RESUMEN
Frontal and parietal cortex are implicated in economic decision-making, but their causal roles are untested. Here we silenced the frontal orienting field (FOF) and posterior parietal cortex (PPC) while rats chose between a cued lottery and a small stable surebet. PPC inactivations produced minimal short-lived effects. FOF inactivations reliably reduced lottery choices. A mixed-agent model of choice indicated that silencing the FOF caused a change in the curvature of the rats' utility function (U = Vρ). Consistent with this finding, single-neuron and population analyses of neural activity confirmed that the FOF encodes the lottery value on each trial. A dynamical model, which accounts for electrophysiological and silencing results, suggests that the FOF represents the current lottery value to compare against the remembered surebet value. These results demonstrate that the FOF is a critical node in the neural circuit for the dynamic representation of action values for choice under risk.
Asunto(s)
Neuronas , Lóbulo Parietal , Ratas , Animales , Lóbulo Parietal/fisiología , Neuronas/fisiologíaRESUMEN
The water maze is one of the most widely employed spatial learning paradigms in the cognitive profiling of genetically modified mice. Oftentimes, tests of reference memory (RM) and working memory (WM) in the water maze are sequentially evaluated in the same animals. However, critical difference in the rules governing efficient escape from the water between WM and RM tests is expected to promote the adoption of incompatible mnemonic or navigational strategies. Hence, performance in a given test is likely poorer if it follows the other test instead of being conducted first. Yet, the presence of such negative transfer effects (or proactive interference) between WM and RM training in the water maze is often overlooked in the literature. To gauge whether this constitutes a serious concern, the present study determined empirically the magnitude, persistence, and directionality of the transfer effect in wild-type C57BL/6 mice. We contrasted the order of tests between two cohorts of mice. Performance between the two cohorts in the WM and RM tests were then separately compared. We showed that prior training of either test significantly reduced performance in the subsequent one. The statistical effect sizes in both directions were moderate to large. Although extended training could overcome the deficit, it could re-emerge later albeit in a more transient fashion. Whenever RM and WM water maze tests are conducted sequentially in the same animals - regardless of the test order, extra caution is necessary when interpreting the outcomes in the second test. Counterbalancing test orders between animals is recommended.
Asunto(s)
Atención/fisiología , Aprendizaje por Laberinto/fisiología , Memoria a Corto Plazo/fisiología , Conducta Espacial/fisiología , Animales , Conducta Animal , Masculino , Ratones Endogámicos C57BL , Transferencia de Experiencia en Psicología/fisiologíaRESUMEN
While pharmacological blockade of dopamine D2 receptor can effectively suppress the psychotic or positive symptoms of schizophrenia, there is no satisfactory medication for the negative and cognitive symptoms of schizophrenia in spite of the proliferation of second generation antipsychotic drugs. Excitements over a new class of third generation antipsychotics that might possibly fill this urgent medical need have been prompted by the recent development of glycine transporter 1 (GlyT1) inhibitors. The impetus of this novel pharmacological strategy stems directly from the prevailing hypothesis that negative and cognitive symptoms are attributable to the hypofunction of glutamatergic signalling via the N-methyl-D-aspartate (NMDA) receptor in the brain. Inhibition of GlyT1 reduces clearance of extra-cellular glycine near NMDA receptor-containing synapses, and thereby increases baseline occupancy of the glycine-B site at the NR1 subunit of the NMDA receptor, which is a prerequisite of channel activation upon stimulation by the excitatory neurotransmitter glutamate. Pharmacological inhibition of GlyT1 is expected to boost NMDA receptor function and therefore alleviate persistent negative and cognitive symptoms without excessive risk of excitotoxicity associated with direct NMDA receptor agonists. The recently completed phase III clinical trials of the Roche compound, bitopertin (a.k.a. RG1678 or RO-4917838) had initially raised hope that this new class of drugs might represent the first successful translation of the glutamate hypothesis of schizophrenia to the clinic. However, the outcomes of the multi-centre bitopertin clinical trials have been disappointing. The present review seeks to examine this promise through a critical survey of the latest clinical and preclinical findings on the therapeutic potential of GlyT1 inhibition or down-regulation.
Asunto(s)
Antipsicóticos/farmacología , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Esquizofrenia/tratamiento farmacológico , Animales , Antipsicóticos/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Descubrimiento de Drogas , Glicina/fisiología , Proteínas de Transporte de Glicina en la Membrana Plasmática/fisiología , Humanos , Neurotransmisores/fisiología , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/fisiología , Esquizofrenia/fisiopatología , Sinapsis/efectos de los fármacos , Sinapsis/fisiologíaRESUMEN
Neurotransmitter receptor density is a major variable in regulating synaptic strength. Receptors rapidly exchange between synapses and intracellular storage pools through endocytic recycling. In addition, lateral diffusion and confinement exchanges surface membrane receptors between synaptic and extrasynaptic sites. However, the signals that regulate this transition are currently unknown. GABAA receptors containing α5-subunits (GABAAR-α5) concentrate extrasynaptically through radixin (Rdx)-mediated anchorage at the actin cytoskeleton. Here we report a novel mechanism that regulates adjustable plasma membrane receptor pools in the control of synaptic receptor density. RhoA/ROCK signalling regulates an activity-dependent Rdx phosphorylation switch that uncouples GABAAR-α5 from its extrasynaptic anchor, thereby enriching synaptic receptor numbers. Thus, the unphosphorylated form of Rdx alters mIPSCs. Rdx gene knockout impairs reversal learning and short-term memory, and Rdx phosphorylation in wild-type mice exhibits experience-dependent changes when exposed to novel environments. Our data suggest an additional mode of synaptic plasticity, in which extrasynaptic receptor reservoirs supply synaptic GABAARs.
Asunto(s)
Proteínas del Citoesqueleto/metabolismo , Aprendizaje/fisiología , Proteínas de la Membrana/metabolismo , Receptores de GABA-A/metabolismo , Sinapsis/fisiología , Animales , Proteínas del Citoesqueleto/genética , Fenómenos Electrofisiológicos , Regulación de la Expresión Génica/fisiología , Hipocampo/citología , Hipocampo/fisiología , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Receptores de GABA-A/genéticaRESUMEN
RATIONALE: The psychoactive substance, caffeine, may improve cognitive performance, but its direct impact on learning and memory remains ill defined. Conflicting reports suggest that caffeine may impair as well as enhance Pavlovian fear conditioning in animals and its effect may vary across different phases of learning. OBJECTIVES: The purpose of this study is to dissect the effect of a motor-stimulant dose of caffeine (30 mg/kg intraperitoneal (i.p.)) on acquisition, retrieval or consolidation of conditioned fear in C57BL/6 mice. METHODS: Fear conditioning was evaluated in a conditioned freezing paradigm comprising 3 tone-shock pairings and a two-way active avoidance paradigm lasting two consecutive days with 80 conditioning trials per test session. RESULTS: Conditioning to both the discrete tone-conditioned stimulus (CS) and the context was markedly impaired by caffeine. The deficits were similarly evident when caffeine was administered prior to acquisition or retrieval (48 and 72 h after conditioning); and the most severe impairment was seen in animals given caffeine before acquisition and before retrieval. A comparable deficit was observed in the conditioned active avoidance test. By contrast, caffeine administered immediately following acquisition neither affected the expression of tone freezing nor context freezing. CONCLUSIONS: The present study challenges the previous report that caffeine primarily disrupts hippocampus-dependent conditioning to the context. At the relevant dose range, acute caffeine likely exerts more widespread impacts beyond the hippocampus, including the amygdala and striatum that are anatomically connected to the hippocampus; together, they support the acquisition and retention of fear memories to discrete stimuli as well as diffused contextual cues.
Asunto(s)
Cafeína/farmacología , Condicionamiento Clásico/efectos de los fármacos , Aprendizaje/efectos de los fármacos , Retención en Psicología/efectos de los fármacos , Amígdala del Cerebelo/efectos de los fármacos , Animales , Estimulantes del Sistema Nervioso Central/farmacología , Señales (Psicología) , Miedo/efectos de los fármacos , Congelación , Hipocampo/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Distribución AleatoriaRESUMEN
Enhanced expression of Pavlovian aversive conditioning but not appetitive conditioning may indicate a bias in the processing of threatening or fearful events. Mice with disruption of glycine transporter 1 (GlyT1) in forebrain neurons exhibit such a bias, but they are at the same time highly sensitive to manipulations that hinder the development of the conditioned response (CR) suggesting that the mutation may modify higher cognitive processes that extract predictive information between environmental cues. Here, we further investigated the development of fear conditioning in forebrain neuronal GlyT1 knockout mice when the predictiveness of a tone stimulus for foot-shock was rendered ambiguous by interspersing [toneâno shock] trials in-between [toneâshock] trials during acquisition. The CR to the ambiguous tone CS (conditioned stimulus) was compared with that generated by an unambiguous CS that was always followed by the shock US (unconditioned stimulus) during acquisition. We showed that rendering the CS ambiguous as described significantly attenuated the CR in the mutants, but it was not sufficient to modify the CR in the control mice. It is concluded that disruption of GlyT1 in forebrain neurons does not increase the risk of forming spurious and potentially maladaptive fear associations.
Asunto(s)
Condicionamiento Psicológico/fisiología , Miedo/fisiología , Proteínas de Transporte de Glicina en la Membrana Plasmática/fisiología , Neuronas/fisiología , Prosencéfalo/fisiología , Animales , Señales (Psicología) , Femenino , Eliminación de Gen , Proteínas de Transporte de Glicina en la Membrana Plasmática/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
RATIONALE: Caffeine is a psychostimulant drug that blocks adenosine A1 and A2A receptors (A1Rs and A2ARs). However, its ability to disrupt early sensory gating as indexed by prepulse inhibition (PPI), which is consistently disrupted by other psychostimulant agents, has never been convincingly demonstrated. OBJECTIVES: To compare the impact of caffeine on PPI expression in C57BL/6 mice by two dose-response experiments differing in terms of chronicity, regimen, and route of administration. To study separately the acute effect of selective antagonists against A1R or A2AR. METHODS: Caffeine (10, 30, 100 mg/kg, intraperitoneal (i.p.)) was either administered shortly before testing or via caffeinated drinking water (0.3, 1.0, 2 g/l) in home cages over 3 weeks. Two separate dose-response studies tested the acute effect of the selective A1R antagonist, 1,3 dipropyl-8 cyclopentyl xanthine (DPCPX), and the selective A2AR antagonist, 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c] (SCH 58261) (0.2, 1.0, 5.0 mg/kg, i.p.). The two drugs were combined in a final experiment to identify their potential synergistic interaction. RESULTS: While the two lower acute doses of caffeine attenuated PPI, the highest dose potentiated PPI. By contrast, chronic caffeine exposure did not affect PPI. Neither DPCPX nor SCH 58261 altered PPI, and no synergism was observed when the two drugs were combined. CONCLUSIONS: This is the first demonstration that acute caffeine disrupts PPI, but the relative contribution of A1R and A2AR blockade remains unclear, and possible non-adenosinergic mechanisms cannot be ruled out. The null effect under chronic caffeine exposure might involve the development of tolerance, but the precise receptor subtypes involved also warrant further investigation.
Asunto(s)
Cafeína/administración & dosificación , Estimulantes del Sistema Nervioso Central/administración & dosificación , Inhibición Prepulso/efectos de los fármacos , Antagonistas de Receptores Purinérgicos P1/administración & dosificación , Filtrado Sensorial/efectos de los fármacos , Antagonistas del Receptor de Adenosina A1/farmacología , Antagonistas del Receptor de Adenosina A2/farmacología , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Pirimidinas/farmacología , Triazoles/farmacología , Xantinas/farmacologíaRESUMEN
The deletion of glycine transporter 1 (GlyT1) in forebrain neurons can apparently strengthen Pavlovian aversive conditioning, but this phenotype is not expressed if conditioning followed non-reinforced pre-exposures of the to-be-conditioned stimulus (CS). To examine whether GlyT1 disruption may only enhance aversive associative learning under conditions that most favour the formation of CS-US excitatory link, we evaluated the impact of GlyT1 disruption on the trace conditioning procedure whereby a trace interval between a tone CS and a shock US was introduced during conditioning. CS and US occurrences were thus rendered discontiguous, which was expected to impede conditioning compared with contiguous CS-US pairing. Conditioned freezing to the CS was measured in a retention test conducted 48 h after conditioning. The genetic disruption significantly modified the temporal dynamics of the freezing response over the course of the 8-min presentation of the CS, although the immediate conditioned response to the CS was unaffected. The separation between "trace" and "no-trace" conditions was augmented in the mutant mice, but this only became apparent in mid-session; and the augmentation can be attributed to the combined effects of (i) weaker conditioned freezing in the mutant relative to control subjects in the "trace" condition, and (ii) stronger conditioned freezing in mutants relative controls in the "no-trace" condition. The demonstrated increased sensitivity to the effect of CS-US temporal discontiguity further highlights the importance of GlyT1-dependent mechanisms in the regulation of associative learning.
Asunto(s)
Aprendizaje por Asociación/fisiología , Condicionamiento Clásico/fisiología , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Neuronas/metabolismo , Prosencéfalo/metabolismo , Animales , Miedo/fisiología , Femenino , Masculino , Ratones , Ratones TransgénicosRESUMEN
Glycine transporter 1 (GlyT1) is a potential pharmacological target to ameliorate memory deficits attributable to N-methyl-d-aspartate receptor (NMDAR) hypofunction. Disruption of glycine-reuptake near excitatory synapses is expected to enhance NMDAR function by increasing glycine-B site occupancy. Genetic models with conditional GlyT1 deletion restricted to forebrain neurons have yielded several promising promnesic effects, yet its impact on working memory function remains essentially unanswered because the previous attempt had yielded un-interpretable outcomes. The present study clarified this important outstanding lacuna using a within-subject multi-test approach. Here, a consistent lack of effects was convincingly demonstrated across three working memory tests - the radial arm maze, the cheeseboard maze, and the water maze. These null outcomes contrasted with the phenotype of enhanced working memory performance seen in mutant mice with GlyT1 deletion extended to cortical/hippocampal glial cells. It follows that glial-based GlyT1 might be more closely linked to the modulation of working memory function, and raises the possibility that neuronal and glial GlyT1 may regulate cognitive functions via dissociable mechanisms.
Asunto(s)
Proteínas de Transporte de Glicina en la Membrana Plasmática/deficiencia , Memoria a Corto Plazo/fisiología , Neuronas/metabolismo , Prosencéfalo/citología , Análisis de Varianza , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Señales (Psicología) , Habituación Psicofisiológica/genética , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Prosencéfalo/metabolismo , Factores de TiempoRESUMEN
Behavioural characterisation of transgenic mice has been instrumental in search of therapeutic targets for the modulation of cognitive function. However, little effort has been devoted to phenotypic characterisation across environmental conditions and genomic differences such as sex and strain, which is essential to translational research. The present study is an effort in this direction. It scrutinised the stability and robustness of the phenotype of enhanced Pavlovian conditioning reported in mice with forebrain neuronal deletion of glycine transporter 1 by evaluating the possible presence of sex and circadian dependency, and its consistency across aversive and appetitive conditioning paradigms. The Pavlovian phenotype was essentially unaffected by the time of testing between the two circadian phases, but it was modified by sex in both conditioning paradigms. We observed that the effect size of the phenotype was strongest in female mice tested during the dark phase in the aversive paradigm. Critically, the presence of the phenotype in female mutants was accompanied by an increase in resistance to extinction. Similarly, enhanced conditioned responding once again emerged solely in female mutants in the appetitive conditioning experiment, which was again associated with an increased resistance to extinction across days, but male mutants exhibited an opposite trend towards facilitation of extinction. The present study has thus added hitherto unknown qualifications and specifications of a previously reported memory enhancing phenotype in this mouse line by identifying the determinants of the magnitude and direction of the expressed phenotype. This in-depth comparative approach is of value to the interpretation of behavioural findings in general.
Asunto(s)
Aprendizaje por Asociación/fisiología , Ritmo Circadiano/fisiología , Condicionamiento Psicológico/fisiología , Proteínas de Transporte de Glicina en la Membrana Plasmática/genética , Neuronas/fisiología , Prosencéfalo/fisiología , Animales , Ansiedad/genética , Electrochoque , Extinción Psicológica/fisiología , Femenino , Masculino , Ratones , Ratones Noqueados , Actividad Motora/fisiología , Fenotipo , Factores SexualesRESUMEN
Deterioration in attention and related processes is an early sign in schizophrenia predictive of disease development. Amongst the various translational paradigms for assessing attention in rodents, it is not known if they are equivalent in detecting individual differences. Answers here are pertinent to their use in the general human population for identifying individuals at high risk of developing schizophrenia. The present study employed a within-subject approach to examine in mice two common paradigms for assessing attention that differ markedly in their implementation. An operant-based two-choice visual discrimination task (2-CVDT) that depends on effortful attention to brief visual cues was contrasted with prepulse inhibition (PPI) of the acoustic startle reflex, a well-established test of pre-attentive gating whereby processing of a startle-eliciting stimulus is inhibited by a preceding weak prepulse stimulus. Here, we revealed a correlation showing that individual mice with low PPI tended to perform poorly in the 2-CVDT in terms of choice accuracy but not response speed. This specific positive correlation suggests that the two readouts might be regulated via common attentional mechanisms, which might be critically dependent on normal muscarinic and N-methyl-d-asparate receptor functions. As demonstrated here, blockade of either receptor type by scopolamine or dizocilpine impaired 2-CVDT performance at doses that have been shown to disrupt PPI in mice. Further studies contrasting these two paradigms would be warranted to characterize the possible underlying psychological constructs that give rise to this correlation and to clarify whether the two paradigms may effectively capture schizophrenia-related cognitive deficits belonging to orthogonal domains.
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Atención/efectos de los fármacos , Conducta de Elección/efectos de los fármacos , Filtrado Sensorial , Animales , Condicionamiento Operante/efectos de los fármacos , Discriminación en Psicología/efectos de los fármacos , Maleato de Dizocilpina/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , N-Metilescopolamina/farmacología , Reflejo de Sobresalto , Escopolamina/farmacología , Percepción Visual/efectos de los fármacosRESUMEN
Genetic deletion of glycine transporter 1 (GlyT1) in forebrain neurons gives rise to multiple-procognitive phenotypes, presumably due to enhanced N-methyl-d-aspartate receptor (NMDAR) functions. However, concerns over possible harmful excitotoxic effects under lifelong elevation of synaptic glycine have been raised. Such effects might accelerate the aging process, weakening or even reversing the procognitive phenotypes identified in adulthood. Here, we examined if one of the most robust phenotypes in the mutant mouse line (CamKIIαCre;GlyT1tm1.2fl/fI), namely, enhanced aversive Pavlovian conditioning, might be modified by age. Comparison between 3-month-old (adult) and 22-month-old (aged) mutants confirmed the presence of this phenotype at both ages. However, the temporal expression of the Pavlovian phenotype was modified in senescence; while adult mutants showed a pronounced within-session extinction, aged mutants did not. Expression of NR2B subunits of NMDAR and neural proliferation were examined in the same animals by immunohistochemistry. These were reduced in the aged mice as expected, but not exacerbated by the mutation. Thus, our results do not substantiate the concerns of neurotoxic effects through lifelong GlyT1 disruption in forebrain neurons, but provide evidence for a modification of phenotypic expression as a function of age. The latter points to the need to further investigate other procognitive phenotypes identified at adulthood in this mutant line. In addition, we revealed here for the first time a clear increase in the number of immature neurons in the hippocampus of the mutants, although the behavioral significance of this phenotype remains to be determined.