Papers by Daniel beracochea
Frontiers in Pharmacology, Dec 22, 2016
Donepezil, an acetylcholinesterase inhibitor, induces only moderate symptomatic effects on memory... more 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 0.1 and 0.3 mg/kg) and S 38093 (at 0.1, 0.3, and 1.0 mg/kg), a H3 histaminergic antagonist developed by Servier, alone or in combination and tested for memory in a contextual memory task that modelized the age-induced memory dysfunction. The present study shows that the combination of Donepezil and S 38093 induced a dose-dependent synergistic memory-enhancing effect in middle-aged mice with a statistically higher size of effect never obtained with compounds alone and without any pharmacokinetic interaction between both compounds. We demonstrated that the memory-enhancing effect of the S 38093 and Donepezil combination is mediated by its action on the septo-hippocampal circuitry, since it canceled out the reduction of CREB phosphorylation (pCREB) observed in these brain areas in vehicle-treated middle-aged animals. Overall, the effects of drug combinations on pCREB in the hippocampus indicate that the synergistic promnesiant effects of the combination on memory performance in middle-aged mice stem primarily from an enhancement of neural activity in the septo-hippocampal system.
Psychobiology, Sep 1, 1997
The aims of this study were to examine the effects of systemic injection of diazepam on memory as... more The aims of this study were to examine the effects of systemic injection of diazepam on memory as measured by the intrasession evolution of alternation response rates in both sequential and delayed procedures. We showed that diazepam injection produced delay-dependent impairments in both sequential and delayed alternation protocols. However, the delayed alternation deficit produced by diazepam was totally alleviated by an intramaze context change occurring only before the retention trial. The memory-enhancing effect of the intramaze context change in experimental mice demonstrated that diazepam injection induced, during the usual testing (no-context change) conditions, a time-dependent retrieval memory deficit. Several studies have been carried out to determine the effects of administering benzodiazepines (BDZ) agonists and antagonists on memory in humans. Specifically, these studies aimed at comparing the types of memory impairment induced by BDZ compounds with the forms ofmemory dysfunctions observed in organic amnesia. It has been shown that the administration of BDZ compounds in humans produces deficits in episodic memory, but not in semantic or procedural memory (
Neuropsychopharmacology, Sep 5, 2012
The present study was aimed at determining the relative contribution of the dorsal (DH) and ventr... more The present study was aimed at determining the relative contribution of the dorsal (DH) and ventral (VH) hippocampus in stressinduced memory retrieval impairments. Thus, we studied the temporal involvement of corticosterone and its receptors, i.e. mineralocorticoid (MR) and glucocorticoid (GR) in the DH and VH, in relation with the time-course evolution of stress-induced memory retrieval impairments. In a first experiment, double microdialysis allowed showing on the same animal that an acute stress (electric footshocks) induced an earlier corticosterone rise in the DH (15-60 min post-stress) and then in the VH (90-105 min post-stress). The return to baseline was faster in the DH (105 min) than in the VH (120 min). Memory deficits assessed by delayed alternation occurred at 15-, 60-, and 105-min delays after stress and were closely related to the kinetic of corticosterone rises within the DH and VH. In a second experiment, the GR antagonist RU-38486 and the MR antagonist RU-28318 were administered in the DH or VH 15 min before stress. RU-38486 restored memory at 60 but not at 105 min post-stress delays in the DH, whereas the opposite pattern was observed in the VH. By contrast, RU-28318 had no effect on memory impairments at both the 60-and 105-min post-stress delays, showing that MR receptors are not involved at these delays. However, RU-28318 administered in the DH restored memory when administered at a shorter post-stress delay (15 min). Overall, our data are first to evidence that stress induces a functional switch from the DH to VH via different corticosterone time-course evolutions in these areas and the sequential GR receptors involvement in the DH and then in the VH, as regards the persistence of stress-induced memory retrieval deficits over time.
Psychobiology, Dec 1, 1992
Frontiers in Psychiatry
IntroductionThe hippocampus and striatum have dissociable roles in memory and are necessary for s... more IntroductionThe 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. This cognitive imbalance could contribute to maintain addictive behaviors and increase the risk of relapse.MethodsWe first examined, in C57BL/6 J male mice, whether chronic alcohol consumption (CAC) and alcohol withdrawal (AW) might modulate the respective use of spatial vs. single cue-based learning strategies, using a competition protocol in the Barnes maze task. We then performed in vivo electrophysiological studies in freely moving mice to assess learning-induced synaptic plasticity in both the basolateral amygdala ...
Psychobiology
The experiments reported here examined the effects of radiofrequency lesions of the median mammil... more The experiments reported here examined the effects of radiofrequency lesions of the median mammillary nuc1eus (MM) in mice on spatial memory performance in a T-maze. The spontaneous alternation task used consisted of two forced trials (acquisition) followed, at varying retention intervals ranging from 5 min to 72 h, by a free test trial (retention). Moreover, tests were conducted under different conditions by varying the intramaze context on the acquisition trials, the retention trial, or both. Thus, as compared with the usual condition of testing (OFF), animals were given trials with a change ofintramaze context (cue added: ON). The first experiment conducted with retention intervals of 5 min and 6 h showed that MM-Iesioned mice exhibited an accelerated rate of decay of spontaneous alternation when tested in normal conditions (OFF); however, changing the context (ON) on the acquisition, retention, or both acquisition and retention trials resulted in quite normal performance at the 6-h retention interval, as compared with that of controls. Since the most important effect of the context change was observed when it occurred on the retention test alone, this procedure was used in the second and third experiments in order to further analyze the phenomenon. These two experiments confirmed that when tested in the usual conditions, MM-Iesioned mice reached chance level performance (6 h) more rapidly than controls (48 h), but that the between-group difference was totally alleviated when both groups were provided with the context change on the retention test. Moreover, whatever the retention interval (from 6 to 72 h), this context change had no significant effect on the performance of control animals. These results suggest that MM lesions induce an accelerated rate of "forgetting" for spatial information, which is more likely due to an impairment of retrieval processes than to either an encoding deficit or a faster decay of the memory trace. In these conditions, the context change is supposed to stimulate searching operations, thus leading to normal remembering.
Psychobiology
This study showed that both chronic ethanol consumption and mammillary body (MB) lesions induced ... more This study showed that both chronic ethanol consumption and mammillary body (MB) lesions induced a trial-dependent sequential alternation deficit together with a reduction of anxiety-like reactions in an elevated plus maze and in an open field. The administration of J3-CCM (0.5 mg/kg, s.c.) increased anxiety-like reactions in all groups but significantly improved spontaneous alternation rates only in the alcohol group. However, increasing the dose of J3-CCM from 0.5 to 1.0 mg/kg also produced a memory-enhancing effect in MB-Iesioned subjects. Taken together, this study shows that (1) memory deficits induced by chronic ethanol administration and MB lesions are reversed by J3-CCM administration and that (2) given the dose effects in MB mice, the MB could mediate, at least in part, the memory-enhancing effects of the drug. The mammillary bodies (MBs) of the hypothalamus playa significant role in emotional behavior and have been proposed as a major site for the antianxiety actions ofbenzodiazepine (BDZ) in the brain . This concept has gained recent support from a study showing that, in the human brain, particularly high densities of BDZ binding sites are observed in the mammillary bodies as well as in the hippocampus and the anterior and posterior cingulate cortical areas . In parallel to the possible involvement of the MBs in emotion, the mammillo-cingular pathway also plays a role in memory processes. For example, the amnesia resulting from chronic alcohol consumption in Korsakoff's syndrome is due, at least in part, to damage of the mammillo-thalamiccingular pathway . Animal models of Korsakoff syndrome have also demonstrated a relation between damage to the mammillothalamic-cingular pathway and memory dysfunction. For example, we previously showed that chronic ethanol con-This research was supported by the CNRS (URA 339). The authors thank G. Chapouthier and R. H. Dodd for their collaboration and helpful advice, and Thomas Durkin for his help with the English in the writing of this paper. Correspondence should be addressed to D. Bera-coch6a,
Frontiers in Psychiatry, 2019
Persistent regional glucocorticoid (GC) dysregulation in alcohol-withdrawn subjects emerges as a ... more 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. Data from animal research show that acting directly on GC receptors during the withdrawal period, via selective antagonists, can significantly counteract the development and persistence of cognitive and neural plasticity disorders during protracted abstinence. A critical remaining issue is to better assess the relative long-term efficacy of GC antagonists and other compounds targeting the corticotropic axis activity such as gamma-aminobutyric acid A (GABA A ) and GABA B agonists. Indeed, benzodiazepines (acting indirectly on GABA A receptors) and baclofen (agonist of the GABA B receptor) are the compounds most widely used to reduce alcohol dependence. Clinical and preclinical data suggest that baclofen exerts an effective and more powerful counteracting action on such persistent cognitive and endocrine dysfunctions as compared to diazepam, even though its potential negative effects on memory processes, particularly at high doses, should be better taken into account.
CNS Neuroscience & Therapeutics, 2019
SummaryAimAlthough cognitive deficits commonly co‐occur with stress‐related emotional disorders, ... more SummaryAimAlthough cognitive deficits commonly co‐occur with stress‐related emotional disorders, effect of procognitive drugs such as histaminergic H3 receptor antagonists are scarcely studied on memory retrieval in stress condition.MethodsExperiment 1. Memory of two successive spatial discriminations (D1 then D2) 24 hours after learning was studied in a four‐hole board in mice. H3 receptor antagonist ciproxifan (ip 3 mg/kg) and acute stress (three electric footshocks; 0.9 mA; 15 ms) were administered 30 and 15 minutes respectively before memory retrieval test. Fos immunostaining was performed to evaluate the neural activity of several brain areas. Experiment 2. Effects of ciproxifan and acute stress were evaluated on anxiety‐like behavior in the elevated plus maze and glucocorticoid activity using plasma corticosterone assay.ResultsExperiment 1. Ciproxifan increased memory retrieval of D2 in nonstress condition and of D1 in stress one. Ciproxifan mitigated the stress‐induced increa...
Frontiers in psychiatry, 2018
Neuropsychopharmacology, 2016
Altered brain somatostatin functions recently appeared as key elements for the pathogenesis of st... more 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 2 or sst 4 knockout mice. Inhibitory effects of hippocampal infusions of somatostatin agonists on stress-induced hypothalamo-pituitary-adrenal axis (HPA) activity were tested by monitoring peripheral blood and local hippocampus corticosterone levels, the latter by using microdialysis. Anxiolytic and antidepressant-like effects were determined in the elevated-plus maze, open field, forced swimming, and stress-sensitive beam walking tests. Hippocampal injections of somatostatin analogs and sst 2 or sst 4, but not sst 1 or sst 3 receptor agonists produced rapid and sustained inhibition of HPA axis. sst 2 agonists selectively produced anxiolytic-like behaviors whereas both sst 2 and sst 4 agonists had antidepressant-like effects. Consistent with these findings, high corticosterone levels and anxiety were found in sst 2 KO mice and depressive-like behaviors observed in both sst 2 KO and sst 4 KO strains. Both hippocampal sst 2 and sst 4 receptors selectively inhibit stressinduced HPA axis activation but mediate anxiolytic and antidepressive effects through distinct mechanisms. Such results are to be accounted for in development of pathway-specific somatostatin receptor agents in the treatment of hypercortisolism (Cushing's disease) and stress-related neuropsychiatric disorders.
Frontiers in aging neuroscience, 2014
It is now established that vitamin A and its derivatives, retinoic acid (RA), are required for co... more 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. In the present study, we addressed the following issue: whether the stimulation of RA pathway could modulate intrahippocampal corticosterone (CORT) levels in middle-aged mice and thereby impact on hippocampal plasticity and cognitive functions. We firstly investigated the effects of vitamin A supplementation and RA treatment in middle-aged mice, on contextual serial discrimination task, a paradigm which allows the detection of early signs of age-related hippocampal-dependent memory dysfunction. We then measured intrahippocampal CORT concentrations by microdialysis befor...
TheScientificWorldJournal, 2006
Benzodiazepines are known as "acquisition-impairing" molecules, and their effects on an... more Benzodiazepines are known as "acquisition-impairing" molecules, and their effects on anterograde memory processes are well described. In contrast, the impact of benzodiazepines on retrograde memory and, more particularly, on retrieval processes, is only marginally studied. This mini-review provides an overlook of the main studies evidencing an effect of benzodiazepines on retrograde memory, both in humans and animals, with special emphasis on retrieval processes. The conditions for the emergence of the benzodiazepine-induced retrieval impairments are also discussed.
Neural plasticity, 2005
Chronic alcohol consumption (CAC) can lead to the Korsakoff syndrome (KS), a memory deficiency at... more Chronic alcohol consumption (CAC) can lead to the Korsakoff syndrome (KS), a memory deficiency attributed to diencephalic damage and/or to medial temporal or cortical related dysfunction. The etiology of KS remains unclear. Most animal models of KS involve thiamine-deficient diets associated with pyrithiamine treatment. Here we present a mouse model of CAC-induced KS. We demonstrate that CAC-generated retrieval memory deficits in working/ episodic memory tasks, together with a reduction of fear reactivity, result from damage to the mammillary bodies (MB). Experimental lesions of MB in non-alcoholic mice produced the same memory and emotional impairments. Drugs having anxiogenic-like properties counteract such impairments produced by CAC or by MB lesions. We suggest (a) that MB are the essential components of a brain network underlying emotional processes, which would be critically important in the retrieval processes involved in working/ episodic memory tasks, and (b) that failure t...
Frontiers in Behavioral Neuroscience, 2014
Most of the deleterious effects of stress on memory retrieval are due to a dysfunction of the hip... more 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; 0.9 mA each) delivered before memory testing reversed the memory retrieval pattern (MRP) in a serial discrimination task in which mice learned two successive discriminations. More precisely, whereas non-stressed animals remembered accurately the first learned discrimination and not the second one, stressed mice remembered more accurately the second discrimination but not the first one. We demonstrated that local inactivation of dHPC or mPFC with the anesthetic lidocaine recruited the dHPC activity in non-stress conditions whereas the stress-induced MRP inversion recruited the mPFC activity. In a second experiment, we showed that acute stress induced a very similar time-course evolution of corticosterone rises within both the mPFC and dHPC. In a 3rd experiment, we found however that in situ injections of corticosterone either within the mPFC or the dHPC before memory testing favored the emergence of the mPFC-dependent MRP but blocked the emergence of the dHPC-dependent one. Overall, our study evidences that the simultaneous increase of corticosterone after stress in both areas induces a shift from dHPC (non-stress condition) to mPFC-dependent MRP and that corticosterone is critically involved in mediating the deleterious effects of stress on cognitive functions involving the mPFC-HPC interplay.
HPC of young adult mice induced memory impairments similar to those observed in stressed middle-a... more HPC of young adult mice induced memory impairments similar to those observed in stressed middle-aged mice . Because of the impact of benzodiazepines (BDZ) on GABAergic neurons, these compounds are widely prescribed in the treatment of anxiety disorders associated to aging. Indeed, it has been shown that aging causes organisms to become vulnerable to stress, which might be mediated by dysfunction of the brain system regulating emotional and stress responses . However, it is also known that compounds modulating GABA-A receptors such as BDZ, also affect HPCdependent memory functions (for review, see . Furthermore, it has already been demonstrated that GABAergic neurons also act on hypothalamic nuclei of the HPA axis (
Psychopharmacology, 2007
This study investigated the dose-effect relationship of modafinil administration on contextual me... more This study investigated the dose-effect relationship of modafinil administration on contextual memory processes, in parallel with the measurements of plasma corticosterone levels in acutely-stressed mice. Memory was first evaluated in normal (non stressed) mice either in contextual (CSD) or spatial (SSD) tasks. Thus, C57 Bl/6 Jico mice learned two consecutive discriminations (D1 and D2) in a four hole-board. The discriminations occured on either distinct (CSD) or identical (SSD) floors (internal contextual cues). All mice received a vehicle i.p. injection before learning, and were injected 24 hours later (twenty minutes prior to the test session) either with vehicle or modafinil. Results showed that modafinil-treated mice behaved similarly as vehicles in the spatial SSD task whereas in contrast, memory of the first-learned discrimination (D1) in the CSD task was enhanced by a 32 mg/kg but not a 16 mg/kg modafinil dose. Hence, we studied the effect of a pre-test acute stress (electric footshocks) specifically on D1 performance in modafinil-treated subjects. Immediately after behavioral testing, blood was sampled to measure plasma corticosterone levels. Results showed that : i) stress significantly improved performance in vehicles, ii) stress decreased the efficiency threshold of modafinil, since performance was enhanced at the low dose (16 mg/kg), whereas this enhancement was obtained for the high dose (32 mg/kg) in non-stress conditions, iii) the performance was impaired at the high (32mg/kg) dose and iv) modafinil significantly reduced the magnitude of the stress-induced corticosterone secretion, mainly at the dose of 32mg/kg.
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Papers by Daniel beracochea