Repeated exposure to ethanol alters memory acquisition and neurotransmission parameters in zebrafish brain.

Alcohol is widely consumed worldwide and its abuse can cause cognitive dysfunction, affecting memory and learning due to several neurophysiological changes. An imbalance in several neurotransmitters, including the cholinergic and glutamatergic systems, have been implicated in these effects. Zebrafish are sensitive to alcohol, respond to reward stimuli, and tolerate and exhibit withdrawal behaviors. Therefore, we investigated the effects of repetitive exposure to ethanol (REE) and the NMDA receptor antagonist dizocilpine (MK-801) on memory acquisition and glutamatergic and cholinergic neurotransmission. Memory was assessed using the inhibitory avoidance and object recognition tasks. Brain glutamate levels and the activity of Na+-dependent transporters were evaluated as indexes of glutamatergic activity, while acetylcholinesterase (AChE) and choline acetyltransferase (ChAT), enzyme activity were evaluated as indexes of cholinergic activity. Behavioral assessments showed that REE impaired aversive and spatial memory, an effect that MK-801 mimicked. Glutamate levels, but not transporter activity, were significantly lower in the REE group; similarly, REE increased the activity of AChE, but not ChAT, activity. These findings suggest that intermittent exposure to ethanol leads to impairments in zebrafish memory consolidation, and that these effects could be associated with alterations in parameters related to neurotransmission systems mediated by glutamate and acetylcholine. These results provide a better understanding of the neurophysiological and behavioral changes caused by repetitive alcohol use.

Impacts of linseed oil diet on anxiety and memory extinction after early life stress: A sex-specific analysis of mitochondrial dysfunction, astrocytic markers, and inflammation in the amygdala.

Early exposure to stressors affects how the organism reacts to stimuli, its emotional state throughout life, and how it deals with emotional memories. Consequently, it may affect susceptibility to psychopathology later in life. We used an animal model of early stress by maternal separation to study its potential impact on the extinction of aversive memories and anxiety-like behavior in adulthood, as well as its effects on mitochondrial functionality, inflammatory and astrocytic markers in the amygdala. We also assessed whether a diet enriched with linseed oil, known for its high content in omega-3 fats, could be used to attenuate the behavioral and neurochemical effects of early stress. Litters of Wistar rats were divided into controls (intact) or subjected to maternal separation (MS). They were subdivided into two groups receiving isocaloric diets enriched in soy or linseed oils at weaning. In adulthood, the animals were exposed to the open field and the elevated plus maze, to evaluate exploratory activity and anxiety-like behavior. They were also trained in a context of fear conditioning, and afterward subjected to an extinction session, followed by a test session to evaluate the extinction memory. Amygdalae were evaluated for inflammatory cytokines (interleukin (IL)-1beta, IL-6, and tumor-necrose factor (TNF)-alpha), mitochondrial functionality, and astrocyte markers (glial fibrillary acidic protein - GFAP, S100B, and glutamine synthetase activity). MS induced anxiety-like behavior in the elevated plus-maze, which was reversed by a diet enriched in linseed oil offered from weaning. When testing the memory of an extinction session of fear conditioning, MS animals showed more freezing behavior. MS males receiving a linseed oil-enriched diet had lower functional mitochondria in the amygdala. In addition, MS led to increased inflammatory cytokines, particularly IL-1beta, and the diet enriched in linseed oil further increased these levels in MS animals. MS also increased S100B levels. These results point to a higher emotionality presented by MS animals, with higher levels of inflammatory cytokines and S100B. While a diet enriched in linseed oil attenuated anxiety-like behavior, it further altered amygdala IL-1beta and reduced mitochondria functionality, particularly in males. MS also increased glutamine synthetase activity in the amygdala, and this effect was higher when the animals received a diet enriched in linseed oil, particularly in females. In conclusion, these results point to MS effects on emotional behavior, and neurochemical alterations in the amygdala, with sex-specific effects. Although a diet enriched in linseed oil appears to be able to reverse some of MS behavioral effects, these results must be considered with caution, since biochemical parameters could be worsened in MS animals receiving a linseed oil-enriched diet. This knowledge is important for the understanding of mechanisms of action of strategies aiming to reverse early stress effects, and future studies are warranted to determine possible interventions to promote resilience.

Acute glyphosate and aminomethylphosphonic acid (AMPA), its major metabolite, impaired spatial orientation, navigation, learning and/or memory in female rats.

Human exposure to glyphosate-based herbicides (GBH) has been associated with a range of toxicological effects involving the central nervous system (CNS) such as alterations in learning and memory. Nevertheless, the effects of aminomethylphosphonic acid (AMPA), the main metabolite of glyphosate, remain essentially obscure. Previous preclinical reports suggest that acute intoxication with AMPA and glyphosate exerts decrease on hippocampal acetylcholinesterase activity and produces more metabolomic alterations in the female brain over the male one. Therefore, this work explored the effects of acute AMPA and glyphosate on spatial learning, memory and navigation in female rats. Sprague Dawley rats received a single injection (i.p.) of: (i) vehicle; (ii) 10 or 100 mg/kg of AMPA; or (iii) 10 or 100 mg/kg of glyphosate; subsequently, the Barnes maze paradigm was performance. Animals from the control group decreased latency and the attempts to solve the Barnes maze; and increased the degree of orientation when compared first training sessions (S1) vs. the last one (S4; p < 0.05). In contrast, both 10 and 100 mg/kg of glyphosate and 100 mg/kg of AMPA prevented the decrease in latency and attempts; and the increase of orientation (p > 0.05; S1 vs. S4). Both treatments decreased the use of the spatial navigation strategy (p < 0.05). Besides, glyphosate at the higher dose but not AMPA impaired the spatial memory during the test. Our findings suggest that acute exposure to glyphosate and AMPA similarly affected spatial orientation, navigations, learning and/or memory.

Macaiba palm pulp (Acrocomia intumescens Drude) improves memory and induces anxiolytic-like behavior in dyslipidemic rats.

Macaiba pulp is a source of bioactive compounds. This study aimed to evaluate the effects of macaiba pulp on anxiety behavior, memory and brain oxidative stress in dyslipidemic rats. The animals were divided into four groups (n = 10): Control (CG), Macaíba (MG), Dyslipidemic (DG) and Dyslipidemic Macaiba (DMG). Animals from the DG and DMG were induced to dyslipidemia consuming a high fatty emulsion for 14 days before treatment with macaiba pulp. During treatment the MG and DMG received the macaiba pulp (1 g/kg body weight) for 28 days. The rats were evaluated with the open field (OFT) and elevated plus maze (EPM) tests to measure anxiety-like behavior; memory was evaluated using the object recognition test (ORT). After euthanasia, the fatty acid profile of the animals' brain tissue was measured and the levels of malondialdehyde (MDA) and total glutathione (GSH) were quantified. The data were evaluated using one-way ANOVA followed by the Tukey (p < 0.05) test. Both groups (MG and DMG) that consumed the macaiba pulp showed anxiolytic-like behavior for parameters of grooming, rearing and ambulation in the OFT test and time in the center and time and entries in the open arms in the EMP test; The MG and DMG groups increased exploration rate in the ORT. The DMG showed a reduction in MDA levels (p < 0.05); however, MG and DMG had decreased in GSH (p < 0.05). The results showed that macaiba pulp consumption induces anxiolytic-like behavior and reduces brain oxidative damage in dyslipidemic animals, and improves memory in healthy and dyslipidemic rats.

Harmful Effects on the Hippocampal Morpho-Histology and on Learning and Memory in the Offspring of Rats with Streptozotocin-Induced Diabetes.

Learning alterations in the child population may be linked to gestational diabetes as a causal factor, though this remains an open and highly controversial question. In that sense, it has been reported that maternal hyperglycemia generates a threatening condition that affects hippocampal development in offspring. The pyramidal cells of the CA3 subfield, a key structure in learning and memory processes, are particularly important in cognitive deficiencies. We evaluate the effect of the hyperglycemic intrauterine environment on hippocampal histomorphometry in offspring, correlating it with spatial learning and memory, as well as the morphology of dendrites and spines in 30-day-old pups (P30). The maternal hyperglycemia affected the body weight, height, and brain size of fetuses at 21 days of gestation (F21), newborn pups (P0) and P30 pups from diabetic rats, which were smaller compared to the control group. Consequently, this resulted in a decrease in hippocampal size, lower neuronal density and cytoarchitectural disorganization in the CA3 region of the hippocampus in the offspring at the three ages studied. The behavioral tests performed showed a direct relationship between morpho-histological alterations and deficiencies in learning and memory, as well as alterations in the morphology of the dendrites and spines. Therefore, knowing the harmful effects caused by gestational diabetes can be of great help to establish therapeutic and educational strategies that can help to improve learning and memory in children.

Acute exercise performed during the late consolidation phase improves memory persistence by hippocampal protein synthesis and catecholamine modulation.

Memory persistence is a crucial aspect of long-term memory (LTM) and involves late consolidation processes that modulate memory stability over time. Acute physical exercise (PE) has emerged as a potential strategy to modulate memory consolidation and enhance memory persistence. While its effects have been extensively explored in the early consolidation phase, its impact on the late phase remains unexplored. In this study, we investigated the effects and mechanisms of an acute PE on the late consolidation window of novel object recognition (NOR) memory in rats. A 30-minute running session applied 11 h after NOR memory acquisition significantly increased memory persistence for at least 7 days. The inhibition of hippocampal protein synthesis immediately after acute PE using anisomycin (a ribosomal inhibitor) or rapamycin (an mTOR pathway inhibitor) impaired the effect of PE on memory persistence. Animals only presented memory 1 day after acquisition. The same effect was observed with the inhibition of beta-adrenergic receptors by timolol. Although there were no differences between the groups' comparison, blocking D1/D5 receptors after acute PE resulted in a lack of memory persistence in the dichotomous testing (remember/non-remember). Therefore, our exploration of the mechanisms underlying this enhancement revealed the involvement of protein synthesis and the requirement of beta-adrenergic and dopaminergic D1/D5 receptors in the dorsal hippocampus. These findings provide valuable insights into PE as a potential memory modulator, contributing to expanding our understanding of memory consolidation dynamics and acute PE effects.

Footshock drives remodeling of perineuronal nets in retrosplenial cortex during contextual fear memory formation.

The retrosplenial cortex (RSC) plays a critical role in complex cognitive functions such as contextual fear memory formation and consolidation. Perineuronal nets (PNNs) are specialized structures of the extracellular matrix that modulate synaptic plasticity by enwrapping the soma, proximal neurites and synapsis mainly on fast spiking inhibitory GABAergic interneurons that express parvalbumin (PV). PNNs change after contextual fear conditioning (CFC) in amygdala or hippocampus, yet it is unknown if similar remodeling takes place at RSC. Here, we used Wisteria floribunda agglutinin (WFA), a ubiquitous marker of PNNs, to study the remodeling of PNNs in RSC during the acquisition or retrieval of contextual fear conditioning (CFC). Adult male mice were exposed to paired presentations of a context and footshock, or to either of these stimuli alone (control groups). The mere exposure of animals to the footshock, either alone or paired with the context, evoked a significant expansion of PNNs, both in the number of WFA positive neurons and in the area occupied by WFA staining, across the entire RSC. This was not associated with c-Fos expression in RSC nor correlated with c-Fos expression in individual PNNs-expressing neurons in RSC, suggesting that PNNs remodeling is triggered by inputs external to the RSC. We also found that PNNs remodeling was independent of the level of PV expression. Notably, PNNs in RSC remained expanded long-after CFC. These results suggest that, in male mice, the threatening experience is the main cause of PNNs remodeling in the RSC.

The role of the claustrum in the acquisition, consolidation and reconsolidation of memories in mice.

The claustrum is a brain structure that remains shrouded in mystery due to the limited understanding of its cellular structure, neural pathways, functionality and physiological aspects. Significant research has unveiled connections spanning from the claustrum to the entire cortex as well as subcortical areas. This widespread connectivity has led to speculations of its role in integrating information from different brain regions, possibly contributing to processes such as attention, consciousness, learning and memory. Our working hypothesis posits that claustrum neural activity contributes to the acquisition, consolidation and reconsolidation of long-term memories in mice. We found evidence in CF-1 mice of a decline in behavioral performance in an inhibitory avoidance task due to intra-claustral administration of 2% lidocaine immediately after a training session or memory recall. Nevertheless, this does not seem to be the case for the acquisition or retrieval of this type of memory, although its neural activity is significantly increased after training, evaluated through c-Fos expression. Moreover, inhibition of the claustrum's synaptic activity appears to impair the consolidation but not acquisition or retrieval of an unconditioned memory formed in a nose-poke habituation task.

Stimulus intensity and temporal configuration interact during bimodal learning and memory in honey bees.

Multimodal integration is a core neural process with a keen relevance during ecological tasks requiring learning and memory, such as foraging. The benefits of learning multimodal signals imply solving whether the components come from a single event. This challenge presumably depends on the timing and intensity of the stimuli. Here, we used simultaneous and alternate presentations of olfactory and visual stimuli, at low and high intensities, to understand how temporal and intensity variations affect the learning of a bimodal stimulus and its components. We relied on the conditioning of the proboscis extension response (PER) to train honey bees to an appetitive learning task with bimodal stimuli precisely controlled. We trained bees to stimuli with different synchronicity and intensity levels. We found that synchronicity, order of presentation, and intensity significantly impacted the probability of exhibiting conditioned PER responses and the latency of the conditioned responses. At low intensities, synchronous bimodal inputs produced maximal multisensory enhancement, while asynchronous temporal orders led to lower performances. At high intensities, the relative advantage of the synchronous stimulation diminished, and asynchronous stimuli produced similar performances. Memory retention was higher for the olfactory component and bimodal stimuli compared to the visual component, irrespective of the training's temporal configuration. Bees retained the asynchronous bimodal configuration to a lesser extent than the synchronous one, depending on the stimulus intensity. We conclude that time (synchrony), order of presentation, and intensity have interdependent effects on bee learning and memory performance. This suggests caution when assessing the independent effects of each factor.

El rol del sueño REM en la memoria emocional: "Dormir para recordar y dormir para olvidar2 / The role of REM sleep in emotional memory: "Sleep to remember and sleep to forget"

El sueño es vital para los seres vivos. Está estrechamente relacionado con la maduración del cerebro y sus funciones. Se divide en dos tipos principales: sueño REM con movimientos oculares rápidos y NREM sin movimientos oculares rápidos; este último se divide actualmente en tres etapas N1, N2 y N3 (correspondientes a una mayor profundidad del sueño). En esta revisión nos centraremos en el sueño REM y en cómo este estado cerebral único permite la integración de emociones moduladas por memorias neo-corticales, previamente consolidadas durante el sueño NREM. Palabras clave: Sueño REM, codificación, acetilcolina, memoria emocional.

Summary. Sleep is vital for living beings. It is closely related to brain maturation and its functions. It is divided into two main types: REM sleep with rapid eye movements and NREM without rapid eye movements; the latter is currently divided into three stages N1, N2 and N3 (corresponding to greater depth of sleep). In this review we will focus on REM sleep and how this unique brain state allows the integration of emotions modulated by neocortical memories, previously consolidated during NREM sleep. Keywords: REM sleep, encoding, acetylcholine, emotional memory.

Unveiling a novel memory center in human brain: neurochemical identification of the nucleus incertus, a key pontine locus implicated in stress and neuropathology.

BACKGROUND: The nucleus incertus (NI) was originally described by Streeter in 1903, as a midline region in the floor of the fourth ventricle of the human brain with an 'unknown' function. More than a century later, the neuroanatomy of the NI has been described in lower vertebrates, but not in humans. Therefore, we examined the neurochemical anatomy of the human NI using markers, including the neuropeptide, relaxin-3 (RLN3), and began to explore the distribution of the NI-related RLN3 innervation of the hippocampus. METHODS: Histochemical staining of serial, coronal sections of control human postmortem pons was conducted to reveal the presence of the NI by detection of immunoreactivity (IR) for the neuronal markers, microtubule-associated protein-2 (MAP2), glutamic acid dehydrogenase (GAD)-65/67 and corticotrophin-releasing hormone receptor 1 (CRHR1), and RLN3, which is highly expressed in NI neurons in diverse species. RLN3 and vesicular GABA transporter 1 (vGAT1) mRNA were detected by fluorescent in situ hybridization. Pons sections containing the NI from an AD case were immunostained for phosphorylated-tau, to explore potential relevance to neurodegenerative diseases. Lastly, sections of the human hippocampus were stained to detect RLN3-IR and somatostatin (SST)-IR. RESULTS: In the dorsal, anterior-medial region of the human pons, neurons containing RLN3- and MAP2-IR, and RLN3/vGAT1 mRNA-positive neurons were observed in an anatomical pattern consistent with that of the NI in other species. GAD65/67- and CRHR1-immunopositive neurons were also detected within this area. Furthermore, RLN3- and AT8-IR were co-localized within NI neurons of an AD subject. Lastly, RLN3-IR was detected in neurons within the CA1, CA2, CA3 and DG areas of the hippocampus, in the absence of RLN3 mRNA. In the DG, RLN3- and SST-IR were co-localized in a small population of neurons. CONCLUSIONS: Aspects of the anatomy of the human NI are shared across species, including a population of stress-responsive, RLN3-expressing neurons and a RLN3 innervation of the hippocampus. Accumulation of phosphorylated-tau in the NI suggests its possible involvement in AD pathology. Further characterization of the neurochemistry of the human NI will increase our understanding of its functional role in health and disease.

Retrieval of contextual memory can be predicted by CA3 remapping and is differentially influenced by NMDAR activity in rat hippocampus subregions.

Episodic memory is essential to navigate in a changing environment by recalling past events, creating new memories, and updating stored information from experience. Although the mechanisms for acquisition and consolidation have been profoundly studied, much less is known about memory retrieval. Hippocampal spatial representations are key for retrieval of contextually guided episodic memories. Indeed, hippocampal place cells exhibit stable location-specific activity which is thought to support contextual memory, but can also undergo remapping in response to environmental changes. It is unclear if remapping is directly related to the expression of different episodic memories. Here, using an incidental memory recognition task in rats, we showed that retrieval of a contextually guided memory is reflected by the levels of CA3 remapping, demonstrating a clear link between external cues, hippocampal remapping, and episodic memory retrieval that guides behavior. Furthermore, we describe NMDARs as key players in regulating the balance between retrieval and memory differentiation processes by controlling the reactivation of specific memory traces. While an increase in CA3 NMDAR activity boosts memory retrieval, dentate gyrus NMDAR activity enhances memory differentiation. Our results contribute to understanding how the hippocampal circuit sustains a flexible balance between memory formation and retrieval depending on the environmental cues and the internal representations of the individual. They also provide new insights into the molecular mechanisms underlying the contributions of hippocampal subregions to generate this balance.

Social interaction-induced fear memory reduction: exploring the influence of dopamine and oxytocin receptors on memory updating.

It has been well established that a consolidated memory can be updated during the plastic state induced by reactivation. This updating process opens the possibility to modify maladaptive memory. In the present study, we evaluated whether fear memory could be updated to less-aversive level by incorporating hedonic information during reactivation. Thus, male rats were fear conditioned and, during retrieval, a female was presented as a social rewarding stimulus. We found that memory reactivation with a female (but not a male) reduces fear expression within-session and in the test, without presenting reinstatement or spontaneous recovery. Interestingly, this intervention impaired extinction. Finally, we demonstrated that this emotional remodeling to eliminate fear expression requires the activation of dopamine and oxytocin receptors during retrieval. Hence, these results shed new lights on the memory updating process and suggests that the exposure to natural rewarding information such as a female during retrieval reduces a previously consolidated fear memory.

Ketogenic diet administration later in life improves memory by modifying the synaptic cortical proteome via the PKA signaling pathway in aging mice.

Aging compromises brain function leading to cognitive decline. A cyclic ketogenic diet (KD) improves memory in aged mice after long-term administration; however, short-term effects later in life and the molecular mechanisms that govern such changes remain unclear. Here, we explore the impact of a short-term KD treatment starting at elderly stage on brain function of aged mice. Behavioral testing and long-term potentiation (LTP) recordings reveal that KD improves working memory and hippocampal LTP. Furthermore, the synaptosome proteome of aged mice fed a KD long-term evidence changes predominantly at the presynaptic compartment associated to the protein kinase A (PKA) signaling pathway. These findings were corroborated in vivo by western blot analysis, with high BDNF abundance and PKA substrate phosphorylation. Overall, we show that a KD modifies brain function even when it is administered later in life and recapitulates molecular features of long-term administration, including the PKA signaling pathway, thus promoting synaptic plasticity at advanced age.

The ketamine metabolite (2R,6R)-hydroxynorketamine rescues hippocampal mRNA translation, synaptic plasticity and memory in mouse models of Alzheimer's disease.

INTRODUCTION: Impaired brain protein synthesis, synaptic plasticity, and memory are major hallmarks of Alzheimer's disease (AD). The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) has been shown to modulate protein synthesis, but its effects on memory in AD models remain elusive. METHODS: We investigated the effects of HNK on hippocampal protein synthesis, long-term potentiation (LTP), and memory in AD mouse models. RESULTS: HNK activated extracellular signal-regulated kinase 1/2 (ERK1/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)/ribosomal protein S6 signaling pathways. Treatment with HNK rescued hippocampal LTP and memory deficits in amyloid-ß oligomers (AßO)-infused mice in an ERK1/2-dependent manner. Treatment with HNK further corrected aberrant transcription, LTP and memory in aged APP/PS1 mice. DISCUSSION: Our findings demonstrate that HNK induces signaling and transcriptional responses that correct synaptic and memory deficits in AD mice. These results raise the prospect that HNK could serve as a therapeutic approach in AD. HIGHLIGHTS: The ketamine metabolite HNK activates hippocampal ERK/mTOR/S6 signaling pathways. HNK corrects hippocampal synaptic and memory defects in two mouse models of AD. Rescue of synaptic and memory impairments by HNK depends on ERK signaling. HNK corrects aberrant transcriptional signatures in APP/PS1 mice.

Neuroprotective effect of hormone replacement therapy: a review of the literature.

OBJECTIVE: Menopause is a physiological period characterized by the cessation of ovarian activity. Sequential changes during this transition affect multiple systems, including the brain. Sixty percent of women experience cognitive impairment. The objective of this review is to show the neuroprotective effect of hormone replacement therapy (HRT) through the different scales and whether there is a benefit of this in women. METHOD: A search was conducted in six databases. Eligibility criteria included women within 10 years of menopause, receiving HRT controlled with placebo, studies lasting more than 6 months and women without a history of chronic underlying pathology. RESULTS: A total of nine randomized controlled trials met the inclusion criteria. Regarding memory, two studies reported better performance of HRT with a significant odds ratio (OR) of 0.67; regarding attention, one study reported potential improvement in women receiving HRT with a significant OR of 0.87; and neuroimaging assessment found an increase in ventricular volume compared to placebo over a 3-year period. CONCLUSIONS: The early initiation of menopausal HRT in healthy women appears to yield a positive effect on certain cognitive aspects, such as attention and cortical volume in the central nervous system. These findings should be confirmed through future prospective studies.

Effects of a Ketogenic Diet on the Assessment of Biochemical and Clinical Parameters in Duchenne Muscular Dystrophy: A Preclinical Investigation.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive skeletal muscle degeneration and systemic effects, including the central nervous system (CNS). This study aimed to assess the impact of a 14-day ketogenic diet (DCet) on biochemical and clinical parameters in a DMD mouse model. Young adult mice (50 days old) were fed DCet, while control groups received a standard diet. On the 14th day, memory and behavior tests were conducted, followed by biochemical evaluations of oxidative stress, inflammatory biomarkers, body weight, feed intake, and brain-derived neurotrophic factor (BDNF) levels. mdx + DCet mice showed reduced mass (0.2 g ± 2.49) and improved memory retention (p < 0.05) compared to controls. Oxidative damage in muscle tissue and CNS decreased, along with a significant cytokine level reduction (p <0.05). The protocol led to an increase in hippocampal BDNF and mitochondrial respiratory complex activity in muscle tissue and the central nervous system (CNS), while also decreasing creatine kinase activity only in the striatum. Overall, a 14-day DCet showed protective effects by improving spatial learning and memory through reductions in oxidative stress and immune response, as well as increases in BDNF levels, consistent with our study's findings.

PARP1 in the intersection of different DNA repair pathways, memory formation, and sleep pressure in neurons.

Poly(ADP-ribose) polymerase-1 (PARP1) is a bottleneck that connects different DNA pathways during a DNA damage response. Interestingly, PARP1 has a dualist role in neurons, acting as a neuroprotector and inducer of cell death in distinct neurological diseases. Recent studies significantly expanded our knowledge of how PARP1 regulates repair pathways in neurons and uncovered new roles for PARP1 in promoting sleep to enhance DNA repair. Likewise, PARP1 is deeply associated with memory consolidation, implying that it has multiple layers of regulation in the neural tissue. In this review, we critically discuss PARP1 recent advances in neurons, focusing on its interplay with different DNA repair mechanisms, memory, and sleep. Provocative questions about how oxidative damage is accessed, and different hypotheses about the molecular mechanisms influenced by PARP1 in neurons are presented to expand the debate of future studies.

Memory in female adolescents with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

INTRODUCTION: In females with congenital adrenal hyperplasia (CAH), the influence of hyperandrogenism and glucocorticoid supplementation on neurocognition is controversial. OBJECTIVES: To identify possible differences in visual working memory and verbal memory in adolescent girls with CAH due to 21-hydroxylase deficiency and matched controls. Moreover, to study if any relationship between variables associated with CAH and the scores of the selected memory tests was present. MATERIAL AND METHODS: In total 39 individuals were studied, female adolescents with CAH and age and pubertal stage matched healthy male and female controls (13 in each group). Sociodemographic, clinical, hormonal, and neurocognitive variables were explored. In female adolescents with CAH, variables related to the disease (age at diagnosis, clinical form, time since diagnosis, and glucocorticoid doses) were correlated with the scores obtained for neurocognitive variables. RESULTS: The mean age was 13.9 ± 3.3 years. In female adolescents with CAH the results were worse compared to controls in Free Recall (p = 0.039) and in Visual Memory Span score (p = 0.016). Age at diagnosis was negatively correlated to number of hits (p = 0.04), number recalled backward (p = 0.03), Visual Memory Span test score (p = 0.04) and Total Free Recall (p = 0.04), i.e., memory was worse with later diagnosis. CONCLUSIONS: Female adolescents with CAH had worse visual working memory compared to matched controls, but not in verbal memory. Age at diagnosis was negatively associated with the memory tests.

Dual-step pharmacological intervention for traumatic-like memories: implications from D-cycloserine and cannabidiol or clonidine in male and female rats.

RATIONALE: Therapeutic approaches to mitigating traumatic memories have often faced resistance. Exploring safe reconsolidation blockers, drugs capable of reducing the emotional valence of the memory upon brief retrieval and reactivation, emerges as a promising pharmacological strategy. Towards this objective, preclinical investigations should focus on aversive memories resulting in maladaptive outcomes and consider sex-related differences to enhance their translatability. OBJECTIVES: After selecting a relatively high training magnitude leading to the formation of a more intense and generalized fear memory in adult female and male rats, we investigated whether two clinically approved drugs disrupting its reconsolidation remain effective. RESULTS: We found resistant reconsolidation impairment by the α2-adrenergic receptor agonist clonidine or cannabidiol, a major non-psychotomimetic Cannabis sativa component. However, pre-retrieval administration of D-cycloserine, a partial agonist at the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor complex, facilitated their impairing effects on reconsolidation. A similar reconsolidation blockade by clonidine or cannabidiol was achieved following exposure to a non-conditioned but generalized context after D-cycloserine administration. This suggests that sufficient memory destabilization can accompany generalized fear expression. Combining clonidine with cannabidiol without potentiating memory destabilization by D-cycloserine was ineffective. CONCLUSIONS: These findings highlight the importance of NMDA receptor signaling in memory destabilization and underscore the efficacy of a dual-step pharmacological intervention in attenuating traumatic-like memories, even in a context different from the original learning environment.