Chronic alcohol-induced long-lasting working memory deficits are associated with altered histone H3K9 dimethylation in the prefrontal cortex.

Introduction: Epigenetic modifications have emerged as key contributors to the enduring behavioral, molecular and epigenetic neuroadaptations during withdrawal from chronic alcohol exposure. The present study investigated the long-term consequences of chronic alcohol exposure on spatial working memory (WM) and associated changes of transcriptionally repressive histone H3 lysine 9 dimethylation (H3K9me) in the prefrontal cortex (PFC).

Methods: Male C57BL/6 mice were allowed free access to either 12% (v/v) ethanol for 5 months followed by a 3-week abstinence period or water.

Chronic alcohol consumption shifts learning strategies and synaptic plasticity from hippocampus to striatum-dependent pathways.

Introduction: The hippocampus and striatum have dissociable roles in memory and are necessary for spatial and procedural/cued learning, respectively. Emotionally charged, stressful events promote the use of striatal- over hippocampus-dependent learning through the activation of the amygdala. An emerging hypothesis suggests that chronic consumption of addictive drugs similarly disrupt spatial/declarative memory while facilitating striatum-dependent associative learning.

Preventive Effects of Baclofen but Not Diazepam on Hippocampal Memory and Glucocorticoid Alterations After Prolonged Alcohol Withdrawal in Mice.

Our study aims at comparing in C57/Bl male mice, the impact of repeated injections of baclofen (an agonist of GABAB receptor) or diazepam (a benzodiazepine acting through a positive allosteric modulation of GABAA receptor) administered during the alcohol-withdrawal period on hippocampus-dependent memory impairments and brain regional glucocorticoid dysfunction after a short (1-week) or a long (4-week) abstinence. Hence, mice were submitted to a 6-month alcohol consumption (12%v/v) and were progressively withdrawn to water. Then, after a 1- or 4-weeks abstinence, they were submitted to a contextual memory task followed by measurements of corticosterone concentrations in the dorsal hippocampus (dHPC), the ventral hippocampus (vHPC) and the prefrontal cortex (PFC).

Targeting the Glucocorticoid Receptors During Alcohol Withdrawal to Reduce Protracted Neurocognitive Disorders.

Persistent regional glucocorticoid (GC) dysregulation in alcohol-withdrawn subjects emerges as a key factor responsible for protracted molecular and neural alterations associated with long-term cognitive dysfunction. Regional brain concentrations of corticosterone vary independently from plasma concentrations in alcohol-withdrawn subjects, which may account for the treatment of alcohol withdrawal-induced persistent pathology. Thus, from a pharmacological point of view, a main issue remains to determine the relative efficacy of compounds targeting the GC receptors to attenuate or suppress the long-lasting persistence of brain regional GC dysfunctions in abstinent alcoholics, as well as persistent changes of neural plasticity.

Sustained corticosterone rise in the prefrontal cortex is a key factor for chronic stress-induced working memory deficits in mice.

Exposure to prolonged, unpredictable stress leads to glucocorticoids-mediated long-lasting neuroendocrine abnormalities associated with emotional and cognitive impairments. Excessive levels of serum glucocorticoids (cortisol in humans, corticosterone in rodents) contribute notably to deficits in working memory (WM), a task which heavily relies on functional interactions between the medial prefrontal cortex (PFC) and the dorsal hippocampus (dHPC). However, it is unknown whether stress-induced increases in plasma corticosterone mirror corticosterone levels in specific brain regions critical for WM.

Baclofen but Not Diazepam Alleviates Alcohol-Seeking Behavior and Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Stressed Withdrawn Mice.

This study compares the impact of repeated injections of baclofen (an agonist of GABA receptors) or diazepam (a benzodiazepine having an agonist action on GABA receptors) given during the alcohol-withdrawal period on the stress-induced restoration of alcohol-seeking behavior and hypothalamic-pituitary-adrenal (HPA) axis dysfunction after a long (4 weeks) abstinence. Thus, C57BL/6 mice were submitted to a 6-month alcohol consumption [12% volume/volume (v/v)] and were progressively withdrawn to water before testing. Diazepam (Valium, Roche) and baclofen (Baclofen, Mylan) were administered intraperitoneally for 15 consecutive days (1 injection/day) during the withdrawal period at decreasing doses ranging from 1.

Lesion of the dorsal hippocampus alters the time-course evolution of corticosterone rise in the ventral hippocampus after stress.

We previously showed that an acute stress-induced an early corticosterone rise in the dorsal hippocampus (dHPC) and a delayed one in the ventral hippocampus (vHPC). Congruently, we hypothesized that the dHPC may influence the time-course evolution of poststress glucocorticoid rise in the vHPC. To probe this issue, we performed ibotenic acid lesions of the dHPC and measured by microdialysis the time-course evolution of corticosterone rise in the vHPC after an acute stress delivery.

Procognitive impact of ciproxifan (a histaminergic H receptor antagonist) on contextual memory retrieval after acute stress.

Aim: Although cognitive deficits commonly co-occur with stress-related emotional disorders, effect of procognitive drugs such as histaminergic H receptor antagonists are scarcely studied on memory retrieval in stress condition.

Methods: Experiment 1. Memory of two successive spatial discriminations (D1 then D2) 24 hours after learning was studied in a four-hole board in mice.

New procognitive enhancers acting at the histamine H3 and AMPA receptors reverse natural forgetting in mice: comparisons with donepezil and memantine in the object recognition task.

This study evaluated the procognitive effects of S 38093 (a new inverse agonist of the histaminergic H3 receptor) and S 47445 (a new α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) in 2-3-month-old Swiss mice as compared with donepezil and memantine, two main reference compounds in the treatment of Alzheimer's disease. The object recognition task allows the study of natural forgetting and is classically used in assessing drug effects on memory. Here, we show that mice exhibit significant object recognition at short (15 min) but not long (24 h) retention intervals separating the familiarization and recognition phases.

Repeated diazepam administration reversed working memory impairments and glucocorticoid alterations in the prefrontal cortex after short but not long alcohol-withdrawal periods.

The study was designed to assess whether repeated administration of diazepam (Valium®, Roche)-a benzodiazepine exerting an agonist action on GABA receptors-may alleviate both the short (1 week, 1W) and long-term (6 weeks, 6W) deleterious effects of alcohol withdrawal occurring after chronic alcohol consumption (6 months; 12% v/v) in C57/BL6 male mice. More pointedly, we first evidenced that 1W and 6W alcohol-withdrawn mice exhibited working memory deficits in a sequential alternation task, associated with sustained exaggerated corticosterone rise and decreased pCREB levels in the prefrontal cortex (PFC). In a subsequent experiment, diazepam was administered i.

sst-receptor gene deletion exacerbates chronic stress-induced deficits: Consequences for emotional and cognitive ageing.

This study investigated whether sst2 gene deletion interacts with age and chronic stress exposure to produce exacerbated emotional and cognitive ageing. Middle-aged (10-12 month) sst2 knockout (sst2KO) and wild-type (WT) mice underwent an unpredictable chronic mild stress (UCMS) procedure for 6 weeks or no stress for control groups. This was followed by a battery of tests to assess emotional and cognitive functions and neuroendocrine status (CORT level).

Cognitive and emotional impairments after cutaneous intoxication by CEES (a sulfur mustard analog) in mice.

Cognitive and emotional disorders have been reported in veterans intoxicated with sulfur mustard (SM) a chemical weapon belonging to the category of vesicating agents. However, the intense stress associated with the SM intoxication may render difficult determining the exact role played by SM intoxication itself on the emergence and maintaining of cognitive disorders. Animal's model would allow overcoming this issue.

The Synergistic Enhancing-Memory Effect of Donepezil and S 38093 (a Histamine H Antagonist) Is Mediated by Increased Neural Activity in the Septo-hippocampal Circuitry in Middle-Aged Mice.

Donepezil, an acetylcholinesterase inhibitor, induces only moderate symptomatic effects on memory in Alzheimer's disease patients. An alternative strategy for treatment of cognitive symptoms could be to act simultaneously on both histaminergic and cholinergic pathways, to create a synergistic effect. To that aim, 14 month old C57/Bl6 mice were administered per oesophagy during nine consecutive days with Donepezil (at 0.

Roles of Hippocampal Somatostatin Receptor Subtypes in Stress Response and Emotionality.

Altered brain somatostatin functions recently appeared as key elements for the pathogenesis of stress-related neuropsychiatric disorders. The hippocampus exerts an inhibitory feedback on stress but the mechanisms involved remain unclear. We investigated herein the role of hippocampal somatostatin receptor subtypes in both stress response and behavioral emotionality using C57BL/6, wild type and sst or sst knockout mice.

Behavioral effects of chronic stress in the Fmr1 mouse model for fragile X syndrome.

Fragile X Syndrome (FXS) is a pervasive developmental disorder due to a mutation in the FMR1 X-linked gene. Despite its clear genetic cause, the expression of FXS symptoms is known to be modulated by environmental factors, including stress. Furthermore, several studies have shown disturbances in stress regulatory systems in FXS patients and Fmr1 mice.

Behavioral Neuroadaptation to Alcohol: From Glucocorticoids to Histone Acetylation.

A prime mechanism that contributes to the development and maintenance of alcoholism is the dysregulation of the hypothalamic-pituitary-adrenal axis activity and the release of glucocorticoids (cortisol in humans and primates, corticosterone in rodents) from the adrenal glands. In the brain, sustained, local elevation of glucocorticoid concentration even long after cessation of chronic alcohol consumption compromises functional integrity of a circuit, including the prefrontal cortex (PFC), the hippocampus (HPC), and the amygdala (AMG). These structures are implicated in learning and memory processes as well as in orchestrating neuroadaptive responses to stress and anxiety responses.

Intake of Wild Blueberry Powder Improves Episodic-Like and Working Memory during Normal Aging in Mice.

The number of Americans older than 65 years old is projected to more than double in the next 40 years. Cognitive changes associated to aging can affect an adult's day-to-day functioning. Among these cognitive changes, reasoning, episodic memory, working memory, and processing speed decline gradually over time.

Alcohol withdrawal induces long-lasting spatial working memory impairments: relationship with changes in corticosterone response in the prefrontal cortex.

This study intends to determine whether long-lasting glucocorticoids (GCs) dysregulation in the prefrontal cortex (PFC) or the dorsal hippocampus (dHPC) play a causal role in the maintenance of working memory (WM) deficits observed after alcohol withdrawal. Here, we report that C57/BL6 male mice submitted to 6 months alcohol consumption (12 percent v/v) followed by 1 (1W) or 6 weeks (6W) withdrawal periods exhibit WM deficits in a spatial alternation task and an exaggerated corticosterone rise during and after memory testing in the PFC but not the dHPC. In contrast, emotional reactivity evaluated in a plus-maze is altered only in the 1W group.

Hippocampal Injections of Oligomeric Amyloid β-peptide (1-42) Induce Selective Working Memory Deficits and Long-lasting Alterations of ERK Signaling Pathway.

Increasing evidence suggests that abnormal brain accumulation of soluble rather than aggregated amyloid-β1-42 oligomers (Aβo(1-42)) plays a causal role in Alzheimer's disease (AD). However, as yet, animal's models of AD based on oligomeric amyloid-β1-42 injections in the brain have not investigated their long-lasting impacts on molecular and cognitive functions. In addition, the injections have been most often performed in ventricles, but not in the hippocampus, in spite of the fact that the hippocampus is importantly involved in memory processes and is strongly and precociously affected during the early stages of AD.

Acute stress blocks the caffeine-induced enhancement of contextual memory retrieval in mice.

This study investigated in mice the dose-effect of caffeine on memory retrieval in non-stress and stress conditions. C57 Bl/6 Jico mice learned two consecutive discriminations (D1 and D2) in a four-hole board which involved either distinct contextual (CSD) or similar contextual (SSD) cues. All mice received an i.

Post-training, intrahippocampal HDAC inhibition differentially impacts neural circuits underlying spatial memory in adult and aged mice.

Converging evidence indicates that pharmacologically elevating histone acetylation using post-training, systemic or intrahippocampal, administration of histone deacetylase inhibitor (HDACi) can enhance memory consolidation processes in young rodents but it is not yet clear, whether such treatment is sufficient to prevent memory impairments associated with aging. To address this question, we used a 1-day massed spatial learning task in the water maze to investigate the effects of immediate post-training injection of the HDACi trichostatin A (TSA) into the dorsal hippocampus on long-term memory consolidation in 3-4 and 18-20 month-old mice. We show that TSA improved the 24 h-memory retention for the hidden platform location in young-adults, but failed to rescue memory impairments in older mice.

Stress induced a shift from dorsal hippocampus to prefrontal cortex dependent memory retrieval: role of regional corticosterone.

Most of the deleterious effects of stress on memory retrieval are due to a dysfunction of the hippocampo-prefrontal cortex interplay. The role of the stress-induced regional corticosterone increase in such dysfunction remains however unclear, since there is no published study as yet dedicated to measuring corticosterone concentrations simultaneously in both the prefrontal cortex (mPFC) and the hippocampus (dHPC) in relation with memory impairments. To that aim, we first showed in Experiment 1 that an acute stress (3 electric footschocks; 0.

Retinoic acid modulates intrahippocampal levels of corticosterone in middle-aged mice: consequences on hippocampal plasticity and contextual memory.

It is now established that vitamin A and its derivatives, retinoic acid (RA), are required for cognitive functions in adulthood. RA hyposignaling and hyperactivity of glucocorticoid (GC) pathway appear concomitantly during aging and would contribute to the deterioration of hippocampal synaptic plasticity and functions. Furthermore, recent data have evidenced counteracting effects of retinoids on GC signaling pathway.

Working memory deficits and related disinhibition of the cAMP/PKA/CREB are alleviated by prefrontal α4β2*-nAChRs stimulation in aged mice.

The present study investigates in aged mice the working memory (WM) enhancing potential of the selective α4β2* nicotinic receptor agonist S 38232 as compared with the cholinesterase inhibitor donepezil, and their effect on cAMP response element binding protein (CREB) phosphorylation (pCREB) as a marker of neuronal activity. We first showed that aged mice exhibit a WM deficit and an increase of pCREB in the prelimbic cortex (PL) as compared with young mice, whereas no modification appears in the CA1. Further, we showed that systemic administration of S 38232 restored WM in aged mice and alleviated PL CREB overphosphorylation.