RESUMO
Acetylation of histone proteins by histone acetyltransferases (HATs), and the resultant change in gene expression, is a well-established mechanism necessary for long-term memory (LTM) consolidation, which is not required for short-term memory (STM). However, we previously demonstrated that the HAT p300/CBP-associated factor (PCAF) also influences hippocampus (HPC)-dependent STM in male rats. In addition to their epigenetic activity, HATs acetylate non-histone proteins involved in non-genomic cellular processes, such as estrogen receptors (ERs). Given that ERs have rapid, non-genomic effects on HPC-dependent STM, we investigated the potential interaction between ERs and PCAF for STM mediated by the dorsal HPC (dHPC). Using a series of pharmacological agents administered directly into the dHPC, we reveal a functional interaction between PCAF and ERα in the facilitation of short-term object-in-place memory in male but not female rats. This interaction was specific to ERα, while ERß agonism did not enhance STM. It was further specific to dHPC STM, as the effect was not present in the dHPC for LTM or in the perirhinal cortex. Additional experiments indicated that while STM required local (i.e., dHPC) estrogen synthesis, the facilitatory interaction effect might be independent of estrogens. Finally, western blot analyses demonstrated that PCAF activation in the dHPC rapidly (5min) activated downstream estrogen-related cell signaling kinases (c-Jun N-terminal kinase and extracellular signal-related kinase). Collectively, these findings indicate that PCAF, which is typically implicated in LTM through epigenetic processes, also influences STM in the dHPC, possibly via non-genomic ER activity. Critically, this novel PCAF-ER interaction might exist as a male-specific mechanism supporting STM.Significance Statement Due to their ability to modulate gene expression, epigenetic mechanisms are necessary for long-term, but not short-term, memory. Recently, the histone acetyltransferase PCAF, has been shown to be necessary in the hippocampus for short-term object memory, but its mechanism of action is unknown. Here, we present evidence for a novel functional interaction between PCAF and estrogen receptors (ERs) in the hippocampus of gonadally-intact male - but not female - rats that enhanced short-term object memory. Further, enhancing PCAF led to rapid activation of downstream ER-related signaling cascades, suggesting that PCAF might activate ERs similar to the effects of estrogens. Indeed, experiments suggested that the PCAF-ER interaction could be estrogen-independent. These results demonstrate a novel mechanism mediating short-term memory enhancement that appears to be specific to males.
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The storage of long-term memories is a dynamic process. Reminder cues can destabilize previously consolidated memories, rendering them labile and modifiable. However, memories that are strongly encoded or relatively remote at the time of reactivation can resist destabilization only being rendered labile under conditions that favour memory updating. Using the object location recognition task, here we show in male C57BL/6 mice that novelty-induced destabilization of strongly-encoded memories requires muscarinic acetylcholine receptor (mAChR) activation. Furthermore, we use the objects-in-updated locations task to show that updating of object location memories is mAChR-dependent. Thus, mAChR stimulation appears to be critical for spatial memory destabilization and related memory updating. Enhancing our understanding of the role of ACh in memory updating should inform future research into the underlying causes of behavioural disorders that are characterized by persistent maladaptive memories, such as age-related cognitive inflexibility and post-traumatic stress disorder.
Assuntos
Memória de Longo Prazo , Receptores Muscarínicos , Camundongos , Masculino , Animais , Camundongos Endogâmicos C57BL , Memória de Longo Prazo/fisiologia , Memória Espacial/fisiologia , Sinais (Psicologia)RESUMO
Destabilization of previously consolidated memories places them in a labile state in which they are open to modification. However, strongly encoded fear memories tend to be destabilization-resistant and the conditions required to destabilize such memories remain poorly understood. Our lab has previously shown that exposure to salient novel contextual cues during memory reactivation can destabilize strongly encoded object location memories and that activity at muscarinic cholinergic receptors is critical for this effect. In the current study, we similarly targeted destabilization-resistant fear memories, hypothesizing that exposure to salient novelty at the time of reactivation would induce destabilization of strongly encoded fear memories in a muscarinic receptor-dependent manner. First, we show that contextual fear memories induced by 3 context-shock pairings readily destabilize upon memory reactivation, and that this destabilization is blocked by systemic (ip) administration of the muscarinic receptor antagonist scopolamine (0.3 mg/kg) in male rats. Following that, we confirm that this effect is dorsal hippocampus (dHPC)-dependent by targeting M1 receptors in the CA1 region with pirenzepine. Next, we show that more strongly encoded fear memories (induced with 5 context-shock pairings) resist destabilization. Consistent with our previous work, however, we report that salient novelty (a change in floor texture) presented during the reactivation session promotes destabilization of resistant contextual fear memories in a muscarinic receptor-dependent manner. Finally, the effect of salient novelty on memory destabilization was mimicked by stimulating muscarinic receptors with the selective M1 agonist CDD-0102A (ip, 0.3 mg/kg). These findings reveal further generalizability of our previous results implicating novel cues and M1 muscarinic signaling in promoting destabilization of resistant memories and suggest possible therapeutic options for disorders characterized by persistent, maladaptive fear memories such as PTSD and phobias.
Assuntos
Memória , Receptor Muscarínico M1 , Ratos , Masculino , Animais , Memória/fisiologia , Medo/fisiologia , Antagonistas Muscarínicos/farmacologia , Escopolamina/farmacologiaRESUMO
Impulsivity is a multidimensional heritable phenotype that broadly refers to the tendency to act prematurely and is associated with multiple forms of psychopathology, including substance use disorders. We performed genome-wide association studies (GWAS) of eight impulsive personality traits from the Barratt Impulsiveness Scale and the short UPPS-P Impulsive Personality Scale (N = 123,509-133,517 23andMe research participants of European ancestry), and a measure of Drug Experimentation (N = 130,684). Because these GWAS implicated the gene CADM2, we next performed single-SNP phenome-wide studies (PheWAS) of several of the implicated variants in CADM2 in a multi-ancestral 23andMe cohort (N = 3,229,317, European; N = 579,623, Latin American; N = 199,663, African American). Finally, we produced Cadm2 mutant mice and used them to perform a Mouse-PheWAS ("MouseWAS") by testing them with a battery of relevant behavioral tasks. In humans, impulsive personality traits showed modest chip-heritability (~6-11%), and moderate genetic correlations (rg = 0.20-0.50) with other personality traits, and various psychiatric and medical traits. We identified significant associations proximal to genes such as TCF4 and PTPRF, and also identified nominal associations proximal to DRD2 and CRHR1. PheWAS for CADM2 variants identified associations with 378 traits in European participants, and 47 traits in Latin American participants, replicating associations with risky behaviors, cognition and BMI, and revealing novel associations including allergies, anxiety, irritable bowel syndrome, and migraine. Our MouseWAS recapitulated some of the associations found in humans, including impulsivity, cognition, and BMI. Our results further delineate the role of CADM2 in impulsivity and numerous other psychiatric and somatic traits across ancestries and species.
Assuntos
Estudo de Associação Genômica Ampla , Transtornos Relacionados ao Uso de Substâncias , Humanos , Animais , Camundongos , Fenótipo , Comportamento Impulsivo , Personalidade/genética , Polimorfismo de Nucleotídeo Único , Moléculas de Adesão Celular/genéticaRESUMO
There are indications that drug conditioned stimuli (CS) may activate neurochemical systems of memory modulation that are activated by the drugs themselves. To directly test this hypothesis, a cholinergic nicotinic receptor antagonist (mecamylamine; MEC: 0, 10 or 30 µg/side) and a dopamine D2 receptor antagonist (l-741,626: 0, 0.63, 2.5 µg/side) were infused in the perirhinal cortex (PRh) to block modulation of object recognition memory consolidation induced by 0.4 mg/kg nicotine, 20 mg/kg cocaine, or their CSs. To establish these CSs, male Sprague-Dawley rats were confined for 2 h in a chamber, the CS+, after injections of 0.4 mg/kg nicotine, or 20 mg/kg cocaine, and in another chamber, the CS-, after injections of vehicle. This was repeated over 10 days (5 drug/CS+ and 5 vehicle/CS- pairings in total). It was found that the memory enhancing action of post-sample nicotine was blocked by intra-PRh infusions of both MEC doses, and 30 µg/side MEC also blocked the memory enhancing action of the nicotine CS. Interestingly, intra-PRh MEC did not block the memory enhancing effect of cocaine, nor that of the cocaine CS. In contrast, the memory enhancing action of post-sample cocaine administration was blocked by both l-741,626 doses, and 2.5 µg/side also blocked the effect of the cocaine CS, but not the memory effects of nicotine or of the nicotine CS. This functional double dissociation strongly indicates that drug CSs modulate memory consolidation by activating neural systems that are activated by the drugs themselves.
Assuntos
Cocaína , Consolidação da Memória , Receptores Nicotínicos , Ratos , Animais , Masculino , Nicotina/farmacologia , Cocaína/farmacologia , Ratos Sprague-Dawley , Receptores de Dopamina D2 , Receptores de Dopamina D1RESUMO
Long-term memory storage is a dynamic process requiring flexibility to ensure adaptive behavioural responding in changing environments. Indeed, it is well established that memory reactivation can "destabilize" consolidated traces, leading to various forms of updating. However, the neurobiological mechanisms rendering long-term memories labile and modifiable remain poorly described. Moreover, boundary conditions, such as the age or strength of the memory, can reduce the likelihood of this destabilization; yet, intuitively, these most behaviourally influential of memories should also be modifiable under appropriate conditions. Here, we provide evidence that salient novelty at the time of memory reactivation promotes integrative updating of resistant object memories in rats. Furthermore, blockade of muscarinic acetylcholine receptors (mAChRs; with pirenzepine) or disruption of calcium/calmodulin (Ca2+/CaM) with KN-93, a Ca2+/CaM-binding molecule that inhibits calcium/calmodulin-dependent protein kinase II (CaMKII) activation, in perirhinal cortex (PRh) prevented novelty-induced destabilization and updating of resistant object memories. Finally, PRh M1 mAChR activation (with CDD-0102A) was sufficient to destabilize resistant object memories for updating, and this effect was blocked by KN-93, possibly via inhibition of CaMKII activity. Thus, mAChRs and activation of CaMKII appear to interact as part of a mechanism to override boundary conditions on resistant object memories to ensure integrative modification with novel information. These findings therefore have important implications for understanding the dynamic nature of long-term memory storage and potential treatments for conditions characterized by maladaptive and inflexible memories.
Assuntos
Cálcio , Calmodulina , Ratos , Animais , Cálcio/metabolismo , Calmodulina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Receptores MuscarínicosRESUMO
The content of long-term memory is neither fixed nor permanent. Reminder cues can destabilize consolidated memories, rendering them amenable to change before being reconsolidated. However, not all memories destabilize following reactivation. Characteristics of a memory, such as its age or strength, impose boundaries on destabilization. Previously, we demonstrated that presentation of salient novel information at the time of reactivation can readily destabilize resistant object memories in rats and this form of novelty-induced destabilization is dependent upon acetylcholine (ACh) activity at muscarinic receptors (mAChRs). In the present study, we sought to determine if this same mechanism for initiating destabilization of resistant object memories is present in mice and further expand our understanding of the mechanisms through which ACh modulates object memory destabilization by investigating the role of nicotinic receptors (nAChRs). We provide evidence that in mice mAChRs are necessary for destabilizing object memories that are readily destabilized and those that are resistant to destabilization. Conversely, nAChRs were found to be necessary only when memories are readily destabilized. We then investigated the role of both receptors in the reconsolidation of destabilized object memory traces and determined that nAChRs, but not mAChRs, are necessary for object memory reconsolidation. Together, these results suggest that nAChRs may play a more selective role in the re-storage of object memories following destabilization and that ACh acts through mAChRs to act as an override signal to initiate destabilization of resistant object memories following reactivation with novelty. These findings expand our current understanding of the role of ACh in the dynamic storage of long-term memory.
Assuntos
Memória de Longo Prazo , Receptores Nicotínicos , Ratos , Camundongos , Animais , Memória de Longo Prazo/fisiologia , Acetilcolina , Receptores Muscarínicos/metabolismo , ColinérgicosRESUMO
Enrichment in rodents affects brain structure, improves behavioral performance, and is neuroprotective. Similarly, in humans, according to the cognitive reserve concept, enriched experience is functionally protective against neuropathology. Despite this parallel, the ability to translate rodent studies to human clinical situations is limited. This limitation is likely due to the simple cognitive processes probed in rodent studies and the inability to control, with existing methods, the degree of rodent engagement with enrichment material. We overcome these two difficulties with behavioral tasks that probe, in a fine-grained manner, aspects of higher-order cognition associated with deterioration with aging and dementia, and a new enrichment protocol, the 'Obstacle Course' (OC), which enables controlled enrichment delivery, respectively. Together, these two advancements will enable better specification (and comparisons) of the nature of impairments in animal models of complex mental disorders and the potential for remediation from various types of intervention (e.g., enrichment, drugs). We found that two months of OC enrichment produced substantial and sustained enhancements in categorization memory, perceptual object invariance, and cross-modal sensory integration in mice. We also tested mice on behavioral tasks previously shown to benefit from traditional enrichment: spontaneous object recognition, object location memory, and pairwise visual discrimination. OC enrichment improved performance relative to standard housing on all six tasks and was in most cases superior to conventional home-cage enrichment and exercise track groups.
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Histone variants H2A.Z and H3.3 are epigenetic regulators of memory, but roles of other variants are not well characterized. macroH2A (mH2A) is a structurally unique histone that contains a globular macrodomain connected to the histone region by an unstructured linker. Here we assessed if mH2A regulates memory and if this role varies for the two mH2A-encoding genes, H2afy (mH2A1) and H2afy2 (mH2A2). We show that fear memory is impaired in mH2A1, but not in mH2A2-deficient mice, whereas both groups were impaired in a non-aversive spatial memory task. However, impairment was larger for mH2A1- deficient mice, indicating a preferential role for mH2A1 over mH2A2 in memory. Accordingly, mH2A1 depletion in the mouse hippocampus resulted in more extensive transcriptional de-repression compared to mH2A2 depletion. mH2A1-depleted mice failed to induce a normal transcriptional response to fear conditioning, suggesting that mH2A1 depletion impairs memory by altering transcription. Using chromatin immunoprecipitation (ChIP) sequencing, we found that both mH2A proteins are enriched on transcriptionally repressed genes, but only mH2A1 occupancy was dynamically modified during learning, displaying reduced occupancy on upregulated genes after training. These data identify mH2A as a regulator of memory and suggest that mH2A1 supports memory by repressing spurious transcription and promoting learning-induced transcriptional activation.
Assuntos
Hipocampo , Histonas , Animais , Hipocampo/metabolismo , Histonas/genética , Histonas/metabolismo , CamundongosRESUMO
Systematic investigation of reactivation-induced memory updating began in the 1960s, and a wave of research in this area followed the seminal articulation of "reconsolidation" theory in the early 2000s. Myriad studies indicate that memory reactivation can cause previously consolidated memories to become labile and sensitive to weakening, strengthening, or other forms of modification. However, from its nascent period to the present, the field has been beset by inconsistencies in researchers' abilities to replicate seemingly established effects. Here we review these many studies, synthesizing the human and nonhuman animal literature, and suggest that these failures-to-replicate reflect a highly complex and delicately balanced memory modification system, the substrates of which must be finely tuned to enable adaptive memory updating while limiting maladaptive, inaccurate modifications. A systematic approach to the entire body of evidence, integrating positive and null findings, will yield a comprehensive understanding of the complex and dynamic nature of long-term memory storage and the potential for harnessing modification processes to treat mental disorders driven by pervasive maladaptive memories.
Assuntos
Consolidação da Memória , Memória de Longo Prazo , Animais , Humanos , Consolidação da Memória/fisiologia , Memória de Longo Prazo/fisiologiaRESUMO
Histone acetylation, catalyzed by histone acetyltransferases, has emerged as a promising therapeutic strategy in Alzheimer's disease (AD). By longitudinally characterizing spatial memory at 3, 6, and 9 mo of age, we show that acute activation and inhibition of the histone acetyltransferase PCAF remediated memory impairments in 3xTG-AD mice in an age-related bidirectional manner. At 3 and 6 mo of age, PCAF activation ameliorated memory deficits. At 9 mo of age, PCAF activation had no effect on spatial memory, whereas PCAF inhibition improved memory deficits in females. This work reveals a complex potential therapeutic role for PCAF in AD, initially benefitting memory but becoming detrimental as the disease progresses.
Assuntos
Doença de Alzheimer , Histona Acetiltransferases , Acetilação , Doença de Alzheimer/genética , Animais , Feminino , Histona Acetiltransferases/genética , Transtornos da Memória , Camundongos , Memória Espacial , Fatores de Transcrição de p300-CBPRESUMO
Following the initial consolidation process, memories can become reactivated by exposure to a reminder of the original learning event. This can lead to the memory becoming destabilized and vulnerable to disruption or other forms of modification. The memory must then undergo the protein-synthesis dependent process of reconsolidation in order to be retained. However, older and/or stronger memories resist destabilization, but can become labile when reactivated in the presence of salient novelty. We have implicated the neurotransmitter acetylcholine, acting at M1 muscarinic cholinergic receptors (mAChRs) within perirhinal cortex (PRh), in novelty-induced destabilization of remote object memories. It remains unclear, however, whether mAChRs are involved in destabilization of other forms of memory. We hypothesized that the role of M1 mAChRs previously demonstrated for PRh-dependent object memory would extend to hippocampus-dependent spatial memory. Using the object location (OL) task, which relies on the dorsal hippocampus (dHPC), we showed that (a) reactivation-dependent reconsolidation of OL memories requires protein synthesis within the dHPC; (b) destabilization of relatively weak OL memories depends on M1 mAChR activation within the dHPC; (c) salient novelty during reactivation promotes destabilization of resistant strongly encoded OL memories; (d) novelty-induced destabilization of strong OL memories requires activation of mAChRs within the dHPC; and (e) M1 mAChR activation within the dHPC in the absence of novelty during memory reactivation mimics the effect of novelty, destabilizing strongly encoded OL memories. These results implicate ACh acting at M1 mAChRs in the destabilization of dHPC-dependent spatial memories, demonstrating generalizability of this cholinergic function beyond memory for object identity. These findings therefore enhance our understanding of the dynamics of long-term memory storage and suggest implications for the treatment of human conditions such as Alzheimer's disease and aging, which are characterized by behavioral and mnemonic inflexibility.
Assuntos
Córtex Perirrinal , Receptores Colinérgicos , Animais , Colinérgicos/metabolismo , Hipocampo/metabolismo , Humanos , Córtex Perirrinal/metabolismo , Ratos , Ratos Long-Evans , Receptor Muscarínico M1/metabolismo , Receptores Colinérgicos/metabolismoRESUMO
BACKGROUND: There is evidence that post-training exposure to nicotine, cocaine, and their conditioned stimuli (CS), enhance memory consolidation in rats. The present study assessed the effects of blocking noradrenergic and dopaminergic receptors on nicotine and cocaine unconditioned and conditioned memory modulation. METHODS: Males Sprague-Dawley rats tested on the spontaneous object recognition task received post-sample exposure to 0.4 mg/kg nicotine, 20 mg/kg cocaine, or their CSs, in combination with 5-10 mg/kg propranolol (PRO; beta-adrenergic antagonist) or 0.2-0.6 mg/kg pimozide (PIM; dopamine D2 receptor antagonist). The CSs were established by confining rats in a chamber (the CS +) after injections of 0.4 mg/kg nicotine, or 20 mg/kg cocaine, for 2 h and in another chamber (the CS -) after injections of vehicle, repeated over 10 days (5 drug/CS + and 5 vehicle/CS - pairings in total). Object memory was tested 72 h post sample in drug-free animals. RESULTS: Co-administration of PRO or PIM blocked the memory-enhancing effects of post-training injections of nicotine, cocaine, and, importantly, exposure to their CSs. CONCLUSIONS: These data suggest that nicotine, cocaine as well as their conditioned stimuli share actions on overlapping noradrenergic and dopaminergic systems to modulate memory consolidation.
Assuntos
Cocaína , Adrenérgicos , Animais , Cocaína/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Masculino , Nicotina/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Cannabis and alcohol co-use is prevalent in adolescence, but the long-term behavioural effects of this co-use remain largely unexplored. The aim of this study is to investigate the effects of adolescent alcohol and Δ9-tetrahydracannabinol (THC) vapour co-exposure on cognitive- and reward-related behaviours. Male Sprague-Dawley rats received vapourized THC (10 mg vapourized THC/four adolescent rats) or vehicle every other day (from post-natal day (PND) 28-42) and had continuous voluntary access to ethanol (10% volume/volume) in adolescence. Alcohol intake was measured during the exposure period to assess the acute effects of THC on alcohol consumption. In adulthood (PND 56+), rats underwent behavioural testing. Adolescent rats showed higher alcohol preference, assessed using the two-bottle choice test, on days on which they were not exposed to THC vapour. In adulthood, rats that drank alcohol as adolescents exhibited short-term memory deficits and showed decreased alcohol preference; on the other hand, rats exposed to THC vapour showed learning impairments in the delay-discounting task. Vapourized THC, alcohol or their combination had no effect on anxiety-like behaviours in adulthood. Our results show that although adolescent THC exposure acutely affects alcohol drinking, adolescent alcohol and cannabis co-use may not produce long-term additive effects.
Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Ansiedade/psicologia , Cognição/efeitos dos fármacos , Dronabinol/administração & dosagem , Recompensa , Vaping/psicologia , Fatores Etários , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/tendências , Animais , Ansiedade/induzido quimicamente , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Cognição/fisiologia , Desvalorização pelo Atraso/efeitos dos fármacos , Desvalorização pelo Atraso/fisiologia , Dronabinol/efeitos adversos , Masculino , Ratos , Ratos Sprague-Dawley , Vaping/efeitos adversos , Vaping/tendênciasRESUMO
Reminder cues can destabilize consolidated memories, rendering them modifiable before they return to a stable state through the process of reconsolidation. Older and stronger memories resist this process and require the presentation of reminders along with salient novel information in order to destabilize. Previously, we demonstrated in rats that novelty-induced object memory destabilization requires acetylcholine (ACh) activity at M1 muscarinic receptors. Other research predominantly has focused on glutamate, which modulates fear memory destabilization and reconsolidation through GluN2B- and GluN2A-containing NMDARs, respectively. In the current study, we demonstrate the same dissociable roles of GluN2B- and N2A-containing NMDARs in perirhinal cortex (PRh) for object memory destabilization and reconsolidation when boundary conditions are absent. However, neither GluN2 receptor subtype was required for novelty-induced destabilization of remote, resistant memories. Furthermore, GluN2B and GluN2A subunit proteins were upregulated selectively in PRh 24 h after learning, but returned to baseline by 48 h, suggesting that NMDARs, unlike muscarinic receptors, have only a temporary role in object memory destabilization. Indeed, activation of M1 receptors in PRh at the time of reactivation effectively destabilized remote memories despite inhibition of GluN2B-containing NMDARs. These findings suggest that cholinergic activity at M1 receptors overrides boundary conditions to destabilize resistant memories when other established mechanisms are insufficient.
Assuntos
Consolidação da Memória , Córtex Perirrinal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Masculino , Rememoração Mental , Córtex Perirrinal/fisiologia , Ratos , Ratos Long-Evans , Receptores Muscarínicos/genética , Receptores Muscarínicos/metabolismo , Receptores de N-Metil-D-Aspartato/genéticaRESUMO
Reactivated long-term memories can become labile and sensitive to modification. Memories in this destabilized state can be weakened or strengthened, but there is limited research characterizing the mechanisms underlying retrieval-induced qualitative updates (i.e., information integration). We have previously implicated cholinergic transmission in object memory destabilization. Here we present a novel rodent paradigm developed to assess the role of this cholinergic mechanism in qualitative object memory updating. The post-reactivation object memory modification (PROMM) task exposes rats to contextual information following object memory reactivation. Subsequent object exploratory performance suggests that the contextual information is integrated with the original memory in a reactivation- and time-dependent manner. This effect is blocked by interference with M1 muscarinic receptors and several downstream signals in perirhinal cortex. These findings therefore demonstrate a hitherto unacknowledged cognitive function for acetylcholine with important implications for understanding the dynamic nature of long-term memory storage in the normal and aging brain.
Assuntos
Memória , Receptor Muscarínico M1/metabolismo , Animais , Benzilaminas/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/antagonistas & inibidores , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Lactonas/farmacologia , Masculino , Memória/efeitos dos fármacos , Córtex Perirrinal/metabolismo , Córtex Perirrinal/cirurgia , Pirenzepina/farmacologia , Inibidores de Proteassoma/farmacologia , Ratos , Ratos Long-Evans , Receptor Muscarínico M1/agonistas , Receptor Muscarínico M1/antagonistas & inibidores , Escopolamina/farmacologia , Sulfonamidas/farmacologiaRESUMO
There is recent evidence that cocaine, nicotine, and their conditioned stimuli have the ability to enhance memory consolidation. The present study compared the effects of post-training heroin and of a heroin contextual conditioned stimulus (CS+) on consolidation of object recognition memory and investigated the roles of opioid and beta-adrenergic receptors in heroin/CS+ memory modulation by co-administering the respective antagonists, naltrexone (NTX) and propranolol (PRO). Three experiments were performed in male Sprague-Dawley rats demonstrating that immediate, but not delayed, post-sample exposure to heroin (0.3, 1 mg/kg), or exposure (30 min) to a contextual CS+ paired with 1 mg/kg heroin (5 pairings, each 120 min), equally enhanced object memory. Importantly, while the memory enhancing effects of 1 mg/kg heroin and of the contextual CS+ were not altered by post-training co-administration of 3 mg/kg naltrexone, they were blocked by post-training co-administration of 10 mg/kg propranolol. Taken together, these data suggest that a context paired with heroin shares the memory enhancing effect of heroin itself and that these unconditioned and conditioned drug stimuli may modulate memory through the activation of beta-noradrenergic receptors.
Assuntos
Heroína/farmacologia , Consolidação da Memória/efeitos dos fármacos , Entorpecentes/farmacologia , Norepinefrina , Receptores Adrenérgicos/efeitos dos fármacos , Receptores Opioides/efeitos dos fármacos , Antagonistas Adrenérgicos beta/farmacologia , Animais , Condicionamento Operante/efeitos dos fármacos , Masculino , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Medição da Dor/efeitos dos fármacos , Propranolol/farmacologia , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
Recent work has suggested that 5α-reduced metabolites of testosterone may contribute to the neuroprotection conferred by their parent androgen, as well as to sex differences in the incidence and progression of Alzheimer's disease (AD). This study investigated the effects of inhibiting 5α-reductase on object recognition memory (ORM), hippocampal dendritic morphology and proteins involved in AD pathology, in male 3xTg-AD mice. Male 6-month old wild-type or 3xTg-AD mice received daily injections of finasteride (50â¯mg/kg i.p.) or vehicle (18% ß-cyclodextrin, 1% v/b.w.) for 20â¯days. Female wild-type and 3xTg-AD mice received only the vehicle. Finasteride treatment differentially impaired ORM in males after short-term (3xTg-AD only) or long-term (3xTg-AD and wild-type) retention delays. Dendritic spine density and dendritic branching of pyramidal neurons in the CA3 hippocampal subfield were significantly lower in 3xTg-AD females than in males. Finasteride reduced CA3 dendritic branching and spine density in 3xTg-AD males, to within the range observed in vehicle-treated females. In the CA1 hippocampal subfield, dendritic branching and spine density were reduced in both male and female 3xTg-AD mice, compared to wild type controls. Hippocampal amyloid ß levels were substantially higher in 3xTg-AD females compared to both vehicle and finasteride-treated 3xTg-AD males. Site-specific Tau phosphorylation was higher in 3xTg-AD mice compared to sex-matched wild-type controls, increasing slightly after finasteride treatment. These results suggest that 5α-reduced neurosteroids may play a role in testosterone-mediated neuroprotection and may contribute to sex differences in the development and severity of AD.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Colestenona 5 alfa-Redutase , Cognição , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Fosforilação , Proteínas tau/metabolismoRESUMO
Open Science has changed research by making data accessible and shareable, contributing to replicability to accelerate and disseminate knowledge. However, for rodent cognitive studies the availability of tools to share and disseminate data is scarce. Automated touchscreen-based tests enable systematic cognitive assessment with easily standardised outputs that can facilitate data dissemination. Here we present an integration of touchscreen cognitive testing with an open-access database public repository (mousebytes.ca), as well as a Web platform for knowledge dissemination (https://touchscreencognition.org). We complement these resources with the largest dataset of age-dependent high-level cognitive assessment of mouse models of Alzheimer's disease, expanding knowledge of affected cognitive domains from male and female mice of three strains. We envision that these new platforms will enhance sharing of protocols, data availability and transparency, allowing meta-analysis and reuse of mouse cognitive data to increase the replicability/reproducibility of datasets.