Reactivation of encoding ensembles in the prelimbic cortex supports temporal associations.

Fear conditioning is encoded by strengthening synaptic connections between the neurons activated by a conditioned stimulus (CS) and those activated by an unconditioned stimulus (US), forming a memory engram, which is reactivated during memory retrieval. In temporal associations, activity within the prelimbic cortex (PL) plays a role in sustaining a short-term, transient memory of the CS, which is associated with the US after a temporal gap. However, it is unknown whether the PL has only a temporary role, transiently representing the CS, or is part of the neuronal ensembles that support the retrieval, i.e., whether PL neurons support both transient, short-term memories and stable, long-term memories. We investigated neuronal ensembles underlying temporal associations using fear conditioning with a 5-s interval between the CS and US (CFC-5s). Controls were trained in contextual fear conditioning (CFC), in which the CS-US overlaps. We used Robust Activity Marking (RAM) to selectively manipulate PL neurons activated by CFC-5s learning and Targeted Recombination in Active Populations (TRAP2) mice to label neurons activated by CFC-5s learning and reactivated by memory retrieval in the amygdala, medial prefrontal cortex, hippocampus, perirhinal cortices (PER) and subiculum. We also computed their co-reactivation to generate correlation-based networks. The optogenetic reactivation or silencing of PL encoding ensembles either promoted or impaired the retrieval of CFC-5s but not CFC. CFC-5s retrieval reactivated encoding ensembles in the PL, PER, and basolateral amygdala. The engram network of CFC-5s had higher amygdala and PER centralities and interconnectivity. The same PL neurons support learning and stable associative memories.

The subiculum role on learning and memory tasks using rats and mice: A scoping review.

This scoping review aimed to systematically identify and summarize data related to subiculum involvement in learning and memory behavioral tasks in rats and mice. Following a systematic strategy based on PICO and PRISMA guidelines, we searched five indexed databases (PubMed, Web of Science, EMBASE, Scopus, and PsycInfo) using a standardized search strategy to identify peer-reviewed articles published in English (pre-registration: osf.io/hm5ea). We identified 31 articles investigating the role of the subiculum in spatial, working, and recognition memories (n = 11), memories related to addiction models (n = 9), aversive memories (n = 7), and memories related to appetitive learning (n = 5). We highlight a dissociation in the dorsoventral axis of the subiculum with many studies exploring the ventral subiculum (n = 21) but only a few exploring the dorsal one (n = 10). We also observe the necessity of more data including mice, female animals, genetic tools, and better statistical approaches for replication purposes and research refinement. These findings provide a broad framework of the subiculum involvement in learning and memory, showing essential questions that can be explored by further studies.

The contextual fear conditioning consolidation depends on the functional interaction of the dorsal subiculum and basolateral amygdala in rats.

Fear conditioning tasks enable us to explore the neural basis of adaptative and maladaptive behaviors related to aversive memories. Recently, we provided the first evidence of the dorsal subiculum (DSub) involvement in contextual fear conditioning (CFC) consolidation by showing that the post-training bilateral NMDA (N-methyl-D-aspartate) receptor blockade in DSub impaired the performance of animals in the test session. As the memory consolidation process depends on the coordinated engagement of different brain regions, and the DSub share reciprocal projections with the basolateral amygdala (BLA), which is also involved in CFC, it is possible that the functional interaction between these sites can be relevant for the consolidation of this task. In this sense, the present study aimed to explore the effects of the functional disconnection of the DSub and BLA in the CFC consolidation after NMDA post-training blockade. In addition, to verify if the observed effects were due to spatial representation processes mediated by the DSub, we employed a hippocampal-independent procedure: tone fear conditioning (TFC). Results showed that the functional disconnection of these regions by post-training NMDA blockade impaired CFC consolidation, whereas there was no impairment in TFC. Altogether, the present data suggest that the DSub and BLA would functionally interact through NMDA-related synaptic plasticity to support CFC consolidation probably due to DSub-related spatial processing showing that the TFC consolidation was not disrupted. This work contributes to filling a gap of studies exploring the DSub involvement in fear conditioning by providing a broad framework of the subicular-amygdaloid connection functionality.

Functional network of contextual and temporal memory has increased amygdala centrality and connectivity with the retrosplenial cortex, thalamus, and hippocampus.

In fear conditioning with time intervals between the conditioned (CS) and unconditioned (US) stimuli, a neural representation of the CS must be maintained over time to be associated with the later US. Usually, temporal associations are studied by investigating individual brain regions. It remains unknown, however, the effect of the interval at the network level, uncovering functional connections cooperating for the CS transient memory and its fear association. We investigated the functional network supporting temporal associations using a task in which a 5-s interval separates the contextual CS from the US (CFC-5s). We quantified c-Fos expression in forty-nine brain regions of male rats following the CFC-5s training, used c-Fos correlations to generate functional networks, and analyzed them by graph theory. Control groups were trained in contextual fear conditioning, in which CS and US overlap. The CFC-5s training additionally activated subdivisions of the basolateral, lateral, and medial amygdala; prelimbic, infralimbic, perirhinal, postrhinal, and intermediate entorhinal cortices; ventral CA1 and subiculum. The CFC-5s network had increased amygdala centrality and higher amygdala internal and external connectivity with the retrosplenial cortex, thalamus, and hippocampus. Amygdala and thalamic nuclei were network hubs. Functional connectivity among these brain regions could support CS transient memories and their association.

Contextual fear conditioning with a time interval induces CREB phosphorylation in the dorsal hippocampus and amygdala nuclei that depend on prelimbic cortex activity.

In temporal associations, a conditioned stimulus (CS) is separated by a time interval from the unconditioned stimulus (US), which activates the prelimbic cortex (PL) to maintain a CS representation over time. However, it is unknown whether the PL participates, besides the encoding, in the memory consolidation, and thus directly, with activity-dependent changes or indirectly, by modulation of activity-dependent changes in other brain regions. We investigated brain regions supporting the consolidation of associations with intervals and the influence of PL activity in this consolidation process. For this, we observed in Wistar rats the effect of pre-training PL inactivation by muscimol in CREB (cAMP response element-binding protein) phosphorylation, which is essential for memory consolidation, in subdivisions of the medial prefrontal cortex (mPFC), hippocampus, and amygdala 3 h after the training in the contextual fear conditioning (CFC) or CFC with 5-s interval (CFC-5s), fear associations without or with an interval between the CS and US, respectively. Both the CFC-5s and CFC training increased phosphorylation of CREB in the PL and infralimbic cortex (IL); lateral (LA) and basolateral (BLA) amygdala; dorsal CA1 (dCA1); dorsal (dDG), and ventral dentate gyrus, and the CFC-5s training in the central amygdala (CEA). PL activity was necessary for the CREB phosphorylation in the PL, BLA, CEA, dCA1, and dDG only in animals trained in the CFC-5s. The cingulate cortex, ventral CA1, and ventral subiculum did not have learning-induced phosphorylation of CREB. These results suggest that the mPFC, hippocampus, and amygdala support the consolidation of associations with or without intervals and that PL activity influences consolidation in the dorsal hippocampus and amygdala in temporal associations. Thereby, the PL contributes directly and indirectly by modulation to memory consolidation. The time interval engaged the PL early in recent memory consolidation. Results expanded PL's role beyond the time interval and remote memory consolidation.

Effects of repeated ayahuasca administration on behaviour and c-Fos expression in male rats exposed to the open field.

Considering the long-lasting effects of ayahuasca on the brain and emotional processing, the objective of this study was to evaluate the behavioural and neurobiological effects of repeated ayahuasca administration in an animal model of exploratory behaviour related to novel-environment anxiety. Male Wistar rats received water, 120, 240, 480 or 3600 mg/kg of resuspended freeze-dried ayahuasca by gavage once a day for 30 days; there was also a non-manipulated homecage group. One hour after the last administration, animals were placed individually in the open field for 20 min. We analysed the weight gain, the behavioural response through a stochastic analysis, and c-Fos immunoreactive levels in the hippocampus, amygdala, pre-frontal and barrel field cortex. Ayahuasca at 120 mg/kg increased ambulation, and at 3600 mg/kg decreased vertical exploration and reduced weight gain. Aya3600 had higher c-Fos expression in regions of the hippocampus and infralimbic cortex than homecage, water or aya120 groups. Water-receiving animals had less c-Fos expression in the anterior basolateral amygdala than others groups. Our results show different behavioural effects of ayahuasca: a stimulant-like effect in small doses, and decreased activity in extreme high-dose, probably due to adverse effects. Higher activation of areas involved in emotional processing and the serotonergic pathway adds to the neurobiological literature on repeated/chronic ingestion of ayahuasca. Our data do not support an anxiolytic effect of repeated ayahuasca related to exploring new anxiogenic-environment but suggest that low ayahuasca doses should be further studied. The absence of severe impairment and behavioural syntax alteration reinforce ayahuasca safety.

Ayahuasca Lyophilization (Freeze-drying) Protocol with Pre- and Post-procedure Alkaloids Quantification.

Ayahuasca is a psychoactive brew from the decoction of different Amazonian plants, traditionally used in several cultures, religions, and rituals. Scientific studies with ayahuasca are rapidly increasing due to its subjective effects and therapeutic potential. Although ayahuasca is traditionally used in its liquid presentation, lyophilized (freeze-dried) ayahuasca is often used in scientific experimentation settings. However, there is no standard process or guideline to freeze-dry ayahuasca nor comparison of the chemical profile between the liquid and freeze-dried presentations. Therefore, we describe a reproducible five-day protocol for ayahuasca lyophilization with alkaloids quantification by liquid chromatography coupled to tandem mass spectrometry of both the liquid and the final freeze-dried ayahuasca. By the end of the protocol, approximately 295 g of freeze-dried extract with similar alkaloids concentration were obtained from two liters of ayahuasca (dry matter: 14.75 %). The final extract was stored for three years inside a vacuum desiccator (approximately 6°C) with its texture quality preserved. Further studies should address the impact of different storage conditions and the lyophilization on the alkaloids' quantity of the freeze-dried ayahuasca, especially the use of heat in regards to the ß-carbolines.

The dorsal subiculum is not necessary for step-through inhibitory avoidance acquisition and consolidation in rats.

The dorsal subiculum (DSub) has reciprocal connections with the dorsal hippocampus, and these regions play a role in spatial representation in contextual fear conditioning (CFC). Recently, we used AP5 and muscimol infusions to show that the DSub is required for CFC consolidation. The CFC component can be present in other learning tasks, such as step-through inhibitory avoidance (ST IA), which requires the dorsal hippocampus for acquisition and consolidation. This suggests that the DSub may be also involved in ST IA if the CFC component of the protocol is strong enough. Therefore, this study tested whether the DSub participates in ST IA acquisition and consolidation in male Wistar rats. Our data showed that pre-or posttraining infusions of AP5 or muscimol into the DSub did not affect ST IA acquisition and consolidation. We discuss the present results in relation to our previous findings, which showed the involvement of the DSub in CFC consolidation, and highlight some reasons that may explain the divergent results between the tasks. First, we note the possibility to escape from the unconditioned stimulus that occurs in ST IA, but not in CFC. We also suggest that the instrumental component of ST IA seems to be more prominent than the CFC one. Finally, we consider the possible influence of aspects of anxiety present in the ST IA, but not in CFC. These possible interpretations provide a broad framework in respect of the present results and raise new questions that demand further studies exploring the DSub function in inhibitory avoidance. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The effect of sleep medications on prospective and retrospective memory: a population-based study.

Sleep medications, especially benzodiazepines, are known to cause motor and cognitive impairments as side-effects from their use. However, an evaluation of the effects of sleep medications in general on prospective and retrospective memory remains to be seen. Thus, the effects of the different types of sleep medicines were assessed using the total score and the 8 subscales of the Prospective and Retrospective Memory Questionnaire (PRMQ) in a representative sample from the Municipality of São Paulo. The effects of each type of medication on these same parameters were evaluated afterwards. Each analysis was performed controlling for different covariates to observe their degree of interference on the observed results. Impairment due to use of sleep aid medication was observed in 6 of the 8 subscales, as well in the overall score of the PRMQ when compared to non-users. Prospective subscales were particularly affected, even when controlling for highly interfering covariates such as depression and anxiety, and objective sleep variables related to sleep architecture and wakefulness in the night. Few effects were detected between the various types of medication even when controlling for covariates, suggesting that a sample with higher power is necessary to conduct a more detailed analysis. Using pharmacological aids to improve sleep may impair prospective and (to some extent) retrospective memory. Therefore, the relationship between sleep impairment, memory deficits and medication use must be considered by physicians.

The dorsal subiculum is required for contextual fear conditioning consolidation in rats.

The hippocampal formation has a well-known role in contextual fear conditioning. The dorsal subiculum connects the hippocampus to the entorhinal cortex through pathways that seemingly rely on NMDA-dependent synaptic plasticity. The role of the dorsal subiculum in contextual fear conditioning retrieval, but not acquisition, has been previously reported. However, most of the critical biological phenomena involved in memory formation occur in the consolidation phase. The present study aimed to assess the effects of intra-dorsal subiculum muscimol or AP5 infusion on contextual fear conditioning consolidation. Our data show that dorsal subiculum integrity, as well as NMDA transmission in this region, seem to be necessary for contextual fear conditioning consolidation.

Functional interaction of ventral hippocampal CA1 region and prelimbic cortex contributes to the encoding of contextual fear association of stimuli separated in time.

Although stimuli that are associated often overlap in time, previous events can also predict the occurrence of a later aversive stimulus and be associated with it to better guide future behavior. Associations of stimuli separated in time have been studied using discrete stimulus as the conditioned stimulus (CS) in trace conditioning or, more recently in our lab, using the context as the CS in contextual fear conditioning with temporal discontinuity (CFC-5s), a task that simultaneously includes the processing of time and space components. It is thought that fear memories are encoded by the strengthening of synaptic connections in a distributed neural network. However, it is unclear how this temporal factor, which may differentially require the maintenance of the stimulus over time, affects the interactivity between brain regions to form the association. Because the prelimbic cortex (PL) and the hippocampus have been individually engaged in trace conditioning, they may functionally interact to encode associations separated in time. This is anatomically supported by direct ipsilateral projections from the ventral hippocampal CA1 region (vCA1) to PL. The aim of the present study was to investigate the effect of the functional disconnection of vCA1 and PL on CFC-5s using pre-training asymmetric reversible inactivation with muscimol. For comparison, we also observed its effect on contextual fear conditioning (CFC). Results showed that the functional disconnection impaired the encoding of the CFC-5s, an association of stimuli separated in time, while did not affect the CFC, an association of stimuli overlapped in time. In addition, the preserved connection in one hemisphere was sufficient to support the encoding of CFC-5s. The time interval by itself did not increase freezing responses and both CFC and CFC tasks had similar generalization and higher freezing responses than unconditioned groups. These findings suggest that the time factor alters the requirement of the interactivity of the brain regions underlying fear conditioning and extend the relevance of hippocampal-prefrontal interactions in memory.

Consequence of Two Protocols of Social Defeat Stress on Nicotine-Induced Psychomotor Effects in Mice.

Exposure to stress may contribute to enhanced vulnerability to drug use disorders, by altering sensitivity to drug-related reward and psychomotor effects. This study aimed to characterize the psychomotor effects of nicotine administration and then investigate the consequences of two types of repeated social defeat stress (episodic and continuous) on nicotine-induced psychomotor effects in mice. Adult male Swiss mice were treated for 13 days with daily injections of nicotine (0.1, 0.4, or 1.0 mg/kg, s.c.) and received saline and nicotine challenges (0, 0.1 and 0.4 mg/kg) after a withdrawal period. Dose-dependent effects were observed in locomotor response to nicotine, with trends for locomotor stimulation after intermittent (but not acute) administration of 0.1 mg/kg. Higher nicotine doses caused acute locomotor suppression (0.4 and 1.0 mg/kg) and tolerance after intermittent administration (0.4 mg/kg dose). In separate cohorts, experimental mice were daily defeated by aggressive mice, using the resident-intruder model, for 10 days. After brief confrontations, intruders returned to their home cage (episodic stress) or were continuously exposed to the aggressive resident for 24 h (continuous stress), until the following defeat. After the 10-day stress protocol, mice received saline and nicotine challenges (0 and 0.1 mg/kg, s.c.) in locomotor tests. Mice were also tested for methamphetamine-induced locomotor response (1.0 mg/kg, i.p.). Both defeat protocols induced short-term locomotor suppression (24h after stress), which was further suppressed by nicotine only in mice exposed to continuous defeat stress. Ten days after stress, locomotor behavior was no longer suppressed in defeated mice of either stress protocol. Mice exposed to continuous defeat stress showed a reduced stimulant response to methamphetamine, 12 days after termination of stress. Our findings indicate that exposure to continuous defeat stress facilitates nicotine-induced locomotor suppression shortly after stress and reduces methamphetamine-induced stimulation in the long term.

Involvement of the prelimbic cortex in contextual fear conditioning with temporal and spatial discontinuity.

Time plays an important role in conditioning, it is not only possible to associate stimuli with events that overlap, as in delay fear conditioning, but it is also possible to associate stimuli that are discontinuous in time, as shown in trace conditioning for a discrete stimuli. The environment itself can be a powerful conditioned stimulus (CS) and be associated to unconditioned stimulus (US). Thus, the aim of the present study was to determine the parameters in which contextual fear conditioning occurs by the maintenance of a contextual representation over short and long time intervals. The results showed that a contextual representation can be maintained and associated after 5s, even in the absence of a 15s re-exposure to the training context before US delivery. The same effect was not observed with a 24h interval of discontinuity. Furthermore, optimal conditioned response with a 5s interval is produced only when the contexts (of pre-exposure and shock) match. As the pre-limbic cortex (PL) is necessary for the maintenance of a continuous representation of a stimulus, the involvement of the PL in this temporal and contextual processing was investigated. The reversible inactivation of the PL by muscimol infusion impaired the acquisition of contextual fear conditioning with a 5s interval, but not with a 24h interval, and did not impair delay fear conditioning. The data provided evidence that short and long intervals of discontinuity have different mechanisms, thus contributing to a better understanding of PL involvement in contextual fear conditioning and providing a model that considers both temporal and contextual factors in fear conditioning.

M1 muscarinic receptors are necessary for retrieval of remote context fear memory.

Several studies have investigated the transition of consolidation of recent memory to remote memory in aversively motivated tasks, such as contextual fear conditioning (CFC) and inhibitory avoidance (IA). However, the mechanisms that serve the retrieval of remote memories, has not yet been fully understood. Some evidences suggest that the central cholinergic system appears be involved in the modulation of these processes. Therefore, the present study aimed to investigate the effects of a pre-test administration of dicyclomine, a high-affinity M1 muscarinic receptor antagonist, on the retrieval of remote memories in fear conditioning and IA tasks. Male Wistar rats were trained, and after 1 or 28days, the rats received dicyclomine (16 or 32mg/kg, intraperitoneally, i.p.) and were tested in CFC, tone fear conditioning (TFC) and IA tasks. At both time intervals, 32mg/kg dicyclomine induced impairment of CFC. In TFC task only the performance of the rats 28days after training was impaired. The IA task was not affected in any of the studied intervals. These findings suggest a differential contribution of muscarinic receptors on recent and remote memories retrieval revealing a more generalized role in remote memory.

Effects of the M1 muscarinic antagonist dicyclomine on emotional memory retrieval.

Extensive research has shown the involvement of the central cholinergic system in the acquisition and consolidation of tasks involving conditioned fear responses, such as those observed in contextual fear conditioning (CFC), tone fear conditioning (TFC) and inhibitory avoidance (IA). However, there are few data concerning the role of this system in the memory retrieval process. Therefore, the present study aimed to compare the effects of the administration of an M1 antagonist on retrieval during these tasks. For each behavioral procedure, groups of male Wistar rats were trained. Twenty-four hr later, they were treated with different doses of dicyclomine (16, 32, or 64 mg/kg, i.p.) or with saline 30 min before the test session. The results showed that dicyclomine at doses of 16 and 32 mg/kg impaired CFC without interfering with IA performance. Moreover, only 64 mg/kg impaired TFC. These data suggest that M1 muscarinic receptors contribute to memory retrieval in CFC and TFC but are not essential for retrieval in IA.

Effects of Long-Term Ayahuasca Administration on Memory and Anxiety in Rats.

Ayahuasca is a hallucinogenic beverage that combines the action of the 5-HT2A/2C agonist N,N-dimethyltryptamine (DMT) from Psychotria viridis with the monoamine oxidase inhibitors (MAOIs) induced by beta-carbonyls from Banisteriopsis caapi. Previous investigations have highlighted the involvement of ayahuasca with the activation of brain regions known to be involved with episodic memory, contextual associations and emotional processing after ayahuasca ingestion. Moreover long term users show better performance in neuropsychological tests when tested in off-drug condition. This study evaluated the effects of long-term administration of ayahuasca on Morris water maze (MWM), fear conditioning and elevated plus maze (EPM) performance in rats. Behavior tests started 48h after the end of treatment. Freeze-dried ayahuasca doses of 120, 240 and 480 mg/kg were used, with water as the control. Long-term administration consisted of a daily oral dose for 30 days by gavage. The behavioral data indicated that long-term ayahuasca administration did not affect the performance of animals in MWM and EPM tasks. However the dose of 120 mg/kg increased the contextual conditioned fear response for both background and foreground fear conditioning. The tone conditioned response was not affected after long-term administration. In addition, the increase in the contextual fear response was maintained during the repeated sessions several weeks after training. Taken together, these data showed that long-term ayahuasca administration in rats can interfere with the contextual association of emotional events, which is in agreement with the fact that the beverage activates brain areas related to these processes.

Early postnatal nociceptive stimulation results in deficits of spatial memory in male rats.

Prematurely-born infants are exposed to multiple invasive procedures while in the intensive care unit. Newborn rats and humans have similar behavioral responses to noxious stimulation. Previous studies have shown that early noxious stimuli may alter dentate gyrus neurogenesis and the behavioral repertoire of adult rats. We evaluated the late effects of noxious stimulation administered during different phases of development on two spatial memory tests; object recognition (OR) and Morris water maze (WM) tests. Noxious stimulation was induced by an intra-plantar injection of complete Freund's adjuvant (CFA) on postnatal (P) day 1 (group P1) or 8 (P8). Control animals were not stimulated. Behavioral tests were conducted on P60 in both male and female animals. In the WM, three domains were evaluated: acquisition, probe trial performance and reversal re-acquisition. The number of Nissl stained cells in the dentate granule cell layer was assessed by stereological counting. The OR test revealed that P1 male rats had poor long-term memory compared to the control and P8 groups. In the WM, no short- or long-term memory differences were detected between early postnatal-stimulated male and female rats and their respective controls. However, the ability to find the hidden platform in a new position was reduced in P1 male rats. The number of dentate granule cells in P8 males was higher than in all other groups. This study demonstrates that noxious stimulation on P1 results in spatial learning deficits in male animals, but does not disrupt the development of the hippocampus-dependent strategies of learning and memory.

Chronic intermittent hypoxia increases encoding pigment epithelium-derived factor gene expression, although not that of the protein itself, in the temporal cortex of rats.

OBJECTIVE: Obstructive sleep apnea syndrome is mainly characterized by intermittent hypoxia (IH) during sleep, being associated with several complications. Exposure to IH is the most widely used animal model of sleep apnea, short-term IH exposure resulting in cognitive and neuronal impairment. Pigment epithelium-derived factor (PEDF) is a hypoxia-sensitive factor acting as a neurotrophic, neuroprotective, and antiangiogenic agent. Our study analyzed performance on learning and cognitive tasks, as well as PEDF gene expression and PEDF protein expression in specific brain structures, in rats exposed to long-term IH. METHODS: Male Wistar rats were exposed to IH (oxygen concentrations of 21-5%) for 6 weeks-the chronic IH (CIH) group-or normoxia for 6 weeks-the control group. After CIH exposure, a group of rats were allowed to recover under normoxic conditions for 2 weeks (the CIH+N group). All rats underwent the Morris water maze test for learning and memory, PEDF gene expression and PEDF protein expression in the hippocampus, frontal cortex, and temporal cortex being subsequently assessed. RESULTS: The CIH and CIH+N groups showed increased PEDF gene expression in the temporal cortex, PEDF protein expression remaining unaltered. PEDF gene expression and PEDF protein expression remained unaltered in the frontal cortex and hippocampus. Long-term exposure to IH did not affect cognitive function. CONCLUSIONS: Long-term exposure to IH selectively increases PEDF gene expression at the transcriptional level, although only in the temporal cortex. This increase is probably a protective mechanism against IH-induced injury.

OBJETIVO: A síndrome da apneia obstrutiva do sono caracteriza-se principalmente por episódios de hipóxia intermitente (HI) durante o sono e associa-se a diversas complicações. A exposição à HI é o mais usado modelo animal de apneia do sono, e protocolos de curta duração causam diversos prejuízos cognitivos e neuronais. Pigment epithelium-derived factor (PEDF, fator derivado do epitélio pigmentado) é um fator neurotrófico, neuroprotetor e antiangiogênico sensível à hipóxia celular. Nosso estudo analisou o desempenho em tarefas cognitivas e de aprendizagem, bem como a expressão do gene PEDF e da proteína PEDF em estruturas cerebrais específicas em ratos expostos a HI de longa duração. MÉTODOS: Ratos Wistar foram expostos a HI (21-5% de oxigênio) durante 6 semanas - o grupo HI crônica (HIC) - ou a normóxia durante 6 semanas - o grupo controle. Após a exposição à HIC, um grupo de ratos foi exposto a normóxia durante 2 semanas (o grupo HIC+N). Todos os animais foram submetidos ao labirinto aquático de Morris para avaliação de memória e aprendizado; avaliou-se também a expressão do gene PEDF e da proteína PEDF no hipocampo e nos córtices frontal e temporal. RESULTADOS: Os grupos HIC e HIC+N apresentaram um aumento de expressão do gene PEDF no córtex temporal, porém sem aumento dos níveis proteicos. A expressão do gene PEDF e da proteína PEDF manteve-se inalterada nas demais estruturas. A exposição de longa duração à HI não afetou a função cognitiva. CONCLUSÕES: A exposição de longa duração à HI aumenta seletivamente a expressão do gene PEDF ao nível transcricional, embora apenas no córtex temporal. Esse aumento é provavelmente um mecanismo de proteção contra a HI.

Chronic intermittent hypoxia increases encoding pigment epithelium-derived factor gene expression, although not that of the protein itself, in the temporal cortex of rats, / Hipóxia intermitente crônica aumenta a expressão gênica, mas não proteica, de pigment epithelium-derived factor no córtex temporal de ratos

Objective: Obstructive sleep apnea syndrome is mainly characterized by intermittent hypoxia (IH) during sleep, being associated with several complications. Exposure to IH is the most widely used animal model of sleep apnea, short-term IH exposure resulting in cognitive and neuronal impairment. Pigment epithelium-derived factor (PEDF) is a hypoxia-sensitive factor acting as a neurotrophic, neuroprotective, and antiangiogenic agent. Our study analyzed performance on learning and cognitive tasks, as well as PEDF gene expression and PEDF protein expression in specific brain structures, in rats exposed to long-term IH. Methods: Male Wistar rats were exposed to IH (oxygen concentrations of 21-5%) for 6 weeks-the chronic IH (CIH) group-or normoxia for 6 weeks-the control group. After CIH exposure, a group of rats were allowed to recover under normoxic conditions for 2 weeks (the CIH+N group). All rats underwent the Morris water maze test for learning and memory, PEDF gene expression and PEDF protein expression in the hippocampus, frontal cortex, and temporal cortex being subsequently assessed. Results: The CIH and CIH+N groups showed increased PEDF gene expression in the temporal cortex, PEDF protein expression remaining unaltered. PEDF gene expression and PEDF protein expression remained unaltered in the frontal cortex and hippocampus. Long-term exposure to IH did not affect cognitive function. Conclusions: Long-term exposure to IH selectively increases PEDF gene expression at the transcriptional level, although only in the temporal cortex. This increase is probably a protective mechanism against IH-induced injury. .

Objetivo: A síndrome da apneia obstrutiva do sono caracteriza-se principalmente por episódios de hipóxia intermitente (HI) durante o sono e associa-se a diversas complicações. A exposição à HI é o mais usado modelo animal de apneia do sono, e protocolos de curta duração causam diversos prejuízos cognitivos e neuronais. Pigment epithelium-derived factor (PEDF, fator derivado do epitélio pigmentado) é um fator neurotrófico, neuroprotetor e antiangiogênico sensível à hipóxia celular. Nosso estudo analisou o desempenho em tarefas cognitivas e de aprendizagem, bem como a expressão do gene PEDF e da proteína PEDF em estruturas cerebrais específicas em ratos expostos a HI de longa duração. Métodos: Ratos Wistar foram expostos a HI (21-5% de oxigênio) durante 6 semanas - o grupo HI crônica (HIC) - ou a normóxia durante 6 semanas - o grupo controle. Após a exposição à HIC, um grupo de ratos foi exposto a normóxia durante 2 semanas (o grupo HIC+N). Todos os animais foram submetidos ao labirinto aquático de Morris para avaliação de memória e aprendizado; avaliou-se também a expressão do gene PEDF e da proteína PEDF no hipocampo e nos córtices frontal e temporal. Resultados: Os grupos HIC e HIC+N apresentaram um aumento de expressão do gene PEDF no córtex temporal, porém sem aumento dos níveis proteicos. A expressão do gene PEDF e da proteína PEDF manteve-se inalterada nas demais estruturas. A exposição de longa duração à HI não afetou a função cognitiva. Conclusões: A exposição de longa duração à HI aumenta seletivamente a expressão do gene PEDF ao nível transcricional, embora apenas no córtex temporal. Esse aumento é provavelmente um mecanismo de proteção contra a HI. .

Effects of sleep deprivation on different phases of memory in the rat: dissociation between contextual and tone fear conditioning tasks.

Numerous studies show that sleep deprivation (SD) impacts negatively on cognitive processes, including learning and memory. Memory formation encompasses distinct phases of which acquisition, consolidation and retrieval are better known. Previous studies with pre-training SD induced by the platform method have shown impairment in fear conditioning tasks. Nonetheless, pre-training manipulations do not allow the distinction between effects on acquisition and/or consolidation, interfering, ultimately, on recall of/performance in the task. In the present study, animals were first trained in contextual and tone fear conditioning (TFC) tasks and then submitted to SD with the purpose to evaluate the effect of this manipulation on different stages of the learning process, e.g., in the uptake of (new) information during learning, its encoding and stabilization, and the recall of stored memories. Besides, we also investigated the effect of SD in the extinction of fear memory and a possible state-dependent learning induced by this manipulation. For each task (contextual or TFC), animals were trained and then distributed into control, not sleep-deprived (CTL) and SD groups, the latter being submitted to the modified multiple platform paradigm for 96 h. Subsets of eight rats in each group/experiment were submitted to the test of the tasks, either immediately or at different time intervals after SD. The results indicated that (a) pre- but not post-training SD impaired recall in the contextual and TFC; (b) this impairment was not state-dependent; and (c) in the contextual fear conditioning (CFC), pre-test SD prevented extinction of the learned task. Overall, these results suggest that SD interferes with acquisition, recall and extinction, but not necessarily with consolidation of emotional memory.