Adolescent alcohol exposure modifies adult anxiety-like behavior and amygdala sensitivity to alcohol in rats: Increased c-Fos activity and sex-dependent microRNA-182 expression.

Adolescent binge alcohol drinking is a serious health concern contributing to adult alcohol abuse often associated with anxiety disorders. We have used adolescent intermittent ethanol (AIE) administration as a model of binge drinking in rats in order to explore its long-term effect on the basolateral amygdala (BLA) responsiveness to alcohol and anxiety-like behavior. AIE increased the number of BLA c-Fos positive cells in adult Wistar rats and anxiety-like behavior assessed by the open field test (OFT). Additionally, in adult female rats receiving AIE BLA over expression of miR-182 was found. Therefore, our results indicate that alcohol consumption during adolescence can lead to enduring changes in anxiety-like behavior and BLA susceptibility to alcohol that may be mediated by sex-dependent epigenetic changes. These results contribute to understanding the mechanisms involved in the development of alcohol use disorders (AUD) and anxiety-related disorders.

Identification of differentially expressed miRNA in the rat hippocampus during adolescence through an epigenome-wide analysis.

INTRODUCTION: Epigenetic mechanisms involving microRNAs (miRNAs) play a fundamental role in many biological processes, particularly during prenatal and early postnatal development. Their role in adolescent brain development, however, has been poorly described. The present study aims to explore miRNA expression in the hippocampus during adolescence compared to adulthood in rats. METHOD: The brains of female and male Wistar rats were extracted and the hippocampus was freshly dissected at postnatal day 41 (adolescence) and postnatal day 98 (adulthood). An epigenome-wide analysis was conducted to identify the miRNAs significantly expressed in adolescence compared to adulthood. Additionally, target genes of such miRNAs were considered to perform an exploratory gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. RESULTS: We identified 16 differentially expressed miRNAs in adolescent male rats compared with adult male rats, and 4 differentially expressed miRNAs in adolescent females compared with adult females. Enrichment analysis reinforced that the target genes found are related to neurodevelopmental processes such as cell proliferation, cell migration and nervous system development. CONCLUSION: Our findings suggest a complex pattern of miRNA expression during adolescence, which differs from that in adulthood. The differential expression of miRNA in the hippocampus during adolescence may be associated with the late developmental changes occurring in this brain region. Furthermore, the observed sex differences in miRNA expression patterns indicate potential sexual differentiation in hippocampal development. Further comprehensive investigations are needed to elucidate the roles of miRNA in normal brain development.

Infant gut microbiota contributes to cognitive performance in mice.

Gut microbiota has been linked to infant neurodevelopment. Here, an association between infant composite cognition and gut microbiota composition is established as soon as 6 months. Higher diversity and evenness characterize microbial communities of infants with composite cognition above (Inf-aboveCC) versus below (Inf-belowCC) median values. Metaproteomic and metabolomic analyses establish an association between microbial histidine ammonia lyase and infant histidine metabolome with cognition. Fecal transplantation from Inf-aboveCC versus Inf-belowCC donors into germ-free mice shows that memory, assessed by a novel object recognition test, is a transmissible trait. Furthermore, Inf-aboveCC mice are enriched in species belonging to Phocaeicola, as well as Bacteroides and Bifidobacterium, previously linked to cognition. Finally, Inf-aboveCC mice show lower fecal histidine and urocanate:histidine and urocanate:glutamate ratios in the perirhinal cortex compared to Inf-belowCC mice. Overall, these findings reveal a causative role of gut microbiota on infant cognition, pointing at the modulation of histidine metabolite levels as a potential underlying mechanism.

Taste Neophobia, Latent Inhibition of Taste Aversion and Object Recognition Memory in Adolescent Rats.

BACKGROUND: Adolescence in mammals is a period marked by increased novelty-seeking and enhanced responsiveness to the stressful properties of novel stimuli. Despite the need to taste potentially toxic novel foods during the adolescent growth spurt, there has been little study of taste neophobia and its attenuation. METHOD: Four experiments were carried out to compare taste neophobia and related memory processes in male and female adolescent (PND28) and adult (PND70) Wistar rats. Experiments 1 and 2 evaluated attenuation of taste neophobia to cider vinegar (3%) and sodium saccharin (0.1%) solutions were evaluated. Additionally, to test the role of memory in neophobia during adolescence, latent inhibition of taste aversion and object recognition memory were assessed in Experiment 3 and Experiment 4, respectively. RESULTS: Adolescent and adult rats exhibited taste neophobia to the saccharin solution but adolescent rats required more exposure trials than adults to recognize the vinegar solution as safe. Both groups exhibited similar latent inhibition of taste aversion and object recognition memory. No sex effect was significant. CONCLUSIONS: Contrary to the accepted view associating adolescence with reduced neophobia, adolescent rats exhibited taste neophobia which even increased when sour tastes were encountered.

Choline: An Essential Nutrient for Human Health.

Choline is an essential nutrient that plays a role in the synthesis of the phospholipid membrane, critical for cell functions, and it is the major source of methyl donors relevant for epigenetic modifications of the genome [...].

Taste Neophobia, Latent Inhibition of Taste Aversion and Object Recognition Memory in Adolescent Rats / Neofobia Gustativa, Inhibición Latente de la Aversión Gustativa y Memoria de Reconocimiento de Objetos en Ratas Adolescentes

Background: Adolescence in mammals is a period marked by increased novelty-seeking and enhanced responsiveness to the stressful properties of novel stimuli. Despite the need to taste potentially toxic novel foods during the adolescent growth spurt, there has been little study of taste neophobia and its attenuation. Method: Four experiments were carried out to compare taste neophobia and related memory processes in male and female adolescent (PND28) and adult (PND70) Wistar rats. Experiments 1 and 2 evaluated attenuation of taste neophobia to cider vinegar (3%) and sodium saccharin (0.1%) solutions were evaluated. Additionally, to test the role of memory in neophobia during adolescence, latent inhibition of taste aversion and object recognition memory were assessed in Experiment 3 and Experiment 4, respectively. Results: Adolescent and adult rats exhibited taste neophobia to the saccharin solution but adolescent rats required more exposure trials than adults to recognize the vinegar solution as safe. Both groups exhibited similar latent inhibition of taste aversion and object recognition memory. No sex effect was significant. Conclusions: Contrary to the accepted view associating adolescence with reduced neophobia, adolescent rats exhibited taste neophobia which even increased when sour tastes were encountered.(AU)

Antecedentes: La adolescencia está marcada por búsqueda de la novedad y acentuada sensibilidad a las propiedades estresantes de los estímulos novedosos. A pesar de la necesidad de probar nuevos alimentos potencialmente tóxicos durante el periodo de crecimiento adolescente, la neofobia gustativa y su atenuación durante este periodo apenas ha sido estudiada. Método: Se evaluaron la neofobia gustativa y los procesos de memoria relacionados en ratas Wistar macho y hembra adolescentes (PND28) y adultas (PND70). En los Experimentos 1 y 2 Se exploró la atenuación de la neofobia gustativa a soluciones de vinagre de sidra (3%) y sacarina sódica (0,1%), respectivamente. En los experimentos 3 y 4, se evaluó también la inhibición latente de aversiones gustativas y la memoria de reconocimiento de objetos. Resultados: Adolescentes y adultos mostraron neofobia gustativa a la sacarina, pero las ratas adolescentes requirieron más exposiciones a la solución de vinagre para reconocerla como segura. No hubo diferencias entre los grupos en los Experimentos 3 and 4. No se hallaron efectos significativos del sexo. Conclusiones: A pesar de la ampliamente aceptada asociación entre adolescencia y reducida neofobia, las ratas adolescentes muestran neofobia al sabor que resulta incluso incrementada cuando se trata de sabores ácidos.(AU)

MicroRNA Regulation of the Environmental Impact on Adolescent Neurobehavioral Development: A Systematic Review.

Adolescence is a late developmental period marked by pronounced reorganization of brain networks in which epigenetic mechanisms play a fundamental role. This brain remodeling is associated with a peculiar behavior characterized by novelty seeking and risky activities such as alcohol and drug abuse, which is associated with increased susceptibility to stress. Hence, adolescence is a vulnerable postnatal period since short- and long-term deleterious effects of alcohol drinking and drug abuse are a serious worldwide public health concern. Among several other consequences, it has been proposed that exposure to stress, alcohol, or other drugs disrupts epigenetic mechanisms mediated by small non-coding microRNAs (miRNAs). During adolescence, this modifies the expression of a variety of genes involved in neurodevelopmental processes such as proliferation, differentiation, synaptogenesis, neural plasticity, and apoptosis. Hence, the effect of miRNAs dysregulation during adolescence might contribute to a long-term impact on brain function. This systematic review focuses on the miRNA expression patterns in the adolescent rodent brain with special interest in the impact of stress and drugs such as amphetamine, cocaine, nicotine, cannabis, and ketamine. The results point to a relevant and complex role of miRNAs in the regulation of the molecular processes involved in adolescent brain development as part of a dynamic epigenetic network sensitive to environmental events with distinctive changes across adolescence. Several miRNAs have been assessed evidencing changing expression profiles during the adolescent transition which are altered by exposure to stress and drug abuse. Since this is an emerging rapidly growing field, updating the present knowledge will contribute to improving our understanding of the epigenetic regulation mechanisms involved in the neurodevelopmental changes responsible for adolescent behavior. It can be expected that increased knowledge of the molecular mechanisms mediating the effect of environmental threats during the adolescent critical developmental period will improve understanding of psychiatric and addictive disorders emerging at this stage.

A Systematic Review of the Dietary Choline Impact on Cognition from a Psychobiological Approach: Insights from Animal Studies.

The influence of dietary choline availability on cognition is currently being suggested by animal and human studies which have focused mainly on the early developmental stages. The aim of this review is to systematically search through the available rodent (rats and mice) research published during the last two decades that has assessed the effect of dietary choline interventions on cognition and related attentional and emotional processes for the entire life span. The review has been conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines covering peer-reviewed studies included in PubMed and Scopus databases. After excluding duplicates and applying the inclusion/exclusion criteria we have reviewed a total of 44 articles published in 25 journals with the contribution of 146 authors. The results are analyzed based on the timing and duration of the dietary intervention and the behavioral tests applied, amongst other variables. Overall, the available results provide compelling support for the relevance of dietary choline in cognition. The beneficial effects of choline supplementation is more evident in recognition rather than in spatial memory tasks when assessing nonpathological samples whilst these effects extend to other relational memory tasks in neuropathological models. However, the limited number of studies that have evaluated other cognitive functions suggest a wider range of potential effects. More research is needed to draw conclusions about the critical variables and the nature of the impact on specific cognitive processes. The results are discussed on the terms of the theoretical framework underlying the relationship between the brain systems and cognition.

Effect of hippocampal 6-OHDA lesions on the contextual modulation of taste recognition memory.

Taste recognition memory is evident in rodents because the initial neophobia to novel tastes attenuates across exposures as the taste becomes familiar and safe. This attenuation of taste neophobia (AN) is context-dependent and an auditory background change could induce the recovery of the neophobic response. The AN auditory context-dependency requires the hippocampal integrity but the neurochemical mechanisms underlying the interaction with the taste memory circuit remain unexplored. We have applied pharmacological intervention by 6-hidroxydopamine (6-OHDA) hippocampal lesion for assessing the role of catecholamines in the hippocampal system to Wistar rats that drank a novel 3% vinegar solution for several consecutive days. Additionally, we manipulated the auditory background as a context that could either change or remain constant across all the drinking sessions. We found that a disruption of the context-dependent AN was induced by intracerebral administration of 6-OHDA targeted to the ventral CA1 hippocampus (vCA1). We conclude that the ability of the auditory context to modulate taste recognition memory involves the catecholaminergic activity in the ventral hippocampal circuit for the proper acquisition of safe taste memory.

Lateral habenula lesions disrupt appetitive extinction, but do not affect voluntary alcohol consumption.

This study analyzed the effects of LHb lesions on appetitive extinction and alcohol consumption. Eighteen male Wistar rats received neurochemical lesions of the LHb (quinolinic acid) and 12 received a vehicle infusion (PBS). In a runway instrumental task, rats received acquisition (12 pellets/trial, 6 trials/session, 10 sessions) and extinction training (5 sessions). In a consummatory task, rats had daily access to 32% sucrose (5 min, 10 sessions) followed by access to water (5 sessions). Then, animals received 2 h preference tests with escalating alcohol concentrations (2%-24%), followed by two 24 h preference tests with 24% alcohol. Relative to Shams, LHb lesions delayed extinction, as indicated by lower response latencies (instrumental task) and higher fluid consumption (consummatory task). LHb lesions did not affect alcohol consumption regardless of alcohol concentration or test duration. The LHb modulates appetitive extinction and needs to be considered as part of the brain circuit underlying reward loss.

In Vivo Sub-chronic Treatment with Dichlorvos in Young Rats Promotes Synaptic Plasticity and Learning by a Mechanism that Involves Acylpeptide Hydrolase Instead of Acetylcholinesterase Inhibition. Correlation with Endogenous ß-Amyloid Levels.

Acylpeptide hydrolase (APEH) is a serine hydrolase that displays two catalytic activities, acting both as an exopeptidase toward short N-acylated peptides and as an endopeptidase toward oxidized peptides or proteins. It has been demonstrated that this enzyme can degrade monomers, dimers, and trimers of the Aß1-40 peptide in the conditioned media of neuroblastoma cells. In a previous report, we showed that the specific inhibition of this enzyme by the organophosphate molecule dichlorvos (DDVP) triggers an enhancement of long-term potentiation in rat hippocampal slices. In this study, we demonstrate that the same effect can be accomplished in vivo by sub-chronic treatment of young rats with a low dose of DDVP (0.1 mg/kg). Besides exhibiting a significant enhancement of LTP, the treated animals also showed improvements in parameters of spatial learning and memory. Interestingly, higher doses of DDVP such as 2 mg/kg did not prove to be beneficial for synaptic plasticity or behavior. Due to the fact that at 2 mg/kg we observed inhibition of both APEH and acetylcholinesterase, we interpret that in order to achieve positive effects on the measured parameters only APEH inhibition should be obtained. The treatment with both DDVP doses produced an increase in the endogenous concentration of Aß1-40, although this was statistically significant only at the dose of 0.1 mg/kg. We propose that APEH represents an interesting pharmacological target for cognitive enhancement, acting through the modulation of the endogenous concentration of Aß1-40.

Increased N-Ethylmaleimide-Sensitive Factor Expression in Amygdala and Perirhinal Cortex during Habituation of Taste Neophobia.

Interactions between GluR2 and N-ethylmaleimide-sensitive factor (NSF) mediate AMPA receptors trafficking. This might be linked with molecular mechanisms related with memory formation. Previous research has shown basolateral amygdala (BLA) dependent activity changes in the perirhinal cortex (PRh) during the formation of taste memory. In the present experiments we investigate both the behavioral performance and the expression profile of NSF and GluR2 genes in several brain areas, including PRh, BLA, and hippocampus. Twenty-one naïve male Wistar rats were exposed to a saccharin solution (0.4%) during the first (novel), the second (Familiar I), and the sixth presentation (Familiar II). Total RNA was extracted and gene expression was measured by quantitative PCR (qPCR) using TaqMan gene expression assays. In addition the expression of the synaptic plasticity related immediate early genes, Homer 1 and Narp, was also assessed. We have found increased expression of NSF gene in BLA and PRh in Group Familiar I in comparison with Familiar II. No changes in the expression of GluR2, Homer 1, and Narp genes were found. The results suggest the relevance of a potential network in the temporal lobe for taste recognition memory and open new possibilities for understanding the molecular mechanisms mediating the impact of sensory experience on brain circuit function.

Effects of dietary choline availability on latent inhibition of flavor aversion learning.

OBJECTIVE: It has been previously reported that dietary choline supplementation might affect latent inhibition (LI) using a conditioned suppression procedure in rats. We have assessed the effect of dietary choline on LI of flavor aversion learning. METHOD: Adult male Wistar rats received a choline supplemented (5 g/kg), deficient (0 g/kg), or standard (1.1 g/kg) diet for 3 months. After this supplementation period, all rats went through a conditioned taste aversion (CTA) procedure, half of them being pre-exposed to the conditioned stimulus before the conditioning. RESULTS: The results indicated that choline deficiency prevents LI of conditioned flavor aversion to cider vinegar (3%) induced by a LiCl (0.15 M; 2% body weight) intraperitoneal injection, while choline supplementation enhances CTA leading to slower extinction. DISCUSSION: The role of the brain systems modulating attentional processes is discussed.

Spontaneous object recognition memory in aged rats: Complexity versus similarity.

Previous work on the effect of aging on spontaneous object recognition (SOR) memory tasks in rats has yielded controversial results. Although the results at long-retention intervals are consistent, conflicting results have been reported at shorter delays. We have assessed the potential relevance of the type of object used in the performance of aged rats in SOR tasks. Using standard objects, 24-mo-old rats did not exhibit retention impairment at a 1-h delay. At this retention interval no differences between young and old rats were found in a high-similarity SOR task, but aged rats exhibited deficits when clearly different complex forms were applied.

Basolateral amygdala lesions attenuate safe taste memory-related c-fos expression in the rat perirhinal cortex.

Previous results indicated that damage and pharmacological inactivation of the basolateral amygdala (BLA) interfere with the attenuation of taste neophobia. A similar disruption of safe taste memories formation induced by the inhibition of protein synthesis in the perirhinal cortex (PRh) has been reported. Thus, we have assessed the effect of bilateral BLA neurotoxic lesions on PRh activity after novel and familiar taste exposure. Wistar male rats with NMDA lesions of the BLA and SHAM-operated received two consecutive exposures to a 3% cider vinegar solution. Fos-like immunoreactivity (FLI) was examined as a marker of neuronal activity in PRh. As expected the BLA lesioned group showed no evidence of neophobia attenuation. A similar number of PRh Fos-positive cells were found in SHAM and BLA groups exposed to the novel taste solution. However, the BLA-lesioned group exhibited a lower number of Fos stained cells than the SHAM-lesioned group after being exposed to the familiar taste solution. This supports the notion of BLA and PRh as components of a neural circuit involved in safe taste recognition memory and suggests a role of PRh in various forms of recognition memory.

Taste learning and memory: a window on the study of brain aging.

Taste aversion learning exhibits advantages for research on memory brain systems and its reorganization throughout life. A review of the effects of aging on taste memory abilities offers a complex picture showing preserved, impaired, and enhanced functions. Some of the age-related changes in taste memory seem to be associated with an altered temporal processing. Longer taste-illness delays can be introduced for acquisition of conditioned taste aversions and the modulation of taste learning by the temporal context is absent in naïve old rats. It is suggested that an altered hippocampal function is involved in the peculiar performance of these rats. Evidence is also presented which suggests that hippocampal-dependent taste memory can be reactivated by previous learning experiences in old rats. Results obtained after reversible inactivation of the dorsal Hippocampus by tetrodotoxin (TTX) in old rats support such a view. Therefore, the interaction between the previous experience and acute brain interventions should be taken into account when studying the effect of aging on taste memory.

Intra-amygdala ZIP injections impair the memory of learned active avoidance responses and attenuate conditioned taste-aversion acquisition in rats.

We have investigated the effect of protein kinase Mzeta (PKMζ) inhibition in the basolateral amygdala (BLA) upon the retention of a nonspatial learned active avoidance response and conditioned taste-aversion (CTA) acquisition in rats. ZIP (10 nmol/µL) injected into the BLA 24 h after training impaired retention of a learned avoidance-jumping response assessed 7 d later when compared with control groups injected with scrambled-ZIP. Nevertheless, a retraining session applied 24 h later indicated no differences between the groups. Additionally, a similar ZIP injection into the BLA during the conditioned stimulus-unconditioned stimulus (CS-US) interval attenuated CTA acquisition. These findings support the BLA PKMζ role in various forms of memory.

Peculiar modulation of taste aversion learning by the time of day in developing rats.

The ontogeny of the temporal context modulation of conditioned taste aversion was studied in male Wistar rats using a palatable 1% NaCl solution. A procedure that included two saline preexposures, a single pairing saline-lithium chloride (0.15 M; 1% b.w.) either at the same or a different time of day of preexposures and a one-bottle test at the same time than preexposure was applied. Four age groups (PN32, PN48, PN64, and PN100) covering the complete range from adolescence to the adult period were tested. The results showed no effect of a temporal context shift in PN32. A peculiar enhancement of temporal context-specific saline aversions was exhibited by PN48 and PN64 rats, while the adult typical temporal context specificity of latent inhibition was only evident in PN100 rats. The results are discussed in terms of the peculiar brain functional organization during a protracted adolescence period.