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OBJECTIVES: In view of the neuroprotective characteristic of cannabidiol (CBD) and its beneficial action on aversive memory in non-diabetic animals, we aimed to investigate in animals with experimentally induced type-1 diabetes mellitus (T1DM) whether CBD treatment would be able to impair the contextual fear memory consolidation, its generalisation and whether the effect would be lasting. We also investigated the CBD effect on anxiety-like responses. METHODS: After T1DM induction, animals received single or more prolonged treatment with CBD and were submitted to the contextual fear conditioning test. As expression of activity-regulated cytoskeletal-associated (Arc) protein is necessary for memory consolidation, we evaluated its expression in the dorsal hippocampus (DH). For evaluating anxiety-related responses, animals were submitted to the elevated plus maze test (EPMT), in which the time and number of entries in the open arms were used as anxiety index. RESULTS: A single injection of CBD impaired the contextual fear memory consolidation and its generalisation, which was evaluated by exposing the animal in a neutral context. This single injection was able to reduce the elevated expression of Arc in the DH from these animals. Interestingly, more prolonged treatment with CBD also impaired the persistence of context-conditioned fear memory and induced an anxiolytic-like effect, as the treated group spent more time in the open arms of the EPMT. CONCLUSION: CBD interferes with contextual fear memory and the dosage regimen of treatment seems to be important. Moreover, we cannot rule out the involvement of emotional aspects in these processes related to fear memory.

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Methylmercury (MeHg) is a potent neurotoxic chemical, and gestational exposure to MeHg is known to cause developmental impairments in fetuses. Although it is well established that fetuses are extremely susceptible to MeHg toxicity, limited studies have investigated the effect of low-level MeHg exposure on mothers. In this study, we demonstrated that exposure of pregnant rats to low-level MeHg (1 ppm in drinking water) induced cerebellar synaptic and neuritic remodeling during the perinatal period between gestational day 20 and postnatal day (PND) 1. MeHg-induced neurodegeneration, for example, cerebellar granule cell death, was not detected and fetuses were delivered normally and exhibited normal development. The maternal cerebellar synaptic and neuritic changes were restored by PND 21. To elucidate the mechanisms underlying these perinatal changes in MeHg-exposed pregnant rats, we investigated proteins related to synapse formation and neurite outgrowth. We identified suppression of the tropomyosin receptor kinase (Trk) A pathway and reduced activity-regulated cytoskeleton-associated protein (Arc) expression in MeHg-exposed pregnant rats during the perinatal period, mirroring the decreased expression of synaptic and neuritic proteins. MeHg-exposed pregnant rats also exhibited increased perinatal plasma corticosterone levels and decreased estradiol levels compared to vehicle-exposed pregnant rats. Similar to the synaptic and neuritic changes, TrkA pathway activity, Arc expression, and plasma hormone levels were subsequently normalized. These results suggest that exposure of pregnant rats to low-level MeHg affected perinatal cerebellar synaptic and neuritic remodeling through modulation of the TrkA pathway and Arc expression which may be caused by MeHg-induced hormonal changes.

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The subiculum and the lateral entorhinal cortex (LEC) are the main output areas of the hippocampus which contribute to spatial and non-spatial memory. The proximal part of the subiculum (bordering CA1) receives heavy projections from the perirhinal cortex and the distal part of CA1 (bordering the subiculum), both known for their ties to object recognition memory. However, the extent to which the proximal subiculum contributes to non-spatial memory is still unclear. Comparatively, the involvement of the LEC in non-spatial information processing is quite well known. However, very few studies have investigated its role within the frame of memory function. Thus, it is not known whether its contribution depends on memory load. In addition, the deep layers of the EC have been shown to be predictive of subsequent memory performance, but not its superficial layers. Hence, here we tested the extent to which the proximal part of the subiculum and the superficial and deep layers of the LEC contribute to non-spatial memory, and whether this contribution depends on the memory load of the task. To do so, we imaged brain activity at cellular resolution in these areas in rats performing a delayed nonmatch to sample task based on odors with two different memory loads (5 or 10 odors). This imaging technique is based on the detection of the RNA of the immediate-early gene Arc, which is especially tied to synaptic plasticity and behavioral demands, and is commonly used to map activity in the medial temporal lobe. We report for the first time that the proximal part of the subiculum is recruited in a memory-load dependent manner and the deep layers of the LEC engaged under high memory load conditions during the retrieval of non-spatial memory, thus shedding light on the specific networks contributing to non-spatial memory retrieval.

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Our earlier report on scopolamine-induced amnesia and its improvement by pre-treatment with i-Extract (alcoholic extract of Ashwagandha leaf) suggested that the i-Extract mediated nootropic effect may involve neuronal immediate early gene, Arc. With a hypothesis that the i-Extract induced expression of Arc protein may cause augmentation in Arc function, we examined the effect of i-extract on a major function of Arc protein, i.e. F-actin expansion, using Arc antisense oligodeoxynucleotides (ODN). Stereotaxic infusion of Arc antisense ODN in the CA1 region of hippocampus decreased the level of Arc protein as demonstrated by immunoblotting. However, this decrease was attenuated when treated with i-Extract prior to infusion of Arc antisense ODN. We noted a significant decrease in the polymerization of F-actin during scopolamine-induced amnesia as well as Arc antisense ODN infusion that was restored rather enhanced when pre-treated with i-Extract in both the cases. We also compared the corresponding changes between CA1 (the infusion site) and CA3 (neighbouring site of infusion) regions of hippocampus, and found more pronounced effects in CA1 than in the CA3 region. The extent of F-actin polymerization, as revealed by changes in the dendritic spine architecture through Golgi staining, showed that both scopolamine as well as Arc antisense ODN disrupted the spine density and mushroom-shaped morphology that was again regained if pre-treated with i-Extract. In conclusion, the findings reveal that the Arc helps in polymerization of F-actin and subsequent changes in the morphology of dendritic spines after pre-treatment with i-Extract in scopolamine-induced amnesic mice, suggesting an important role of Arc in scopolamine-induced amnesia and its recovery by i-Extract.

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Norepinephrine is released in the amygdala following negatively arousing learning conditions. This event initiates a cascade of changes including the transcription of activity-regulated cytoskeleton-associated protein (Arc) expression, an early-immediate gene associated with memory encoding. Recent evidence suggests that the valence of emotionally laden encounters may generate lateralized, as opposed to symmetric release of this transmitter in the right or left amygdala. It is currently not clear if valence-induced patterns of selective norepinephrine output across hemispheres are also reproduced in downstream pathways of cellular signaling necessary for memory formation. This question was addressed by determining if Arc expression is differentially distributed across the right and left amygdala following exposure to positively or negatively valenced learning conditions respectively. Male Sprague Dawley rats were randomly assigned to groups exposed to the Homecage only, five auditory tones only, or five auditory tones paired with footshock (0.35 mA) during Pavlovian fear conditioning. Western blot analysis revealed that Arc expression in the right amygdala was elevated significantly above that observed in the left amygdala 60 and 90 min following fear conditioning. Similarly, subjects exposed to a negatively valenced outcome consisting of an unexpected reduction in food rewards showed a greater level of Arc expression in only the right, but not left basolateral amygdala. Presenting a positively valenced event involving an unexpected increase in food reward magnitude following bar pressing, resulted in significantly greater Arc expression in the left, but not right basolateral amygdala (p < 0.01). These findings indicate that the valence of emotionally arousing learning conditions is reflected at later stages of synaptic plasticity involving the transcription of immediate early genes such as Arc.