Aversive Memory Acquisition Research Articles

GADD45B in the ventral hippocampal CA1 modulates aversive memory acquisition and spatial cognition

AimsThis study was designed to investigate the role of growth arrest and DNA damage-inducible β (GADD45B) in modulating fear memory acquisition and elucidate its underlying mechanisms. Main methodsAdeno-associated virus (AAV) that knockdown or overexpression GADD45B were injected into ventral hippocampal CA1 (vCA1) by stereotactic, and verified by fluorescence and Western blot. The contextual fear conditioning paradigm was employed to examine the involvement of GADD45B in modulating aversive memory acquisition. The Y-maze and novel location recognition (NLR) tests were used to examine non-aversive cognition. The synaptic plasticity and electrophysiological properties of neurons were measured by slice patch clamp. Key findingsKnockdown of GADD45B in the vCA1 significantly enhanced fear memory acquisition, accompanied by an upregulation of long-term potentiation (LTP) expression and intrinsic excitability of vCA1 pyramidal neurons (PNs). Conversely, overexpression of GADD45B produced the opposite effects. Notably, silencing the activity of vCA1 neurons abolished the impact of GADD45B knockdown on fear memory development. Moreover, mice with vCA1 GADD45B overexpression exhibited impaired spatial cognition, whereas mice with GADD45B knockdown did not display such impairment. SignificanceThese results provided compelling evidence for the crucial involvement of GADD45B in the formation of aversive memory and spatial cognition.

Dual role of α7 nicotinic acetylcholine receptors in the retrosplenial cortex for aversive memory acquisition and retrieval.

In the retrosplenial cortex (RSC), the role of cholinergic modulation via α7 nicotinic receptors and their involvement in memory is unknown. In recent years, the RSC has been shown to deteriorate in the early stages of Alzheimer's disease (AD). Likewise, the cholinergic system has been postulated as one of those responsible for cognitive impairment in patients with AD. Great interest has arisen in the study of α7 nicotinic receptors as more specific targets for the treatment of this disease. For this reason, we aim to study the role of α7 receptors of the RSC in memory processing. We infused a selective α7 receptor antagonist into the anterior part of the RSC (aRSC) to assess its role in different phases of aversive memory processing using an inhibitory avoidance task. We found that α7 nicotinic receptors are involved in memory acquisition and expression, but not in its consolidation. These results identify aRSC α7 nicotinic receptors as key players in aversive memory processing and highlight their significant potential as therapeutic targets for Alzheimer's disease.

The Effects of Intravermis Cerebellar Microinjections of Dopaminergic Agents in Motor Learning and Aversive Memory Acquisition in Mice.

The cerebellum receives dopaminergic innervation and expresses the five types of described dopaminergic receptors. The cerebellar function involves both motor movement and cognition, but the role of cerebellar dopaminergic system on these processes remain unclear. The present study explores the behavioral responses to intracerebellar microinjection of dopaminergic agents in motor and emotional memory. For this, naïve Swiss mice had their cerebellar vermis implanted with a guide canula, received a intravermis microinjection of Dopamine, D1-like antagonist SCH-23390 or D2-like antagonist Eticlopride, and underwent a behavioral analysis of motor learning (by a Rotarod and balance beam learning protocol) or aversive memory acquisition (by the inhibitory avoidance task). The mixed-effects analysis was used to evaluate groups performance, followed by Tukey’s post hoc when appropriated. In this study, Dopamine, SCH-23390 and Eticlopride at the doses used did not affected motor control and motor learning. In addition, the administration of Dopamine and SCH-233390 had no effects on emotional memory acquisition, but the animals that received the highest dose of Eticlopride had an improvement in aversive memory acquisition, shown by a suppression of its innate preference for the dark compartment of the inhibitory avoidance apparatus following an exposure to a foot shock. We propose that cerebellar dopaminergic D2 receptors seem to participate on the modulation of aversive memory processes, without influencing motor performance at the doses used in this study.

Naloxone-induced conditioned place aversion score and extinction period are higher in C57BL/6J morphine-dependent mice than in Swiss: Role of HPA axis

Intense associative memories develop between drug-paired contextual cues and the drug withdrawal associated aversive feeling. They have been suggested to contribute to the high rate of relapse. Our study was aimed to elucidate the involvement of hypothalamic-pituitary-adrenocortical (HPA) axis activity in the expression and extinction of aversive memory in Swiss and C57BL/6J (B6) mice. The animals were rendered dependent on morphine by i.p. injection of increasing doses of morphine (10–60 mg/kg). The negative state associated with naloxone (1 mg/kg s.c.) precipitated morphine withdrawal was examined by using conditioned place aversion (CPA) paradigm. B6 mice obtained a higher aversion score and took longer to extinguish the aversive memory than Swiss mice. In addition, corticosterone levels were increased after CPA expression. Moreover, corticosterone levels were decreased during CPA extinction in Swiss mice without changes in B6 mice. Pre-treatment with the selective CRF1 receptor antagonist CP-154,526 before naloxone, impaired morphine-withdrawal aversive memory acquisition and decreased the extinction period. CP-154,526 also antagonized the increased levels of corticosterone observed after CPA expression in Swiss mice, without any changes in B6 mice. These results indicate that HPA axis could be a critical factor governing opioid withdrawal memory storage and retrieval, but in a strain or stock-specific manner. The differences observed between Swiss and B6 mice suggest that the treatment of addictive disorders should consider different individual predisposition to associate the aversive learning with the context.

NPY/NPF-Related Neuropeptide FLP-34 Signals from Serotonergic Neurons to Modulate Aversive Olfactory Learning in Caenorhabditis elegans.

Aversive learning is fundamental for animals to increase chances of survival. In addition to classical neurotransmitters, neuropeptides have emerged to modulate such complex behaviors. Among them, neuropeptide Y (NPY) is well known to promote aversive memory acquisition in mammals. Here we identify an NPY/neuropeptide F (NPF)-related neuropeptide system in Caenorhabditis elegans and show that this FLP-34/NPR-11 system is required for learning negative associations, a process that is reminiscent of NPY signaling in mammals. The Caenorhabditis elegans NPY/NPF ortholog FLP-34 displays conserved structural hallmarks of bilaterian-wide NPY/NPF neuropeptides. We show that it is required for aversive olfactory learning after pairing diacetyl with the absence of food, but not for appetitive olfactory learning in response to butanone. To mediate diacetyl learning and thus integrate the aversive food context with the diacetyl odor, FLP-34 is released from serotonergic neurons and signals through its evolutionarily conserved NPY/NPF GPCR, NPR-11, in downstream AIA interneurons. NPR-11 activation in the AIA integration center results in avoidance of a previously attractive stimulus. This study opens perspectives for a deeper understanding of stress conditions in which aversive learning results in excessive avoidance.SIGNIFICANCE STATEMENT Aversive learning evolved early in evolution to promote avoidance of dangerous and stressful situations. In addition to classical neurotransmitters, neuropeptides are emerging as modulators of complex behaviors, including learning and memory. Here, we identified the evolutionary ortholog of neuropeptide Y/neuropeptide F in the nematode Caenorhabditis elegans, and we discovered that it is required for olfactory aversive learning. In addition, we elucidated the neural circuit underlying this avoidance behavior, and we discovered a novel coordinated action of Caenorhabditis elegans neuropeptide Y/neuropeptide F and serotonin that could aid in our understanding of the molecular mechanisms underlying stress disorders in which excessive avoidance results in maladaptive behaviors.

Conditioned aversive memory associated with morphine withdrawal increases brain-derived neurotrophic factor in dentate gyrus and basolateral amygdala.

Morphine has been shown to increase the expression of brain-derived neurotrophic factor (BDNF) in the brain. However, little is known about the effect of conditioned naloxone-precipitated morphine withdrawal on BDNF and its precursor protein, proBDNF. We used the conditioned place aversion (CPA) paradigm to evaluate the role of corticotropin-releasing factor (CRF)/CRF1 receptor signaling on the BDNF expression and corticosterone plasma levels after CPA expression and extinction. Male mice were rendered dependent on morphine and injected acutely with naloxone before paired to confinement in a naloxone-associated compartment. The expression of BDNF and proBDNF in the dentate gyrus (DG) and basolateral amygdala (BLA) was measured in parallel with the corticosterone plasma levels with and without CRF1 receptor blockade. Mice subjected to conditioned naloxone-induced morphine withdrawal showed an increased expression of BDNF (in DG and BLA) in parallel with an enhancement of corticosterone plasma levels. These results demonstrated that BDNF expression together with the increased activity of hypothalamic-pituitary-adrenocortical (HPA) axis are critical to the acquisition of aversive memory. However, we have observed a decrease in corticosterone plasma levels and BDNF expression after CPA extinction reaffirming the importance of BDNF in the maintenance of aversive memory. In addition, the pre-treatment with the CRF1 receptor antagonist CP-154526 before naloxone conditioning session impaired morphine withdrawal-induced aversive memory acquisition, the increased corticosterone plasma levels, and the expression of BDNF observed after CPA expression in the DG and BLA. Altogether, present results are suggesting a clear connection between HPA axis and BDNF in the formation and extinction of aversive memory.

Tetrahydrobiopterin improves hippocampal nitric oxide-linked long-term memory

Tetrahydrobiopterin (BH4) is synthesized by the combined action of three metabolic pathways, namely de novo synthesis, recycling, and salvage pathways. The best-known function of BH4 is its mandatory action as a natural cofactor of the aromatic amino acid hydroxylases and nitric oxide synthases. Thus, BH4 is essential for the synthesis of nitric oxide, a retrograde neurotransmitter involved in learning and memory. We investigated the effect of BH4 (4–4000 pmol) intracerebroventricular administration on aversive memory, and on BH4 metabolism in the hippocampus of rodents. Memory-related behaviors were assessed in Swiss and C57BL/6 J mice, and in Wistar rats. It was consistently observed across all rodent species that BH4 facilitates aversive memory acquisition and consolidation by increasing the latency to step-down in the inhibitory avoidance task. This effect was associated with a reduced threshold to generate hippocampal long-term potentiation process. In addition, two inhibitors of memory formation (N(ω)-nitro-L-arginine methyl ester - L-Name – and dizocilpine - MK-801 -) blocked the enhanced effect of BH4 on memory, while the amnesic effect was not rescue by the co-administration of BH4 or a cGMP analog (8-Br-cGMP). The data strongly suggest that BH4 enhances aversive memory by activating the glutamatergic neurotransmission and the retrograde activity of NO. It was also demonstrated that BH2 can be converted into BH4 by activating the BH4 salvage pathway under physiological conditions in the hippocampus. This is the first evidence showing that BH4 enhances aversive memory and that the BH4 salvage pathway is active in the hippocampus.

Enhanced extinction of aversive memories in mice lacking SPARC-related protein containing immunoglobulin domains 1 (SPIG1/FSTL4).

Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity related to learning and memory. We previously reported that SPARC-related protein containing immunoglobulin domains 1 (SPIG1, also known as Follistatin-like protein 4, FSTL4) binds to pro-BDNF and negatively regulates BDNF maturation; however, its neurological functions, particularly in learning and memory, have not yet been elucidated. We herein examined the electrophysiological and behavioral phenotypes of Spig1-knockout (Spig1-KO) mice. Adult Spig1-KO mice exhibited greater excitability and facilitated long-term potentiation (LTP) in the CA1 region of hippocampal slices than age- and sex-matched wild-type (WT) mice. Facilitated LTP was reduced to the level of WT by the bath application of an anti-BDNF antibody to hippocampal slices. A step-through inhibitory avoidance learning paradigm revealed that the extinction of aversive memories was significantly enhanced in adult Spig1-KO mice, while they showed the normal acquisition of aversive memories; besides, spatial reference memory formation was also normal in the standard Morris water maze task. An intracerebroventricular (icv) injection of anti-BDNF in the process of extinction learning transiently induced the recurrence of aversive memories in Spig1-KO mice, but exerted no effects in WT mice. These results indicate a critical role for SPIG1 in BDNF-mediated synaptic plasticity in extinction of inhibitory avoidance memory.

The involvement of CRF1 receptor within the basolateral amygdala and dentate gyrus in the naloxone-induced conditioned place aversion in morphine-dependent mice

Drug withdrawal-associated aversive memories trigger relapse to drug-seeking behavior. Corticotrophin-releasing factor (CRF) is an important mediator of the reinforcing properties of drugs of abuse. However, the involvement of CRF1 receptor (CRF1R) in aversive memory induced by opiate withdrawal has yet to be elucidated. We used the conditioned-place aversion (CPA) paradigm to evaluate the role of CRF1R on opiate withdrawal memory acquisition, along with plasticity-related processes that occur after CPA within the basolateral amygdala (BLA) and dentate gyrus (DG). Male mice were rendered dependent on morphine and injected acutely with naloxone before paired to confinement in a naloxone-associated compartment. The CPA scores as well as the number of TH-positive neurons (in the NTS-A2 noradrenergic cell group), and the expression of the transcription factors Arc and pCREB (in the BLA and DG) were measured with and without CRF1R blockade.Mice subjected to conditioned naloxone-induced morphine withdrawal robustly expressed CPA. Pre-treatment with the selective CRF1R antagonist CP-154,526 before naloxone conditioning session impaired morphine withdrawal-induced aversive memory acquisition. CP-154,526 also antagonized the enhanced number of TH-positive neurons in the NTS-A2 that was seen after CPA. Increased Arc expression and Arc-pCREB co-localization were seen in the BLA after CPA, which was not modified by CP-154,526. In the DG, CPA was accompanied by a decrease of Arc expression and no changes in Arc-pCREB co-localization, whereas pre-treatment with CP-154,526 induced an increase in both parameters. These results indicate that CRF-CRF1R pathway could be a critical factor governing opiate withdrawal memory storage and retrieval and might suggest a role for TH-NA pathway in the effects of withdrawal on memory. Our results might indicate that the blockade of CRF1R could represent a promising pharmacological treatment strategy approach for the attenuation of the relapse to drug-seeking/taking behavior triggered by opiate withdrawal-associated aversive memories.

Impact of social separation during pregnancy on the manifestation of defensive behaviors related to generalized anxiety and panic throughout offspring development.

The multiple insecurities, anatomical, physiological and psychological changes arising from the gestational period can generate an overload of stress in the mother and cause disturbances in the offspring, affecting it throughout its development. The existing analysis linking prenatal stress and offspring’s anxiety have divergent results, being limited as to gestational week, type of stressor and age of progeny’s assessment. Social separation has been described as a stressor that causes increase in anxiety. Thus, the present study evaluated the effects of social separation applied in one of the three gestational weeks of rat dams on the manifestation of the defensive behaviors related to generalized anxiety disorder and panic in the Elevated T Maze of the male progeny in three stages of development (1, 3 or 6 months of life). It was found, in the offspring of grouped (control) dams, increased behaviors associated with generalized anxiety disorder and a reduction of panic-like behaviors throughout development. For animals whose dams were socially separated during pregnancy, the most critical period of exposure was the 2nd gestational week, which affected the acquisition of aversive memory, demonstrated by the impairment on learning of avoidances of the offspring in all ages evaluated. Stressor exposure in this week also increased the avoidances, related to generalized anxiety of progeny in the 1st month and decreased escapes, related to panic in the 3rd month of life and, at the age of 6 months old, an inverse situation, with the reduction of the defensive behaviors associated to generalized anxiety disorder. The results show that, when assessing effects of prenatal stress on the manifestation of anxiety, not only the period of exposure is important, but also the age of offspring assessed.

Suppression of a single pair of mushroom body output neurons in Drosophila triggers aversive associations.

Memory includes the processes of acquisition, consolidation and retrieval. In the study of aversive olfactory memory in Drosophila melanogaster, flies are first exposed to an odor (conditioned stimulus, CS+) that is associated with an electric shock (unconditioned stimulus, US), then to another odor (CS−) without the US, before allowing the flies to choose to avoid one of the two odors. The center for memory formation is the mushroom body which consists of Kenyon cells (KCs), dopaminergic neurons (DANs) and mushroom body output neurons (MBONs). However, the roles of individual neurons are not fully understood. We focused on the role of a single pair of GABAergic neurons (MBON‐γ1pedc) and found that it could inhibit the effects of DANs, resulting in the suppression of aversive memory acquisition during the CS− odor presentation, but not during the CS+ odor presentation. We propose that MBON‐γ1pedc suppresses the DAN‐dependent effect that can convey the aversive US during the CS− odor presentation, and thereby prevents an insignificant stimulus from becoming an aversive US.

D1-like dopamine receptor dysfunction in the lateral habenula nucleus increased anxiety-like behavior in rat

Lateral habenula (LHb) is important for emotional processing. It is a link node between forebrain and midbrain. LHb is reciprocally connected with ventral tegmental area, acting as a regulatory center for the dopaminergic system. However, the role of dopamine receptors in the LHb in emotional processing is less clear. In the present study, the expression of dopamine D1 and D2 receptors in LHb was testified by western blot. In addition, D1- or D2-like receptor agonist or antagonist was bilaterally administered into the LHb, anxiety-like and depressive-like behaviors were tested 15min later in rats. In addition, the effects of LHb dopamine receptor activation and inactivation on aversive learning and memory were assessed. Our results showed that: (1) activation and inhibition of D1R but not D2R in LHb increased anxiety-like behavior but decreased depressive-like behavior in rats. (2) D1R activation and inactivation in LHb impaired aversive memory acquisition but not consolidation in rats, D1R agonist also impaired aversive memory retrieval in rats. These results might provide new clues about how LHb was involved in emotional processing.

Neopterin acts as an endogenous cognitive enhancer

Neopterin is found at increased levels in biological fluids from individuals with inflammatory disorders. The biological role of this pteridine remains undefined; however, due to its capacity to increase hemeoxygenase-1 content, it has been proposed as a protective agent during cellular stress. Therefore, we investigated the effects of neopterin on motor, emotional and memory functions. To address this question, neopterin (0.4 and/or 4pmol) was injected intracerebroventricularly before or after the training sessions of step-down inhibitory avoidance and fear conditioning tasks, respectively. Memory-related behaviors were assessed in Swiss and C57BL/6 mice, as well as in Wistar rats. Moreover, the putative effects of neopterin on motor and anxiety-related parameters were addressed in the open field and elevated plus-maze tasks. The effects of neopterin on cognitive performance were also investigated after intraperitoneal lipopolysaccharide (LPS) administration (0.33mg/kg) in interleukin-10 knockout mice (IL-10−/−). It was consistently observed across rodent species that neopterin facilitated aversive memory acquisition by increasing the latency to step-down in the inhibitory avoidance task. This effect was related to a reduced threshold to generate the hippocampal long-term potentiation (LTP) process, and reduced IL-6 brain levels after the LPS challenge. However, neopterin administration after acquisition did not alter the consolidation of fear memories, neither motor nor anxiety-related parameters. Altogether, neopterin facilitated cognitive processes, probably by inducing an antioxidant/anti-inflammatory state, and by facilitating LTP generation. To our knowledge, this is the first evidence showing the cognitive enhancer property of neopterin.

Mauritia flexuosa L. protects against deficits in memory acquisition and oxidative stress in rat hippocampus induced by methylmercury exposure

Objective: Methylmercury (MeHg) is the most toxic form of mercury that can affect humans through the food chain by bioaccumulation. Human organism is capable of triggering visual and cognitive disorders, neurodegeneration, as well as increased production of reactive species of O2 and depletion of natural anti-oxidant agents. In this context, Mauritia flexuosa L., a fruit rich in compounds with anti-oxidant properties, emerged as an important strategy to prevent the MeHg damages. So, this work has aimed to elucidate the protective effect of Mauritia flexuosa L. on the damage caused by the exposure of rats to MeHg.Methods: In order to evaluate the effect of MeHg on rat aversive memory acquisition and panic-like behavior, we have used elevated T-maze apparatus and after behavioral test, the hippocampus was removed to perfom lipid peroxidation.Results: Our results demonstrated that the exposure to MeHg caused deficits in inhibitory avoidance acquisition (aversive conditioning) and in the learning process, and increased levels of lipid peroxidation in hippocampus tissue. However, the pretreatment with feed enriched with Mauritia flexuosa L. showed a protective effect against cognitive deficits caused by MeHg and also prevented the occurrence of cytoplasmic membrane damage induced by lipid peroxidation in the hippocampal region.Discussion: Therefore, this study suggests that Mauritia flexuosa L. represents an important strategy to prevent neurocytotoxics and behavioral effects of MeHg.

Early Developmental Low-Dose Methylmercury Exposure Alters Learning and Memory in Periadolescent but Not Young Adult Rats.

Few studies have assessed the effects of developmental methylmercury (MeHg) exposure on learning and memory at different ages. The possibility of the amelioration or worsening of the effects has not been sufficiently investigated. This study aimed to assess whether low-dose MeHg exposure in utero and during suckling induces differential disturbances in learning and memory of periadolescent and young adult rats. Four experimental groups of pregnant Sprague-Dawley rats were orally exposed to MeHg or vehicle from gestational day 5 to weaning: (1) control (vehicle), (2) 250 μg/kg/day MeHg, (3) 500 μg/kg/day MeHg, and (4) vehicle, and treated on the test day with MK-801 (0.15 mg/kg i.p.), an antagonist of the N-methyl D-aspartate receptor. The effects were evaluated in male offspring through the open field test, object recognition test, Morris water maze, and conditioned taste aversion. For each test and stage assessed, different groups of animals were used. MeHg exposure, in a dose-dependent manner, disrupted exploratory behaviour, recognition memory, spatial learning, and acquisition of aversive memories in periadolescent rats, but alterations were not observed in littermates tested in young adulthood. These results suggest that developmental low-dose exposure to MeHg induces age-dependent detrimental effects. The relevance of decreasing exposure to MeHg in humans remains to be determined.

Infralimbic cortex controls the activity of the hypothalamus–pituitary–adrenal axis and the formation of aversive memory: Effects of environmental enrichment

The aim of the present study was to investigate the effects of the stimulation and inhibition of the ventral part of the medial prefrontal cortex (infralimbic cortex) on basal and stress-induced plasma levels of corticosterone and on the acquisition of aversive memory in animals maintained in control and environmental enrichment (EE) conditions. Intracortical microinjections of the GABAA antagonist picrotoxin and agonist muscimol were performed in male Wistar rats to stimulate and inhibit, respectively, the activity of the infralimbic cortex. Injections were performed 60min before foot shock stress and training in the inhibitory avoidance task. Picrotoxin injections into the infralimbic cortex increased basal plasma levels of corticosterone. These increases were higher in EE rats which suggest that EE enhances the control exerted by infralimbic cortex over the hypothalamus–pituitary–adrenal (HPA) axis and corticosterone release. Muscimol injections into the infralimbic cortex reduced the stress-induced plasma levels of corticosterone and the retention latency 24h after training in the inhibitory avoidance performance in control and EE animals, respectively. These results further suggest that the infralimbic cortex is required for the activation of the HPA axis during stress and for the acquisition of contextual aversive memories.

Roles of octopamine and dopamine in appetitive and aversive memory acquisition studied in olfactory conditioning of maxillary palpi extension response in crickets.

Elucidation of reinforcing mechanisms for associative learning is an important subject in neuroscience. Based on results of our previous pharmacological studies in crickets, we suggested that octopamine and dopamine mediate reward and punishment signals, respectively, in associative learning. In fruit-flies, however, it was concluded that dopamine mediates both appetitive and aversive reinforcement, which differs from our suggestion in crickets. In our previous studies, the effect of conditioning was tested at 30 min after training or later, due to limitations of our experimental procedures, and thus the possibility that octopamine and dopamine were not needed for initial acquisition of learning was not ruled out. In this study we first established a conditioning procedure to enable us to evaluate acquisition performance in crickets. Crickets extended their maxillary palpi and vigorously swung them when they perceived some odors, and we found that crickets that received pairing of an odor with water reward or sodium chloride punishment exhibited an increase or decrease in percentages of maxillary palpi extension responses to the odor. Using this procedure, we found that octopamine and dopamine receptor antagonists impair acquisition of appetitive and aversive learning, respectively. This finding suggests that neurotransmitters mediating appetitive reinforcement differ in crickets and fruit-flies.

Hypofunction of prefrontal cortex NMDA receptors does not change stress-induced release of dopamine and noradrenaline in amygdala but disrupts aversive memory

A dysfunction of prefrontal cortex has been associated with the exacerbated response to stress observed in schizophrenic patients and high-risk individuals to develop psychosis. The hypofunction of NMDA glutamatergic receptors induced by NMDA antagonists produces cortico-limbic hyperactivity, and this is used as an experimental model to resemble behavioural abnormalities observed in schizophrenia. The aim of the present study was to investigate whether injections of NMDA antagonists into the medial prefrontal cortex of the rat change (1) the increases of dopamine, noradrenaline and corticosterone concentrations produced by acute stress in amygdala, and (2) the acquisition of aversive memory related to a stressful event. Male Wistar rats were implanted with guide cannulae to perform microdialysis and bilateral microinjections (0.5 μl/side) of the NMDA antagonist 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phophonic acid (CPP) (25 and 100 ng). Prefrontal injections were performed 60 min before restraint stress in microdialysis experiments, or training (footshock; 0.6 mA, 2 s) in inhibitory avoidance test. Retention latency was evaluated 24 h after training as an index of aversive memory. Acute stress increased amygdala dialysate concentrations of dopamine (160% of baseline), noradrenaline (145% of baseline) and corticosterone (170% of baseline). Prefrontal injections of CPP did not change the increases of dopamine, noradrenaline or corticosterone produced by stress. In contrast, CPP significantly reduced the retention latency in the inhibitory avoidance test. These results suggest that the hypofunction of prefrontal NMDA receptors does not change the sensitivity to acute stress of dopamine and noradrenaline projections to amygdala but impairs the acquisition of aversive memory.

Involvement of D₁/D₂ dopamine antagonists upon open-arms exploratory behaviours induced by intra-nucleus accumbens shell administration of N-methyl-D-aspartate.

Glutamatergic system stimulation in some parts of the brain may affect anxiety-related behaviours, aversive learning and memory. This system retains many interactions with dopaminergic neurotransmission. We have studied the effect of nucleus accumbens (NAc) shell glutamatergic system activation on anxiety-related behaviours as well as aversive learning and memory in adult male Wistar rats using the N-methyl-D-aspartate (NMDA) receptor agonist, NMDA. Furthermore, the possible involvement of the NAc shell dopamine D1 and D2 receptors upon NMDA-induced effects was evaluated. The elevated plus-maze task was used to assess the drugs' concomitant effects on anxiety, learning and memory in rats. All drugs were delivered into the NAc shell via bilaterally implanted indwelling cannulae. The NMDA-induced anxiolytic-like behaviours upon retest could possibly be attributed to the further avoidance acquisition impairments. Moreover, the inhibition of dopaminergic system using SCH 23390 and sulpiride induced an anxiolytic-like response and impaired the aversive memory acquisition during retest. However, the concurrent intra-NAc shell microinjection of the subthreshold dose of SCH 23390 and sulpiride (0.125 µg/rat) reversed the anxiolytic-like effect and blocked the aversive memory impairment induced by intra-NAc shell NMDA. Our results suggest a modulatory role of the NAc shell dopaminergic system on NMDA-induced effects in the aversive memory.

S21-2. Influence of sleep deprivation on suppressed aversive event memory

Aversive memory consolidation is implicated in the pathology of PTSD. Sleep is crucial for memory consolidation, thus sleep deprivation immediately following an aversive event reduces fear by eliminating a sleep dependent memory consolidation process. Although acute insomnia could prevent development of PTSD, it is considered as a plausible risk factor for PTSD. We examined the effects of sleep deprivation and memory suppression on the subsequent enhancement of aversive event and fear memories in healthy humans. Subjects were exposed to aversive and nonaversive events, then their contextual recognition performances were tested later the same day and again after 2 days. Half of the subjects were instructed to quickly forget the events and the other half to remember. Moreover, half of the subjects were totally deprived of initial nocturnal sleep while the other half slept normally. Suppression of aversive memory acquisition not only immediately reduced the stress reaction to aversive events, but also impaired retention of event memory. However, it enhanced recognized fear and even enhanced fear when post-event sleep was deprived. Memory suppression, which provides a psychological model of memory repression, enhances fear and ruins the potential of acute insomnia. Our findings provide a hint as to clinical PTSD pathophysiology.