Jacques Micheau

Glutamate receptor function in learning and memory.

The contribution of glutamate to synaptic transmission, plasticity and development is well established; current evidence is based on diverse approaches to decipher function and malfunction of this principal transmitter. With respect to learning and memory, we are now able to identify more specifically the role played by the three main glutamate receptor classes in learning and memory: centre stage is clearly the NMDA receptor, with overwhelming evidence proving its involvement in the actual learning process (encoding), throughout the animal kingdom. This is discussed with respect to many different types of learning. Evidence for the contribution of the AMPA receptors (AMPARs) is less clear-cut due to the general problem of specificity: block of AMPARs will shutdown neuronal communication, and this will affect various components essential for learning. Therefore, the role of AMPARs cannot be established in isolation. Problems of interpretation are outlined and a specific involvement of AMPARs in the regulation of neuronal excitation related to learning is proposed. Metabotropic glutamate receptors (mGluRs) may contribute very little to the actual acquisition of new information. However, memory formation appears to require mGluRs, through the modulation of consolidation and/or recall. Overall, mGluR functions seem variable and dependent on brain structure and learning task.

Extinction of auditory fear conditioning requires MAPK/ERK activation in the basolateral amygdala

Whereas the neuronal substrates underlying the acquisition of auditory fear conditioning have been widely studied, the substrates and mechanisms mediating the acquisition of fear extinction remain largely elusive. Previous reports indicate that consolidation of fear extinction depends on the mitogen‐activated protein kinase/extracellular‐signal regulated kinase (MAPK/ERK) signalling pathway and on protein synthesis in the medial prefrontal cortex (mPFC). Based on experiments using the fear‐potentiated startle paradigm suggesting a role for neuronal plasticity in the basolateral amygdala (BLA) during fear extinction, we directly addressed whether MAPK/ERK signalling in the basolateral amygdala is necessary for the acquisition of fear extinction using conditioned freezing as a read‐out. First, we investigated the regional and temporal pattern of MAPK/ERK activation in the BLA following extinction learning in C57Bl/6J mice. Our results indicate that acquisition of extinction is associated with an increase of phosphorylated MAPK/ERK in the BLA. Moreover, we found that inhibition of the MAPK/ERK signalling pathway by intrabasolateral amygdala infusion of the MEK inhibitor, U0126, completely blocks acquisition of extinction. Thus, our results indicate that the MAPK/ERK signalling pathway is required for extinction of auditory fear conditioning in the BLA, and support a role for neuronal plasticity in the BLA during the acquisition of fear extinction.

Heterozygous neuregulin 1 mice display greater baseline and Δ9-tetrahydrocannabinol-induced c-Fos expression

Cannabis use may increase the risk of developing schizophrenia by precipitating the disorder in genetically vulnerable individuals. Neuregulin 1 (NRG1) is a schizophrenia susceptibility gene and mutant mice heterozygous for the transmembrane domain of this gene (Nrg1 HET mice) exhibit a schizophrenia-related phenotype. We have recently shown that Nrg1 HET mice are more sensitive to the behavioral effects of the main psychoactive constituent of cannabis, Delta(9)-tetrahydrocannabinol (THC). In the present study, we examined the effects of THC (10 mg/kg i.p.) on neuronal activity in Nrg1 HET mice and wild type-like (WT) mice using c-Fos immunohistochemistry. In the lateral septum, THC selectively increased c-Fos expression in Nrg1 HET mice with no corresponding effect being observed in WT mice. In addition, THC promoted a greater increase in c-Fos expression in Nrg1 HET mice than WT mice in the central nucleus of the amygdala, the bed nucleus of the stria terminalis and the paraventricular nucleus of the hypothalamus. Consistent with Nrg1 HET mice exhibiting a schizophrenia-related phenotype, these mice expressed greater drug-free levels of c-Fos in two regions thought to be involved in schizophrenia, the shell of the nucleus accumbens and the lateral septum. Interestingly, the effects of genotype on c-Fos expression, drug-free or following THC exposure, were only observed when animals experienced behavioral testing prior to perfusion. This suggests an interaction with stress was necessary for the promotion of these effects. These data provide neurobiological correlates for the enhanced behavioral sensitivity of Nrg1 HET mice to THC and reinforce the existence of cannabinoid-neuregulin 1 interactions in the CNS. This research may enhance our understanding of how genetic factors increase individual vulnerability to schizophrenia and cannabis-induced psychosis.

Function of the hippocampus in memory formation: desperately seeking resolution

Despite considerable efforts and successes investigating the function of the hippocampal formation in memory processes, there are still numerous elusive key issues. Some of them will be addressed in this review. We will argue that recent evidence supports hippocampal participation in several memory processes, such as encoding, short-term and long-term consolidation and retrieval. While some processes, for example encoding and short-term consolidation, have been the subject of detailed investigations, at least for specific and repeatedly used behavioural paradigms, there appears to be considerable lack of information with respect to other processes, for example long-term consolidation. Although the existence of long-term consolidation is not at debate here, there is only very fragmented information as to the cellular processes enabling long-term consolidation. Recent ample evidence now suggests a potential role in metabotropic glutamate receptors, and more specifically the phospholipase C-coupled receptor 5, in long-term consolidation. The hyperexpression of receptor protein was limited to CA1 indicating a specific role of this brain region in the consolidation of memories. Future work should further explore this important issue especially since long-term consolidation appears to be a necessity for permanent storage of information, and may thus engage memory mechanism that fail during ageing and dementia.

Extracellular Hippocampal Acetylcholine Level Controls Amygdala Function and Promotes Adaptive Conditioned Emotional Response

Ample data indicate that tone and contextual fear conditioning differentially require the amygdala and the hippocampus. However, mechanisms subserving the adaptive selection among environmental stimuli (discrete tone vs context) of those that best predict an aversive event are still elusive. Because the hippocampal cholinergic neurotransmission is thought to play a critical role in the coordination between different memory systems leading to the selection of appropriate behavioral strategies, we hypothesized that this cholinergic signal may control the competing acquisition of amygdala-mediated tone and contextual conditioning. Using pavlovian fear conditioning in mice, we first show a higher level of hippocampal acetylcholine release and a specific pattern of extracellular signal-regulated kinase 1/2 (ERK1/2) activation within the lateral (LA) and basolateral (BLA) amygdala under conditions in which the context is a better predictor than a discrete tone stimulus. Second, we demonstrate that levels of hippocampal cholinergic neurotransmission are causally related to the patterns of ERK1/2 activation in amygdala nuclei and actually determine the selection among the context or the simple tone the stimulus that best predicts the aversive event. Specifically, decreasing the hippocampal cholinergic signal not only impaired contextual conditioning but also mimicked conditioning to the discrete tone, both in terms of the behavioral outcome and the LA/BLA ERK1/2 activation pattern. Conversely, increasing this cholinergic signal not only disrupted tone conditioning but also promoted contextual fear conditioning. Hence, these findings highlight that hippocampal cholinergic neurotransmission controls amygdala function, thereby leading to the selection of relevant emotional information.

Memory deficits following chronic alcohol consumption in mice: Relationships with hippocampal and cortical cholinergic activities

Chronic ethanol consumption (12% v/v for 12 months) produced an accelerated decay of T-maze spontaneous alternation (SA) rates as the interval that elapsed between forced trials, used as acquisition, and a free test trial, used as a retention test, increased. Thus, alcohol-treated mice that exhibited normal SA rates at a short interval (5 min) were impaired at the longer one (6 h) relative to controls. This alcohol-induced deficit was almost completely reversed by physostigmine (0.05 mg/kg, IP) given only before the test trial. Parallel neurochemical analysis showed that chronic alcohol intake produced a significant decrease in hippocampal and cortical sodium-dependent high-affinity choline uptake. In particular, the significant cholinergic activation produced by a T-maze exploration in controls was attenuated in experimental subjects so that the between-groups differences already present in the quiet condition were amplified in the active (exploration) state. These findings suggest that the memory deficits induced by chronic ethanol consumption stem from a failure of some cholinergic-dependent retrieval processes. An attempt is made to relate the present results with our previous ones that emphasized the importance of diencephalic damage in alcohol-induced retrieval deficits.

Dissociation of cholinergic function in spatial and procedural learning in rats.

The cholinergic system has long been known for its role in acquisition and retention of new information. Scopolamine, a muscarinic acetylcholine receptor antagonist impairs multiple memory systems, and this has promoted the notion that drug-induced side effects are responsible for diminished task execution rather than selective impairments on learning and memory per se. Here, we revisit this issue with the aim to dissociate the effects of scopolamine (0.2-1.0 mg/kg) on spatial learning in the water maze. Experiments 1 and 2 showed that acquisition of a reference memory paradigm with constant platform location is compromised by scopolamine independent of whether the animals are pre-trained or not. Deficits were paralleled by drug induced side-effects on sensorimotor parameters. Experiment 3 explored the role of muscarinic receptors in acquisition of an episodic-like spatial delayed matching to position (DMTP) protocol, and scopolamine still caused a learning deficit and side-effects on sensorimotor performance. Rats extensively pre-trained in the DMTP protocol with 30 s and 1 h delays over several months in experiment 4 and tested in a within-subject design under saline and scopolamine had no sensorimotor deficits, but spatial working memory remained compromised. Experiment 5 used the rising Atlantis platform in the DMTP paradigm. Intricate analysis of the amount of dwelling and its location revealed a clear deficit in spatial working memory induced by scopolamine, but there was no effect on sensorimotor or procedural task demands. Apart from the well-known contribution to sensorimotor and procedural learning, our findings provide compelling evidence for an important role of muscarinic acetylcholine receptor signaling in spatial episodic-like memory.

The schizophrenia-susceptibility gene neuregulin 1 modulates tolerance to the effects of cannabinoids

Cannabis increases the risk of schizophrenia in genetically vulnerable individuals. In this study we aim to show that the schizophrenia susceptibility gene neuregulin 1 (Nrg1) modulates the development of tolerance to cannabinoids in mice. Nrg1 heterozygous (HET) and wild-type (WT) mice were treated daily for 15 d with the synthetic analogue of Δ9-tetrahydrocannabinol, CP55,940 (0.4 mg/kg). We measured the impact of this exposure on locomotor activity, anxiety, prepulse inhibition (PPI), body temperature and FosB/ΔFosB immunohistochemistry. Tolerance to CP55,940-induced hypothermia and locomotor suppression developed more rapidly in Nrg1 HET mice than WT mice. Conversely in the light-dark test, while tolerance to the anxiogenic effect of CP55,940 developed in WT mice over days of testing, Nrg1 hypomorphs maintained marked anxiety even after 15 d of treatment. Repeated cannabinoid exposure selectively increased FosB/ΔFosB expression in the lateral septum, ventral part (LSV) of Nrg1 HET but not WT mice. On day 1 of exposure opposite effects of CP55,940 treatment were observed on PPI, i.e. it was facilitated in Nrg1 hypomorphs and impaired in WT mice, despite the drug significantly impairing the acoustic startle reflex equally in both genotypes. These effects of CP55,940 on PPI were not maintained as both genotypes became tolerant to cannabinoid action with repeated exposure. Our results highlight that Nrg1 modulates the development of cannabinoid tolerance dependent on the parameter being measured. Furthermore, these data reinforce the notion that the VLS is an important brain region involved in Nrg1-cannabinoid interactions.

Effects of tianeptine on spontaneous alternation, simple and concurrent spatial discrimination learning and on alcohol-induced alternation deficits in mice

The effects of systemic administration of tianeptine, a new psychotropic agent with antidepressant properties, were investigated on spontaneous alternation behavior, and on simple and concurrent spatial discrimination, in normal mice of the BALB/c strain. Tianeptine increased rates of spontaneous T-maze alternation, facilitated retention of a T-maze left-right discrimination, and speeded up acquisition of concurrent discrimination in a radial maze. These effects were consistent across successive experiments with a dose of 10 mg/kg; lower doses (2.5 and 5.0 mg/kg) had less or no effect depending on the task. These results, together with theoretical considerations, led us to investigate the effect of tianeptine on the sequential-specific alternation deficit induced by long-term ethanol administration in the same strain of mice. Results showed that, at the dose of 10 mg/kg, the drug completely alleviated the alcohol-induced deficit. Unlike tianeptine, fluoxetine impaired discrimination performance in the radial maze. These data are discussed in light of the effects of tianeptine on serotonergic transmission and of the role of serotonin and acetylcholine in learning and memory processes.

Time-dependent effects of posttraining intrahippocampal injections of corticosterone on retention of appetitive learning tasks in mice

In previous studies we suggested that corticosterone may modulate hippocampal functioning during memory formation. To test this assumption, we studied the effects of posttrial administration of corticosterone (1 microgram) injected bilaterally in the hippocampus. The treatment was applied at different time intervals after the learning session and the retention session took place 24 h later. Using appetitive operant conditioning tasks in a Skinner box, we found that the posttrial treatment 1) did not affect the retention of a continuously reinforced schedule, 2) improved the retention of a successive discrimination learning task, and 3) was still effective when given 3 h after the acquisition of this task, but not after 6 h. Taken together, the results suggest that corticosterone modulates the hippocampal mechanisms involved in behavioral suppression during memory formation.