RESUMO
Noradrenergic activation of the basolateral amygdala (BLA) by emotional arousal enhances different forms of recognition memory via functional interactions with the insular cortex (IC). Human neuroimaging studies have revealed that the anterior IC (aIC), as part of the salience network, is dynamically regulated during arousing situations. Emotional stimulation first rapidly increases aIC activity but suppresses it in a delayed fashion. Here, we investigated in male Sprague-Dawley rats whether the BLA influence on recognition memory is associated with an increase or suppression of aIC activity during the postlearning consolidation period. We first employed anterograde and retrograde viral tracing and found that the BLA sends dense monosynaptic projections to the aIC. Memory-enhancing norepinephrine administration into the BLA following an object training experience suppressed aIC activity 1 h later, as determined by a reduced expression of the phosphorylated form of the transcription factor cAMP response element-binding (pCREB) protein and neuronal activity marker c-Fos. In contrast, the number of perisomatic γ-aminobutyric acid (GABA)ergic inhibitory synapses per pCREB-positive neuron was significantly increased, suggesting a dynamic up-regulation of GABAergic tone. In support of this possibility, pharmacological inhibition of aIC activity with a GABAergic agonist during consolidation enhanced object recognition memory. Norepinephrine administration into the BLA did not affect neuronal activity within the posterior IC, which receives sparse innervation from the BLA. The evidence that noradrenergic activation of the BLA enhances the consolidation of object recognition memory via a mechanism involving a suppression of aIC activity provides insight into the broader brain network dynamics underlying emotional regulation of memory.
Assuntos
Complexo Nuclear Basolateral da Amígdala , Emoções , Córtex Insular , Inibição Neural , Reconhecimento Psicológico , Percepção Visual , Animais , Nível de Alerta , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Emoções/efeitos dos fármacos , Emoções/fisiologia , Agonistas GABAérgicos/farmacologia , Córtex Insular/efeitos dos fármacos , Córtex Insular/fisiologia , Masculino , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Norepinefrina/administração & dosagem , Norepinefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Percepção Visual/fisiologiaRESUMO
The two-hit stress model predicts that exposure to stress at two different time-points in life may increase or decrease the risk of developing stress-related disorders later in life. Most studies based on the two-hit stress model have investigated early postnatal stress as the first hit with adult stress as the second hit. Adolescence, however, represents another highly sensitive developmental window during which exposure to stressful events may affect programming outcomes following exposure to stress in adulthood. Here, we discuss the programming effects of different types of stressors (social and nonsocial) occurring during adolescence (first hit) and how such stressors affect the responsiveness toward an additional stressor occurring during adulthood (second hit) in rodents. We then provide a comprehensive overview of the potential mechanisms underlying interindividual and sex differences in the resilience/susceptibility to developing stress-related disorders later in life when stress is experienced in two different life stages.
Assuntos
Estresse Psicológico , Animais , Feminino , Masculino , Estresse Psicológico/complicações , Roedores , Fatores SexuaisRESUMO
Glucocorticoids enhance memory consolidation of emotionally arousing events via largely unknown molecular mechanisms. This glucocorticoid effect on the consolidation process also requires central noradrenergic neurotransmission. The intracellular pathways of these two stress mediators converge on two transcription factors: the glucocorticoid receptor (GR) and phosphorylated cAMP response element-binding protein (pCREB). We therefore investigated, in male rats, whether glucocorticoid effects on memory are associated with genomic interactions between the GR and pCREB in the hippocampus. In a two-by-two design, object exploration training or no training was combined with post-training administration of a memory-enhancing dose of corticosterone or vehicle. Genomic effects were studied by chromatin immunoprecipitation followed by sequencing (ChIP-seq) of GR and pCREB 45 min after training and transcriptome analysis after 3 hr. Corticosterone administration induced differential GR DNA-binding and regulation of target genes within the hippocampus, largely independent of training. Training alone did not result in long-term memory nor did it affect GR or pCREB DNA-binding and gene expression. No strong evidence was found for an interaction between GR and pCREB. Combination of the GR DNA-binding and transcriptome data identified a set of novel, likely direct, GR target genes that are candidate mediators of corticosterone effects on memory consolidation. Cell-specific expression of the identified target genes using single-cell expression data suggests that the effects of corticosterone reflect in part non-neuronal cells. Together, our data identified new GR targets associated with memory consolidation that reflect effects in both neuronal and non-neuronal cells.
Assuntos
Glucocorticoides , Consolidação da Memória , Animais , Corticosterona/metabolismo , Corticosterona/farmacologia , DNA/metabolismo , Glucocorticoides/metabolismo , Glucocorticoides/farmacologia , Hipocampo/metabolismo , Masculino , Ratos , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismoRESUMO
Background and objective: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder for which no treatments exist. Fragile X syndrome (FXS) is the most common form of inherited mental retardation and the most frequent monogenic cause of ASD. Given the lack of pharmacological treatments for ASD, increasing interest is devoted to non-pharmacological approaches, including dietary interventions. Omega-3 polyunsaturated fatty acids (PUFAs) are critical for neurobehavioraldevelopment. This study had two aims: 1. To validatethe recently developed Fmr1-Δexon 8 rat model of FXS; 2. To assess the impact of omega-3 PUFAs dietary supplementation during pregnancy and lactation on the altered behavior displayed by Fmr1-Δexon 8 rats.Methods: Female Fmr1-Δexon 8 and wild-type Sprague-Dawley rats were fed with either an omega-3 PUFAs enriched diet or with an isocaloric control diet during pregnancy and lactation. Behavioral experiments were carried out on the infant (Postnatal days (PNDs) 9 and 13), juvenile (PND 35) and adult (PND 90) male offspring.Results: Fmr1-Δexon 8 pups showed hypolocomotion, reduced ultrasonic vocalizations (USVs) emission and impaired social discrimination compared to wild-type controls. Juvenile and adult Fmr1-Δexon 8 rats showed deficits in the social and cognitive domains, that were counteracted by perinatal omega-3 PUFAs supplementation.Conclusion: Our results support the validity of the Fmr1-Δexon 8 rat model to mimic key autistic-like features and support an important role of omega-3 PUFAs during of neurodevelopment. Although the mechanisms underlying the beneficial effects of omega-3 PUFAs supplementation in ASD needs to be clarified, this dietary intervention holds promise to mitigate core and comorbid autistic features.
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Ácidos Graxos Ômega-3 , Síndrome do Cromossomo X Frágil , Animais , Transtorno do Espectro Autista/prevenção & controle , Transtorno Autístico/prevenção & controle , Cognição , Suplementos Nutricionais , Feminino , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Humanos , Masculino , Modelos Genéticos , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
Creative ideas are thought to result from flexible recombination of concepts from memory. A growing number of behavioural and neuroscientific studies provide evidence of a link between episodic memory and divergent thinking; however, little is known about the potential contributions of autobiographical memory to creative ideation. To provide a novel perspective on this issue, we assessed measures of divergent and convergent creative thinking in a cohort (n = 14) of rare individuals showing Highly Superior Autobiographical Memory (HSAM). The HSAM cohort completed memory tasks in addition to a battery of creativity measures, including the Alternative Uses Task, Consequences Task and Remote Associates Task. We performed statistical analyses to establish whether there were any significant differences between HSAM and controls (n = 28) across these measures. Although HSAM participants were superior in the recall of autobiographical events compared to controls, we observed no overall difference between the groups in relation to the creativity measures. These findings suggest that the constructive episodic processes relevant to creative thinking are not enhanced in individuals with HSAM, perhaps because they are compulsively and narrowly focused on consolidation and retrieval of autobiographical events.
Assuntos
Memória Episódica , Criatividade , Humanos , Rememoração Mental , Projetos de PesquisaRESUMO
Social rewards are fundamental to survival and overall health. Several studies suggest that adequate social stimuli during early life are critical for developing appropriate socioemotional and cognitive skills, whereas adverse social experiences negatively affect the proper development of brain and behavior, by increasing the susceptibility to develop neuropsychiatric conditions. Therefore, a better understanding of the neural mechanisms underlying social interactions, and their rewarding components in particular, is an important challenge of current neuroscience research. In this context, preclinical research has a crucial role: Animal models allow to investigate the neurobiological aspects of social reward in order to shed light on possible neurochemical alterations causing aberrant social reward processing in neuropsychiatric diseases, and they allow to test the validity and safety of innovative therapeutic strategies. Here, we discuss preclinical research that has investigated the rewarding properties of two forms of social interaction that occur in different phases of the lifespan of mammals, that is, mother-infant interaction and social interactions with peers, by focusing on the main neurotransmitter systems mediating their rewarding components. Together, the research performed so far helped to elucidate the mechanisms of social reward and its psychobiological components throughout development, thus increasing our understanding of the neurobiological substrates sustaining social functioning in health conditions and social dysfunction in major psychiatric disorders.
Assuntos
Neuroquímica , Recompensa , Roedores/psicologia , Comportamento Social , Envelhecimento/psicologia , Animais , Humanos , Camundongos , Ratos , Interação SocialRESUMO
Trauma patients treated with ketamine during emergency care present aggravated early post- traumatic stress reaction which is highly predictive of post-traumatic stress disorder (PTSD) development and severity. The use of ketamine in the acute trauma phase may directly or indirectly interfere with neural processes of memory consolidation of the traumatic event, thus leading to the formation of maladaptive memories, a hallmark symptom of PTSD. We have recently shown that ketamine anesthesia, immediately after a traumatic event, enhances memory consolidation and leads to long-lasting alterations of social behavior in rats. Based on the evidence that ketamine induces a robust central and peripheral adrenergic/noradrenergic potentiation and that activation of this system is essential for the formation of memory for stressful events, we explored the possibility that the strong sympathomimetic action of ketamine might underlie its memory enhancing effects. We found that rats given immediate, but not delayed, post-training ketamine anesthesia (125 mg/kg) presented enhanced 48-h memory retention in an inhibitory avoidance task and that these effects were blocked by adrenal medullectomy, lesions of the locus coeruleus, systemic or intra-basolateral amygdala ß-adrenergic receptor antagonism. Thus, the memory enhancing effects of ketamine anesthesia are time-dependent and mediated by a combined peripheral-central sympathomimetic action. We elucidated a mechanism by which ketamine exacerbates acute post-traumatic reaction, possibly leading to development of PTSD symptomatology later in life. These findings will help guide for a better management of sedation/anesthesia in emergency care to promote the prophylaxis and reduce the risk of developing trauma-related disorders in trauma victims.
Assuntos
Neurônios Adrenérgicos/efeitos dos fármacos , Anestésicos Dissociativos/administração & dosagem , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Medo/efeitos dos fármacos , Ketamina/administração & dosagem , Consolidação da Memória/efeitos dos fármacos , Neurônios Adrenérgicos/metabolismo , Animais , Nível de Alerta/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/metabolismo , Ratos , Transtornos de Estresse Pós-Traumáticos/metabolismoRESUMO
Brain systems underlying human memory function have been classically investigated studying patients with selective memory impairments. The discovery of rare individuals who have highly superior autobiographical memory (HSAM) provides, instead, an opportunity to investigate the brain systems underlying enhanced memory. Here, we carried out an fMRI investigation of a group of subjects identified as having HSAM. During fMRI scanning, eight subjects with HSAM and 21 control subjects were asked to retrieve autobiographical memories (AMs) as well as non-AMs (e.g., examples of animals). Subjects were instructed to signal the "access" to an AM by a key press and to continue "reliving" it immediately after. Compared with controls, individuals with HSAM provided a richer AM recollection and were faster in accessing AMs. The access to AMs was associated with enhanced prefrontal/hippocampal functional connectivity. AM access also induced increased activity in the left temporoparietal junction and enhanced functional coupling with sensory cortices in subjects with HSAM compared with controls. In contrast, subjects with HSAM did not differ from controls in functional activity during the reliving phase. These findings, based on fMRI assessment, provide evidence of interaction of brain systems engaged in memory retrieval and suggest that enhanced activity of these systems is selectively involved in enabling more efficient access to past experiences in HSAM.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Conectoma , Imageamento por Ressonância Magnética , Memória/fisiologia , Adulto , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Cannabinoids induce biphasic effects on memory depending on stress levels. We previously demonstrated that different stress intensities, experienced soon after encoding, impaired rat short-term recognition memory in a time-of-day-dependent manner, and that boosting endocannabinoid anandamide (AEA) levels restored memory performance. Here, we examined if two different stress intensities and time-of-day alter hippocampal endocannabinoid tone, and whether these changes modulate short-term memory. METHODS: Male Sprague-Dawley rats were subjected to an object recognition task and exposed, at two different times of the day (i.e., morning or afternoon), to low or high stress conditions, immediately after encoding. Memory retention was assessed 1 hr later. Hippocampal AEA and 2-arachidonoyl glycerol (2-AG) content and the activity of their primary degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), were measured soon after testing. RESULTS: Consistent with our previous findings, low stress impaired 1-hr memory performance only in the morning, whereas exposure to high stress impaired memory independently of testing time. Stress exposure decreased AEA levels independently of memory alterations. Interestingly, exposure to high stress decreased 2-AG content and, accordingly, increased MAGL activity, selectively in the afternoon. Thus, to further evaluate 2-AG's role in the modulation of short-term recognition memory, rats were given bilateral intra-hippocampal injections of the 2-AG hydrolysis inhibitor KML29 immediately after training, then subjected to low or high stress conditions and tested 1 hr later. CONCLUSIONS: KML29 abolished the time-of-day-dependent impairing effects of stress on short-term memory, ameliorating short-term recognition memory performance.
Assuntos
Ácidos Araquidônicos/metabolismo , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Hipocampo/metabolismo , Memória de Curto Prazo/fisiologia , Amidoidrolases/genética , Animais , Ácidos Araquidônicos/antagonistas & inibidores , Ácidos Araquidônicos/genética , Benzodioxóis/farmacologia , Emoções/fisiologia , Endocanabinoides/antagonistas & inibidores , Endocanabinoides/genética , Glicerídeos/antagonistas & inibidores , Glicerídeos/genética , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Humanos , Masculino , Monoacilglicerol Lipases/genética , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/genéticaRESUMO
BACKGROUND: At the earliest stage of Alzheimer's disease (AD), although patients are still asymptomatic, cerebral alterations have already been triggered. In addition to beta amyloid (Aß) accumulation, both glial alterations and neuroinflammation have been documented at this stage. Starting treatment at this prodromal AD stage could be a valuable therapeutic strategy. AD requires long-term care; therefore, only compounds with a high safety profile can be used, such as the new formulation containing palmitoylethanolamide and luteolin (co-ultra PEALut) already approved for human use. Therefore, we investigated it in an in vivo pharmacological study that focused on the prodromal stage of AD. METHODS: We tested the anti-inflammatory and neuroprotective effects of co-ultra PEALut (5 mg/Kg) administered for 14 days in rats that received once, 5 µg Aß(1-42) into the hippocampus. RESULTS: Glial activation and elevated levels of proinflammatory mediators were observed in Aß-infused rats. Early administration of co-ultra PEALut prevented the Aß-induced astrogliosis and microgliosis, the upregulation in gene expression of pro-inflammatory cytokines and enzymes, as well as the reduction of mRNA levels BDNF and GDNF. Our findings also highlight an important neuroprotective effect of co-ultra PEALut treatment, which promoted neuronal survival. CONCLUSIONS: Our results reveal the presence of cellular and molecular modifications in the prodromal stage of AD. Moreover, the data presented here demonstrate the ability of co-ultra PEALut to normalize such Aß-induced alterations, suggesting it as a valuable therapeutic strategy.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Etanolaminas/uso terapêutico , Gliose/tratamento farmacológico , Luteolina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Alzheimer/patologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citocinas/genética , Citocinas/metabolismo , Combinação de Medicamentos , Etanolaminas/administração & dosagem , Etanolaminas/farmacologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Gliose/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Luteolina/administração & dosagem , Luteolina/farmacologia , Masculino , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Sintomas Prodrômicos , Ratos , Ratos Sprague-DawleyRESUMO
Imbalanced dietary n-3 and n-6 PUFA content has been associated with a number of neurological conditions. Endocannabinoids are n-6 PUFA derivatives, whose brain concentrations are sensitive to modifications of fatty acid composition of the diet and play a central role in the regulation of mood and cognition. As such, the endocannabinoid system appears to be an ideal candidate for mediating the effects of dietary fatty acids on mood and cognition. Lifelong administration of isocaloric α-linolenic acid (ALA)-deficient and -enriched diets induced short-term memory deficits, whereas only dietary ALA enrichment altered emotional reactivity in adult male rats compared with animals fed a standard diet that was balanced in ALA/linoleic acid (LA) ratio. In the prefrontal cortex, both diets reduced 2-AG levels and increased MAG lipase expression, whereas only the enriched diet reduced AEA levels, simultaneously increasing FAAH expression. In the hippocampus, an ALA-enriched diet decreased AEA content and NAPE-PLD expression, and reduced 2-AG content while increasing MAG lipase expression. These findings highlight the importance of a diet balanced in fatty acid content for normal brain functions and to support a link between dietary ALA, the brain endocannabinoid system, and behavior, which indicates that dietary ALA intake is a sufficient condition for altering the endocannabinoid system in brain regions modulating mood and cognition.
Assuntos
Encéfalo/metabolismo , Cognição/fisiologia , Emoções/fisiologia , Endocanabinoides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Cognição/efeitos dos fármacos , Dieta , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/metabolismo , Emoções/efeitos dos fármacos , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/administração & dosagem , Ácidos Graxos Ômega-6/metabolismo , Humanos , Ácido Linoleico/administração & dosagem , Ácido Linoleico/metabolismo , Memória de Curto Prazo/efeitos dos fármacos , Memória de Curto Prazo/fisiologia , Ratos , Ácido alfa-Linolênico/administração & dosagem , Ácido alfa-Linolênico/metabolismoRESUMO
This study describes the potential of solid lipid nanoparticles and nanostructured lipid carriers as nano-formulations to administer to the central nervous system poorly water soluble drugs. Different neuroactive drugs, i.e. dimethylfumarate, retinyl palmitate, progesterone and the endocannabinoid hydrolysis inhibitor URB597 have been studied. Lipid nanoparticles constituted of tristearin or tristearin in association with gliceryl monoolein were produced. The nanoencapsulation strategy allowed to obtain biocompatible and non-toxic vehicles, able to increase the solubility of the considered neuroactive drugs. To improve URB597 targeting to the brain, stealth nanoparticles were produced modifying the SLN surface with polysorbate 80. A behavioural study was conducted in rats to test the ability of SLN containing URB597 given by intranasal administration to alter behaviours relevant to psychiatric disorders. URB597 maintained its activity after nanoencapsulation, suggesting the possibility to propose this kind of vehicle as alternative to unphysiological mixtures usually employed for animal and clinical studies.
Assuntos
Benzamidas/química , Carbamatos/química , Portadores de Fármacos/química , Lipídeos/química , Nanopartículas/química , Água/química , Animais , Benzamidas/metabolismo , Encéfalo/metabolismo , Carbamatos/metabolismo , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Glicerídeos/química , Cinética , Masculino , Tamanho da Partícula , Polissorbatos/química , Ratos , Ratos Wistar , Solubilidade , Distribuição Tecidual , Triglicerídeos/químicaRESUMO
Previous studies have provided extensive evidence that administration of cannabinoid drugs after training modulates the consolidation of memory for an aversive experience. The present experiments investigated whether the memory consolidation is regulated by endogenously released cannabinoids. The experiments first examined whether the endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are released by aversive training. Inhibitory avoidance training with higher footshock intensity produced increased levels of AEA in the amygdala, hippocampus, and medial prefrontal cortex (mPFC) shortly after training in comparison with levels assessed in rats trained with lower footshock intensity or unshocked controls exposed only to the training apparatus. In contrast, 2-AG levels were not significantly elevated. The additional finding that posttraining infusions of the fatty acid amide hydrolase (FAAH) inhibitor URB597, which selectively increases AEA levels at active synapses, administered into the basolateral complex of the amygdala (BLA), hippocampus, or mPFC enhanced memory strongly suggests that the endogenously released AEA modulates memory consolidation. Moreover, in support of the view that this emotional training-associated increase in endocannabinoid neurotransmission, and its effects on memory enhancement, depends on the integrity of functional interactions between these different brain regions, we found that disruption of BLA activity blocked the training-induced increases in AEA levels as well as the memory enhancement produced by URB597 administered into the hippocampus or mPFC. Thus, the findings provide evidence that emotionally arousing training increases AEA levels within prefrontal-limbic circuits and strongly suggest that this cannabinoid activation regulates emotional arousal effects on memory consolidation.
Assuntos
Ácidos Araquidônicos/metabolismo , Emoções , Endocanabinoides/metabolismo , Sistema Límbico/fisiologia , Memória , Alcamidas Poli-Insaturadas/metabolismo , Córtex Pré-Frontal/fisiologia , Amidoidrolases/antagonistas & inibidores , Animais , Aprendizagem da Esquiva , Benzamidas/farmacologia , Carbamatos/farmacologia , Glicerídeos/metabolismo , Sistema Límbico/enzimologia , Córtex Pré-Frontal/enzimologia , Ratos , Receptor CB1 de Canabinoide/agonistasRESUMO
Variations in environmental aversiveness influence emotional memory processes in rats. We have previously shown that cannabinoid effects on memory are dependent on the stress level at the time of training as well as on the aversiveness of the environmental context. Here, we investigated whether the hippocampal endocannabinoid system modulates memory retrieval depending on the training-associated arousal level. Male adult Sprague Dawley rats were trained on a water maze spatial task at two different water temperatures (19°C and 25°C) to elicit either higher or lower stress levels, respectively. Rats trained under the higher stress condition had better memory and higher corticosterone concentrations than rats trained at the lower stress condition. The cannabinoid receptor agonist WIN55212-2 (10-30 ng/side), the 2-arachidonoyl glycerol (2-AG) hydrolysis inhibitor JZL184 (0.1-1 µg/side), and the anandamide (AEA) hydrolysis inhibitor URB597 (10-30 ng/side) were administered bilaterally into the hippocampus 60 min before probe-trial retention testing. WIN55212-2 or JZL184, but not URB597, impaired probe-trial performances only of rats trained at the higher stressful condition. Furthermore, rats trained under higher stress levels displayed an increase in hippocampal 2-AG, but not AEA, levels at the time of retention testing and a decreased affinity of the main 2-AG-degrading enzyme for its substrate. The present findings indicate that the endocannabinoid 2-AG in the hippocampus plays a key role in the selective regulation of spatial memory retrieval of stressful experience, shedding light on the neurobiological mechanisms involved in the impact of stress effects on memory processing. SIGNIFICANCE STATEMENT: Endogenous cannabinoids play a central role in the modulation of memory for emotional events. Here we demonstrate that the endocannabinoid 2-arachidonoylglycerol in the hippocampus, a brain region crucially involved in the regulation of memory processes, selectively modulates spatial memory recall of stressful experiences. Thus, our findings provide evidence that the endocannabinoid 2-arachidonoylglycerol is a key player in mediating the impact of stress on memory retrieval. These findings can pave the way to new potential therapeutic intervention for the treatment of neuropsychiatric disorders, such as post-traumatic stress disorder, where a previous exposure to traumatic events could alter the response to traumatic memory recall leading to mental illness.
Assuntos
Nível de Alerta/fisiologia , Emoções/fisiologia , Endocanabinoides/metabolismo , Rememoração Mental/fisiologia , Aprendizagem Espacial/fisiologia , Animais , Ácidos Araquidônicos/farmacologia , Nível de Alerta/efeitos dos fármacos , Benzamidas/farmacologia , Benzoxazinas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Carbamatos/farmacologia , Corticosterona/sangue , Relação Dose-Resposta a Droga , Emoções/efeitos dos fármacos , Endocanabinoides/farmacologia , Inibidores Enzimáticos/farmacologia , Glicerídeos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Morfolinas/farmacologia , Naftalenos/farmacologia , Ratos , Ratos Sprague-Dawley , Aprendizagem Espacial/efeitos dos fármacos , Estresse Psicológico/sangue , Estresse Psicológico/metabolismo , TemperaturaRESUMO
Post-Traumatic Stress Disorder (PTSD) is a psychiatric chronic disease developing in individuals after the experience of an intense and life-threatening traumatic event. The post-traumatic symptomatology encompasses alterations in memory processes, mood, anxiety and arousal. There is now consensus in considering the disease as an aberrant adaptation to traumatic stress. Pharmacological research, aimed at the discovery of new potential effective treatments, has lately directed its attention towards the "so-called" cognitive enhancers. This class of substances, by modulating cognitive processes involved in the development and/or persistence of the post-traumatic symptomatology, could be of great help in improving the outcome of psychotherapies and patients' prognosis. In this perspective, drugs acting on the endocannabinoid system are receiving great attention due to their dual ability to modulate memory processes on one hand, and to reduce anxiety and depression on the other. The purpose of the present review is to offer a thorough overview of both animal and human studies investigating the effects of cannabinoids on memory processes. First, we will briefly describe the characteristics of the endocannabinoid system and the most commonly used animal models of learning and memory. Then, studies investigating cannabinoid modulatory influences on memory consolidation, retrieval and extinction will be separately presented, and the potential benefits associated with each approach will be discussed. In the final section, we will review literature data reporting beneficial effects of cannabinoid drugs in PTSD patients.
Assuntos
Endocanabinoides/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Animais , Canabinoides/uso terapêutico , Humanos , Aprendizagem , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Estresse Psicológico/tratamento farmacológicoRESUMO
There is extensive evidence that glucocorticoid hormones impair the retrieval of memory of emotionally arousing experiences. Although it is known that glucocorticoid effects on memory retrieval impairment depend on rapid interactions with arousal-induced noradrenergic activity, the exact mechanism underlying this presumably nongenomically mediated glucocorticoid action remains to be elucidated. Here, we show that the hippocampal endocannabinoid system, a rapidly activated retrograde messenger system, is involved in mediating glucocorticoid effects on retrieval of contextual fear memory. Systemic administration of corticosterone (0.3-3 mg/kg) to male Sprague-Dawley rats 1 h before retention testing impaired the retrieval of contextual fear memory without impairing the retrieval of auditory fear memory or directly affecting the expression of freezing behavior. Importantly, a blockade of hippocampal CB1 receptors with AM251 prevented the impairing effect of corticosterone on retrieval of contextual fear memory, whereas the same impairing dose of corticosterone increased hippocampal levels of the endocannabinoid 2-arachidonoylglycerol. We also found that antagonism of hippocampal ß-adrenoceptor activity with local infusions of propranolol blocked the memory retrieval impairment induced by the CB receptor agonist WIN55,212-2. Thus, these findings strongly suggest that the endocannabinoid system plays an intermediary role in regulating rapid glucocorticoid effects on noradrenergic activity in impairing memory retrieval of emotionally arousing experiences.
Assuntos
Ácidos Araquidônicos/fisiologia , Moduladores de Receptores de Canabinoides/fisiologia , Endocanabinoides , Medo/fisiologia , Glucocorticoides/fisiologia , Glicerídeos/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Receptor CB1 de Canabinoide/fisiologia , Estimulação Acústica , Antagonistas Adrenérgicos beta/farmacologia , Animais , Nível de Alerta/fisiologia , Benzoxazinas/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Corticosterona/administração & dosagem , Corticosterona/farmacologia , Eletrochoque , Emoções/fisiologia , Medo/efeitos dos fármacos , Reação de Congelamento Cataléptica/fisiologia , Hipocampo/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Morfolinas/farmacologia , Naftalenos/farmacologia , Piperidinas/farmacologia , Propranolol/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptores de Glucocorticoides/fisiologiaRESUMO
Extensive evidence indicates that endocannabinoids modulate cognitive processes in animal models and human subjects. However, the results of endocannabinoid system manipulations on cognition have been contradictory. As for anxiety behavior, a duality has indeed emerged with regard to cannabinoid effects on memory for emotional experiences. Here we summarize findings describing cannabinoid effects on memory acquisition, consolidation, retrieval and extinction. Additionally, we review findings showing how the endocannabinoid system modulates memory function differentially, depending on the level of stress and arousal associated with the experimental context. Based on the evidence reviewed here, we propose that the endocannabinoid system is an emotional buffer that moderates the effects of environmental context and stress on cognitive processes.
Assuntos
Nível de Alerta/fisiologia , Canabinoides/farmacologia , Emoções/fisiologia , Endocanabinoides/fisiologia , Memória/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Canabinoides/administração & dosagem , Humanos , Memória/efeitos dos fármacos , Estresse Psicológico/metabolismoRESUMO
Critically ill patients are at an increased risk for traumatic memories and post-traumatic stress disorder (PTSD). Memories of one or more traumatic events play an important part in the symptom pattern of PTSD. Studies in long-term survivors of intensive care unit (ICU) treatment demonstrated a clear and vivid recall of traumatic experiences and the incidence and intensity of PTSD symptoms increased with the number of traumatic memories present. Preclinical evidence has clearly shown that the consolidation and retrieval of traumatic memories is regulated by an interaction between the noradrenergic, the glucocorticoid and the endocannabinoid system. Critically ill patients in the ICU frequently require treatment with adrenenergic or glucocorticoid drugs and often receive sedative medications; among them propofol is known to influence endocannabinoid signaling. Critical illness could therefore represent a useful model for investigating adrenergic, glucocorticoid as well as endocannabinoid effects on traumatic memory and PTSD development in stressed humans. The endocannabinoid system is an important regulator of HPA-axis activity during stress, an effect which has also been demonstrated in humans. Likewise, a single nucleotide polymorphism (SNP) of the glucocorticoid receptor (GR) gene (the BclI-SNP), which enhances the sensitivity of the glucocorticoid receptors to cortisol and possibly HPA-axis feedback function, was associated with enhanced emotional memory performance in healthy volunteers. The presence of the BclI-SNP increased the risk for traumatic memories and PTSD symptoms in patients after ICU therapy and was linked to lower basal cortisol levels. A number of small studies have demonstrated that the administration of cortisol to critically ill or injured patients results in a significant reduction of PTSD symptoms after recovery without influencing the number of traumatic memories. These glucocorticoid effects can possibly be explained by a cortisol-induced temporary impairment in traumatic memory retrieval which has previously been demonstrated in both rats and humans. The hypothesis that stress doses of glucocorticoids or the pharmacologic manipulation of glucocorticoid-endocannabinoid interaction during traumatic memory consolidation and retrieval could be useful for prophylaxis and treatment of PTSD after critical illness should be tested in larger controlled studies.
Assuntos
Catecolaminas/fisiologia , Estado Terminal , Endocanabinoides/fisiologia , Glucocorticoides/fisiologia , Memória/fisiologia , Transtornos de Estresse Pós-Traumáticos/metabolismo , Sobreviventes , HumanosRESUMO
Alzheimer's disease (AD) is a severe and progressive neurodegenerative condition that exerts detrimental effects on brain function. As of now, there is no effective treatment for AD patients. This review explores two distinct avenues of research. The first revolves around the use of animal studies and preclinical models to gain insights into AD's underlying mechanisms and potential treatment strategies. Specifically, it delves into the effectiveness of interventions such as Optogenetics and Chemogenetics, shedding light on their implications for understanding pathophysiological mechanisms and potential therapeutic applications. The second avenue focuses on non-invasive brain stimulation (NiBS) techniques in the context of AD. Evidence suggests that NiBS can successfully modulate cognitive functions associated with various neurological and neuropsychiatric disorders, including AD, as demonstrated by promising findings. Here, we critically assessed recent findings in AD research belonging to these lines of research and discuss their potential impact on the clinical horizon of AD treatment. These multifaceted approaches offer hope for advancing our comprehension of AD pathology and developing novel therapeutic interventions.
RESUMO
Highly Superior Autobiographical Memory (HSAM) is a rare form of enhanced memory in which individuals demonstrate an extraordinary ability to remember details of their personal lives with high levels of accuracy and vividness. Neuroimaging studies have identified brain regions - specifically, midline areas within the default network - associated with remembering events from one's past. Extending this research on the neural underpinnings of autobiographical memory, the present study utilizes graph theory analyses to compare functional brain connectivity in a cohort of HSAM (n = 12) and control participants (n = 29). We perform seed-based analysis in resting-state fMRI data to assess how specific cortical regions within the autobiographical memory network are differentially connected in HSAM individuals. Additionally, we apply a whole-brain connectivity analysis to identify differences in brain hub-network topology associated with enhanced autobiographical memory. Seed-based results show converging patterns of increased connectivity in HSAM across midline areas. Whole-brain analysis also reveals enhanced connectivity across medial prefrontal and posterior cingulate cortex in HSAM individuals. Together, these results extend prior research, highlighting cortical hubs within the default network associated with enhanced autobiographical memory.