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. This cognitive imbalance could contribute to maintain addictive behaviors and increase the risk of relapse. Methods: We 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 (BLA) to dorsal hippocampus (dCA1) and BLA to dorsolateral striatum (DLS) pathways. Results: We found that both CAC and early AW promote the use of cue-dependent learning strategies, and potentiate plasticity in the BLA → DLS pathway while reducing the use of spatial memory and depressing BLA → dCA1 neurotransmission. Discussion: These results support the view that CAC disrupt normal hippocampo-striatal interactions, and suggest that targeting this cognitive imbalance through spatial/declarative task training could be of great help to maintain protracted abstinence in alcoholic patients.

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. In nonstress condition, we showed that the dHPC lesion induced a significant increase of corticosterone both in plasma and in the vHPC. In addition, an acute stress (electric footshocks) induced a faster and more sustained corticosterone rise in the vHPC of dHPC-lesioned animals, as compared to sham-operated ones. This study provides new found evidence to the effect that the dHPC lesion alters the time-course evolution of corticosterone rise within the vHPC after stress.

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 GABAB receptors) or diazepam (a benzodiazepine having an agonist action on GABAA 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 1.0 mg/kg (Day 15) to 0.25 mg/kg (Day 1) for diazepam and from 1.5 mg/kg (Day 15) to 0.37 mg/kg (Day 1) for baclofen. Alcohol-seeking behavior was evaluated by alcohol-place preference in an odor recognition task. In the stress condition, mice received three electric footshocks 45 min before behavioral testing. Blood was sampled immediately after behavioral testing, and plasma corticosterone concentrations were measured by commercial enzyme immunoassay kits. Results showed that non-stressed withdrawn mice did not exhibit alcohol-place preference or alteration of plasma corticosterone concentrations relative to water controls. After stress, however, withdrawn mice exhibited a significant alcohol-place preference and higher circulating corticosterone concentrations as compared to stressed water controls. Interestingly, repeated administration during the withdrawal phase of baclofen but not diazepam suppressed both the alcohol-place preference and normalized corticosterone levels in stressed withdrawn animals. In conclusion, this study evidences that a pre-treatment with baclofen but not with diazepam during the withdrawal phase normalized, even after a long period of abstinence, the HPA axis response to stress, which contributes to the long-term preventing effects of this compound on alcohol-seeking behavior.

Disrupting effect of drug-induced reward on spatial but not cue-guided learning: implication of the striatal protein kinase A/cAMP response element-binding protein pathway.

The multiple memory systems hypothesis posits that different neural circuits function in parallel and may compete for information processing and storage. For example, instrumental conditioning would depend on the striatum, whereas spatial memory may be mediated by a circuit centered on the hippocampus. However, the nature of the task itself is not sufficient to select durably one system over the other. In this study, we investigated the effects of natural and pharmacological rewards on the selection of a particular memory system during learning. We compared the effects of food- or drug-induced activation of the reward system on cue-guided versus spatial learning using a Y-maze discrimination task. Drug-induced reward severely impaired the acquisition of a spatial discrimination task but spared the cued version of the task. Immunohistochemical analysis of the phosphorylated form of the cAMP response element binding (CREB) protein and c-Fos expression induced by behavioral testing revealed that the spatial deficit was associated with a decrease of both markers within the hippocampus and the prefrontal cortex. In contrast, drug reward potentiated the cued learning-induced CREB phosphorylation within the dorsal striatum. Administration of the protein kinase A inhibitor 8-Bromo-adenosine-3',5'-cyclic monophosphorothioate Rp isomer (Rp-cAMPS) into the dorsal striatum before training completely reversed the drug-induced spatial deficit and restored CREB phosphorylation levels within the hippocampus and the prefrontal cortex. Therefore, drug-induced striatal hyperactivity may underlie the declarative memory deficit reported here. This mechanism could represent an important early step toward the development of addictive behaviors by promoting conditioning to the detriment of more flexible forms of memory.

Differential effects of total sleep deprivation on contextual and spatial memory: modulatory effects of modafinil.

The aim of the present work was to investigate in mice the effects of a total 10-hr sleep deprivation on contextual (episodic-like) and spatial (reference) memory tasks. For that purpose, mice learned two consecutive discriminations (D1 and D2) in a 4-hole board involving either identical (Serial Spatial Discrimination, SSD) or distinct (Contextual Serial Discrimination, CSD) internal contextual cues. In a second step, we intended to assess the corrective effect of modafinil on memory impairments generated by sleep deprivation. Sleep deprivation was triggered through an alternative platform apparatus (water box), previously validated using EEG recording and spectral analysis. We showed that a 10-hr total sleep deprivation impaired the CSD task but not the SSD one. Moreover, the impairment of contextual memory in sleep-deprived animals was dose-dependently corrected by modafinil. Indeed, modafinil administered after the sleep deprivation period and 30 min before the test session restored a memory retrieval pattern identical to non sleep-deprived animals at the doses of 32 and 64 mg/kg, however not at 16 mg/kg. Results hereby evidence that the vigilance-enhancing drug modafinil is able to restore the contextual memory performance at a low dose as compared to other memory tasks, possibly by an enhancement of hippocampal activity known to be both involved in the processing of contextual information and impaired following our sleep deprivation procedure.

Mediodorsal thalamic lesions block the stress-induced inversion of serial memory retrieval pattern in mice.

This study examines the effects of ibotenic acid lesions of the mediodorsal nucleus of the thalamus (MD) on serial contextual memory retrieval in non-stress and stress conditions. Independent groups of mice learned two successive contextual serial discriminations (D1 and D2) in a four-hole board. The discriminations differed each by the color and texture of the floor. Twenty-four hours later, memory testing occurred in independent groups of mice on one of the two floors of the initial acquisition session. Half of the subjects received three electric footschocks (0.9mA, 2s) 5min prior to testing. Results showed that (i) stress induced a plasma corticosterone rise of same magnitude in sham-operated and MD-lesioned mice; (ii) non-stressed sham-operated mice accurately remembered D1 but not D2, whereas stressed sham-operated animals remembered D2 but not D1; (iii) non-stressed MD-lesioned mice exhibited a memory retrieval pattern similar to that observed in non-stressed sham-operated mice; (iv) however, the stress-induced inversion of the memory retrieval pattern was not observed in MD animals. The effects of MD lesions on memory retrieval in this task are similar to those observed in earlier studies in prefrontal cortex or amygdala-lesioned mice [Chauveau F, Piérard C, Coutan M, Drouet I, Liscia P, Béracochéa D. Prefrontal cortex or basolateral amygdala lesions blocked the stress-induced inversion of serial memory pattern in mice. Neurobiol Learn Mem 2008;90:395-403]; they are however in sharp contrast with mice exhibiting hippocampal lesions [Chauveau F, Pierard C, Tronche C, Coutan M, Drouet I, Liscia P, et al. The hippocampus and prefrontal cortex are differentially involved in serial memory retrieval in non-stress and stress condition. Neurobiol Learn Mem; in press; Chauveau F, Pierard C, Tronche C, Coutan M, Drouet I, Liscia P, et al. Rapid stress-induced corticosterone rise in the hippocampus reverses serial memory retrieval pattern. Hippocampus; in press]. Overall, the present findings highlight the involvement of the MD in an AMG/PFC system mediating the rapid effects of stress on serial memory retrieval.

Glucocorticoids down-regulate lipopolysaccharide-induced de novo production of neurotensin mRNA in the rat hypothalamic, paraventricular, corticotrophin-releasing hormone neurons.

OBJECTIVE: Intraperitoneal injection of the endotoxin lipopolysaccharide (LPS) produces inflammation accompanied by activation of the immune system and the secretion of cytokines. Cytokines stimulate the hypothalamo-pituitary-adrenal (HPA) axis to release the anti-inflammatory corticosterone which controls its own production by acting on the HPA axis. Upstream in the HPA axis are neuroendocrine corticotrophin-releasing hormone (CRH) neurons located in the paraventricular nucleus (PVN), whose multipeptidergic phenotype changes during inflammation: while CRH mRNA is up-regulated in these conditions, neurotensin (NT) mRNA expression is induced de novo. The negative feedback control of glucocorticoids on CRH production is well documented; however, their action on NT production in the PVN of the hypothalamus is poorly documented. The aim of this study was to determine if glucocorticoids modulate the de novo production of NT during inflammation. METHODS: Using quantitative in situ hybridization histochemistry, we examined whether the absence (adrenalectomy) or excess (corticosterone implants) of glucocorticoids modulate de novo production of NT mRNA in the PVN during inflammation induced by LPS treatment. RESULTS: A relatively low dose of LPS (50 microg/kg) that is not efficient to induce NT mRNA production in the PVN becomes efficient after adrenalectomy. Moreover, corticosterone excess reduces LPS-induced production of NT mRNA in the PVN. CONCLUSION: Glucocorticoids exert a negative control on NT mRNA production in the PVN of the hypothalamus, and this effect requires that NT mRNA production be triggered, such as during inflammation.

Paraventricular nucleus neurons producing neurotensin after lipopolysaccharide treatment project to the median eminence.

Inflammation consists in secretion of cytokines that stimulate the hypothalamo-pituitary-adrenal (HPA) axis to release the anti-inflammatory corticosterone. Upstream in this axis are corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) whose multipeptidergic phenotype changes: both corticotropin-releasing hormone mRNAs and neurotensin mRNAs are up-regulated. Combining in situ hybridization with a retrograde neuronal marker, we demonstrated that neurotensin-containing neurons in the paraventricular nucleus project to the median eminence.