative, short-term memory trace which determines performance on spatial working memory tasks. These results are discussed in terms of Wagner's SOP model (1981).
Asunto(s)
Aprendizaje por Asociación/fisiología , Memoria/fisiología , Plasticidad Neuronal/fisiología , Receptores AMPA/fisiología , Animales , Hipocampo/citología , Hipocampo/fisiología , Ratones , Ratones Noqueados , Plasticidad Neuronal/genéticaRESUMEN
Previous studies suggest a preferential role for dorsal hippocampus (dHPC) in spatial memory tasks, whereas ventral hippocampus (vHPC) has been implicated in aspects of fear and/or anxiety. In this study, we tested the hypothesis that vHPC may be a critical subregion for performance on a delay-based, cost-benefit decision making task. Rats chose between the two goal arms of a T maze, one containing an immediately available small reward, the other containing a larger reward that was only accessible after a delay. dHPC, vHPC, and complete hippocampal (cHPC) lesions all reduced choice of the delayed high reward (HR) in favor of the immediately available low reward (LR). The deficits were not due to a complete inability to remember which reward size was associated with which arm of the maze. When an equivalent 10-s delay was introduced in both goal arms, all rats chose the HR arm on nearly all trials. The deficit was, however, reinstated when the inequality was reintroduced. Our results suggest an important role for both dHPC and vHPC in the extended neural circuitry that underlies intertemporal choice.
Asunto(s)
Toma de Decisiones/fisiología , Hipocampo/fisiología , Tiempo de Reacción/fisiología , Recompensa , Animales , Conducta Animal , Hipocampo/anatomía & histología , Masculino , Aprendizaje por Laberinto/fisiología , Ratas , Análisis y Desempeño de TareasRESUMEN
The glycine transporter (GlyT1) regulates levels of the neurotransmitter glycine, a coagonist of the N-methyl-D-aspartate receptor (NMDAR), and as such may represent a novel site for developing cognition-enhancing drugs. Genetically modified mice with reduced levels of GlyT1 have been generated to test this hypothesis. P. Singer, D. Boison, H. Möhler, J. Feldon, and B. K. Yee now show, through a spontaneous exploration task, that mice in which GlyT1 has been deleted, specifically in neurons in the forebrain, demonstrate enhanced object recognition memory. Whereas both control and mutant mice show a preference for a novel object over a familiar object 2 min after the initial presentation of 1 of the objects, only the mutant mice show a preference for the novel object when tested after a 2-hr delay. The longer-lasting habituation displayed by the GlyT1 mice is consistent with a role for glycine/NMDAR-dependent synaptic plasticity in supporting a nonassociative, short-term memory trace of a recently experienced stimulus. This short-term habituation process may be independent of associative learning mechanisms and may be best described by A. R. Wagner's (1981) sometimes opponent process model.
Asunto(s)
Proteínas de Transporte de Glicina en la Membrana Plasmática/genética , Inteligencia/genética , Animales , Animales Modificados Genéticamente , Glicina/fisiología , Habituación Psicofisiológica/fisiología , Memoria/fisiología , Memoria a Corto Plazo/fisiología , Ratones , Ratones Noqueados , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Reconocimiento en Psicología/fisiologíaRESUMEN
Genetically modified mice lacking the glutamate receptor A (GluR-A) subunit of the AMPA receptor (GluR-A-/- mice) display normal spatial reference memory but impaired spatial working memory (SWM). This study tested whether the SWM impairment in these mice could be explained by a greater sensitivity to within-session proactive interference. The SWM performance of GluR-A-/- and wild-type mice was assessed during nonmatching-to-place testing under conditions in which potential proactive interference from previous trials was reduced or eliminated. SWM was impaired in GluR-A-/- mice, both during testing with pseudotrial-unique arm presentations on the radial maze and when conducting each trial on a different 3-arm maze, each in a novel testing room. Experimentally naive GluR-A-/- mice also exhibited chance performance during a single trial of spontaneous alternation. This 1-trial spatial memory deficit was present irrespective of the delay between the sample information and the response choice (0 or 45 min) and the length of the sample phase (0.5 or 5 min). These results imply that the SWM deficit in GluR-A-/- mice is not due to increased susceptibility to proactive interference.
Asunto(s)
Trastornos de la Memoria/genética , Memoria a Corto Plazo/fisiología , Receptores AMPA/deficiencia , Percepción Espacial/fisiología , Animales , Conducta Exploratoria/fisiología , Femenino , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Noqueados , Tiempo de Reacción/genéticaRESUMEN
Novel spatially restricted genetic manipulations can be used to assess contributions made by synaptic plasticity to learning and memory, not just selectively within the hippocampus, but even within specific hippocampal subfields. Here we generated genetically modified mice (NR1(deltaDG) mice) exhibiting complete loss of the NR1 subunit of the N-methyl-D-aspartate receptor specifically in the granule cells of the dentate gyrus. There was no evidence of any reduction in NR1 subunit levels in any of the other hippocampal subfields, or elsewhere in the brain. NR1(deltaDG) mice displayed severely impaired long-term potentiation (LTP) in both medial and lateral perforant path inputs to the dentate gyrus, whereas LTP was unchanged in CA3-to-CA1 cell synapses in hippocampal slices. Behavioural assessment of NR1(deltaDG) mice revealed a spatial working memory impairment on a three-from-six radial arm maze task despite normal hippocampus-dependent spatial reference memory acquisition and performance of the same task. This behavioural phenotype resembles that of NR1(deltaCA3) mice but differs from that of NR1(deltaCA1) mice which do show a spatial reference memory deficit, consistent with the idea of subfield-specific contributions to hippocampal information processing. Furthermore, this pattern of selective functional loss and sparing is the same as previously observed with the global GluR-A L-alpha-amino-3-hydroxy-5-methyl-4-isoxazelopropionate receptor subunit knockout, a mutation which blocks the expression of hippocampal LTP. The present results show that dissociations between spatial working memory and spatial reference memory can be induced by disrupting synaptic plasticity specifically and exclusively within the dentate gyrus subfield of the hippocampal formation.
Asunto(s)
Giro Dentado/fisiología , Memoria a Corto Plazo/fisiología , Recuerdo Mental/fisiología , Receptores de N-Metil-D-Aspartato/genética , Percepción Espacial/fisiología , Animales , Conducta Animal/fisiología , Electrofisiología , Inmunohistoquímica , Hibridación in Situ , Potenciación a Largo Plazo/fisiología , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Noqueados , Plasticidad Neuronal/fisiología , Técnicas de Cultivo de Órganos , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
How we decide whether a course of action is worth undertaking is largely unknown. Recently, neuroscientists have been turning to ecological approaches to address this issue, examining how animals evaluate the costs and benefits of different options. We present here evidence from rodents and monkeys that demonstrate the degree to which they take into account work and energetic requirements when deciding what responses to make. These calculations appear to be critically mediated by the anterior cingulate cortex (ACC) and mesolimbic dopamine (DA) pathways, with damage to either causing a bias towards options that are easily obtained but yield relatively smaller reward rather than alternatives that require more work but result in greater reward. The evaluation of such decisions appears to be carried out in systems independent of those involved in delay-discounting. We suggest that top-down signals from ACC to nucleus accumbens (NAc) and/or midbrain DA cells may be vital for overcoming effort-related response costs.
Asunto(s)
Conducta Animal/fisiología , Toma de Decisiones , Vías Nerviosas/fisiología , Refuerzo en Psicología , Trabajo/psicología , Animales , Dopamina/fisiología , Sistema Límbico/fisiología , Macaca mulatta , Masculino , Aprendizaje por Laberinto/fisiología , Corteza Prefrontal/fisiología , Ratas , Tiempo de Reacción , Esquema de Refuerzo , Factores de TiempoRESUMEN
OBJECTIVE: The aim of this article is to provide a review of studies using N-methyl-D-aspartate (NMDA) receptor antagonists to assess the hippocampal long-term potentiation (LTP)/learning hypothesis. DISCUSSION: In particular, we will re-examine the validity of both (1) the original hippocampal LTP/spatial learning hypothesis of Morris and (2) the sensorimotor account put forward by Cain, among others, both from the point of view of the pharmacological studies on which they were based and with regard to recent studies with genetically modified mice. More specifically, we will review the pharmacological studies in the light of recent work on the glutamate receptor A (GluR-A or GluR1) L-alpha-amino-3-hydroxy-5-methyl-4-isoxazelopropionate (AMPA) receptor sub-unit knockout mouse. We will argue that neither the original hippocampal LTP/spatial learning hypothesis nor a sensorimotor account can adequately explain all of the available data. We argue instead that hippocampal synaptic plasticity, which requires NMDA receptors for its induction and GluR-A-containing AMPA receptors for its continued expression, contributes to a process whereby appropriate behavioural responses are selected rapidly on the basis of conditional information provided by the context. These contextual cues could include not only the spatial context (i.e. the 'where') and the temporal context (the 'when'), but also other aspects of context, such as internal state cues (hunger and fear state), and can be used to rapidly and flexibly alter valences of specific response options. RECOMMENDATIONS: We also suggest that there is a separate, distinct, NMDA/GluR-A-independent mechanism through which the context can gradually (incrementally or decrementally) alter the valence of a particular response option.
Asunto(s)
Hipocampo/fisiología , Memoria/fisiología , Receptores AMPA/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , 2-Amino-5-fosfonovalerato/farmacología , Animales , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Memoria/efectos de los fármacos , Ratones , Ratones Noqueados , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
Four related experiments studied operant performance of mice on differential reinforcement of low rates of responding (DRL) paradigms. Experiment 1 showed that excitotoxic hippocampal lesions impaired performance of a 10-s DRL schedule (DRL-10). Experiments 2 and 3 showed that GluR-A AMPA receptor subunit knockout mice, which are deficient in CA3-CA1 long-term potentiation (LTP), were markedly impaired at 15 s (DRL-15), but less impaired at DRL-10. Experiment 4 compared DRL-15 performance in mice from the 2 strains from which the GluR-A colony was derived and showed that they did not differ. The results show that GluR-A-containing AMPA receptors are required for normal performance on hippocampus-dependent, nonspatial working memory tasks, consistent with a role for GluR-A in the temporal encoding (what happened when) of nonspatial information.
Asunto(s)
Condicionamiento Operante/fisiología , Plasticidad Neuronal/fisiología , Receptores AMPA/fisiología , Sinapsis/fisiología , Animales , Conducta Animal , Peso Corporal/fisiología , Femenino , Hipocampo/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores AMPA/deficiencia , Esquema de Refuerzo , RecompensaRESUMEN
RATIONALE: Although tasks assessing the role of dopamine in effort-reward decisions are similar to those concerned with the role of serotonin in impulsive choice in that both require analysis of the costs and benefits of possible actions, they have never been directly compared. OBJECTIVES: This study investigated the involvement of serotonin and dopamine in two cost-benefit paradigms, one in which the cost was delay and the other in which it was physical effort. METHODS: Sixteen rats were trained on a T-maze task in which they chose between high and low reward arms. In one version, the high reward arm was obstructed by a barrier, in the other, delivery of the high reward was delayed by 15 s. Serotonin and dopamine function were manipulated using systemic pCPA and haloperidol injections, respectively. RESULTS: Haloperidol-treated rats were less inclined either to exert more effort or to countenance a delay for a higher reward. pCPA had no effect on the performance of the rats on the effortful task, but significantly increased the rats' preference for an immediate but smaller reward. All animals (drug treated and controls) chose the high reward arm on the majority of trials when the delay or effort costs were matched in both high and low reward arms. CONCLUSION: A dissociation was found between the neurotransmitter systems involved in different types of cost-benefit decision making. While dopaminergic systems were required for decisions about both effort and delay, serotonergic systems were only needed for the latter.