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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. No behavioral alterations are observed in mice still drinking alcohol. To determine the causal role of corticosterone in the withdrawal-associated long-lasting WM deficits, we further show that a single intraperitoneal injection injection of metyrapone (an inhibitor of corticosterone synthesis) 30 minutes before testing, prevents withdrawal-associated WM deficits and reestablishes PFC activity, as assessed by increased phosphorylated C-AMP Response Element-binding protein (CREB) immunoreactivity in withdrawn mice. Finally, we show that intra-PFC blockade of mineralocorticoid receptors by infusion of spironolactone and, to a lesser extent, of GCs receptors by injection of mifepristone reverses the WM deficits induced by withdrawal whereas the same injections into the dHPC do not. Overall, our study evidences that long-lasting GCs dysfunction selectively in the PFC is responsible for the emergence and maintenance of WM impairments after withdrawal and that blocking prefrontal mineralocorticoid receptors receptors restores WM in withdrawn animals., (© 2016 Society for the Study of Addiction.)

Introduction: We investigated the association between cerebral perfusion perturbations in sepsis with possible cognitive decline (CD) after patients' discharge from the intensive care unit (ICU)., Methods: We studied 28 patients with sepsis and Lawton's Instrumental Activities of Daily Living scale (IADL) scores ≥5 who were discharged from a university ICU institution. We evaluated cerebral circulatory parameters (pulsatility index (PI) and cerebral blood flow index (CBFi) was calculated based on the measured velocity of the middle cerebral artery. Use of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) test was performed daily, and either the Mini Mental State Examination test (MMSE) or Clock Drawing test was performed at ICU discharge. CD was categorized as persistent coma, positive CAM-ICU test at discharge, MMSE <24, or an abnormal Clock test., Results: Patients had a median pre-ICU IADL score of 6.3 (95% CI 5.9-6.7). Fourteen patients (50%) had CD at discharge. Two were in persistent coma despite sepsis resolution. Information recall was the most affected mental function of the other 12 patients. Only on the first day, patients with CD had higher PI and lower CBFi compared to those without CD (2.2 ± 0.7 vs. 1.4 ± 0.5, p = 0.02; 363 ± 170 vs. 499 ± 133, p = 0.03, respectively). Multivariable analysis revealed delirium, but not PI, as an independent prognostic factor for CD (OR: 29.62, 95%CI 1.91-458.01, p = 0.01)., Conclusion: Delirium, but not cerebral perfusion alterations, is an independent risk factor for cognitive impairment in septic patients who were discharged from the ICU.

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.p. injection of vehicle or caffeine (8, 16 or 32mg/kg) 30min before the test session. Results showed that in non-stress conditions, the 16mg/kg caffeine dose induced a significant enhancement of D1 performance in CSD but not in SSD. Hence, we studied the effect of an acute stress (electric footshocks) administered 15min before the test session on D1 performance in caffeine-treated mice. Results showed that stress significantly decreased D1 performance in vehicle-treated controls and the memory-enhancing effect induced by the 16mg/kg caffeine dose in non-stress condition is no longer observed. Interestingly, whereas caffeine-treated mice exhibited weaker concentrations of plasma corticosterone as compared to vehicles in non-stress condition, stress significantly increased plasma corticosterone concentrations in caffeine-treated mice which reached similar level to that of controls. Overall, the acute stress blocked both the endocrinological and memory retrieval enhancing effects of caffeine., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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. The results further indicate that Young-TSA mice sacrificed 1 h after training had a robust increase in histone H4 acetylation in the dorsal hippocampal CA1 region (dCA1) and the dorsomedial part of the striatum (DMS), a structure important for spatial information processing. Importantly, TSA infusion in aged mice completely rescued altered H4 acetylation in the dCA1 but failed to alleviate age-associated decreased H4 acetylation in the DMS. Moreover, intrahippocampal TSA infusion produced concomitant decreases (in adults) or increases (in older mice) of acetylated histone levels in the ventral hippocampus (vCA1 and vCA3) and the lateral amygdala, two structures critically involved in stress and emotional responses. These data suggest that the failure of post-training, intrahippocampal TSA injection to reverse age-associated memory impairments may be related to an inability to recruit appropriate circuit-specific epigenetic patterns during early consolidation processes., (© 2014 Wiley Periodicals, Inc.)

Background: Transcranial Doppler can detect cerebral perfusion alteration in septic patients. We correlate static Transcranial Doppler findings with clinical signs of sepsis-associated encephalopathy., Methods: Forty septic patients were examined with Transcranial Doppler on the first and third day of sepsis diagnosis. The pulsatility index (PI) and cerebral blood flow index (CBFi) were calculated by blood velocity in the middle cerebral artery (cm/sec). Patients underwent a daily cognitive assessment with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) test., Results: Twenty-one patients (55%) were found to present confusion. The majority of the patients presented a PI > 1.1 (76%). PI on the first day (but not the third day) could predict a positive CAM-ICU test in septic patients (PI cut-off: 1.3, AUC: 0.905, p < 0.01, sensitivity: 95%, specificity: 88%, AUC: 0.618, p = 0.24). Multivariable analysis showed that PI on the first day is related to a positive CAM-ICU test independent of age and APACHE II score (OR: 5.6, 95% CI: 1.1-29, p = 0.03). A decrease of the PI on the third day was observed in the group that presented initially high PI (>1.3) (2.2 ± 0.71 vs. 1.81 ± 0.64; p = 0.02). On the other hand, an increase in PI was observed in the other patients (1.01 ± 0.15 vs. 1.58 ± 0.57; p < 0.01). On only the first day, the mean blood velocity in the middle cerebral artery and CBFi were found to be lower in those patients with a high initial PI (36 ± 21 vs. 62 ± 28 cm/sec; p < 0.01, 328 ± 101 vs. 581 ± 108; p < 0.01, respectively)., Conclusions: Cerebral perfusion disturbance observed with Transcranial Doppler could explain clinical symptoms of sepsis-associated encephalopathy.

Neurostimulation is a promising treatment for refractory epilepsy. We studied the effect of cortical stimulation with different parameters in the rat motor cortex stimulation model. High intensity simulation (threshold for motor response--100 μA), high frequency (130 Hz) stimulation during 1 h decreased cortical excitability, irrespective of the interpulse interval used (fixed or Poisson distributed). Low intensity (10 μA) and/or low frequency (5 Hz) stimulation had no effect. Cortical stimulation appears promising for the treatment of neocortical epilepsy if frequency and intensity are high enough.

The Mobile Geriatric Team (MGT) is part of the Geriatric Care Program and aims to provide interdisciplinary geriatric expertise to other professionals for old patients hospitalized outside geriatric department. Our hospital has a MGT since 2008. Our objective is to retrospectively describe the population of patients of 75 years and older hospitalized outside the geriatric ward and screened for the risk of functional decline by the MGT between 1 October 2009 and 30 September 2011. We recorded the risk of functional decline, as indicated by the Identification of Senior At Risk score (ISAR) performed within 48 h after admission, place of living, discharge destination, Mini Mental State Examination (MMSE) and Geriatric Depression Scale (GDS) scores. In two years, 1.568 patients > or = 75 Y were screened with the ISAR score (mean age 82.5 Y, 60.7% of women). We identified 833 patients with a high-risk of functional decline (ISAR > or = 3). The majority of high-risk subjects (78%) were living at home before hospitalization and 58.7% returned home after discharge. Depression and cognitive impairment were identified among respectively 41% and 59% of high-risk subjects. Only 128 patients were admitted for fall. Most of the faller patients were living at home prior hospitalization and had an ISAR score > or = 3. The MGT allowed identifying many patients > or = 75 Y living at home and presenting with high-risk of functional decline and geriatric syndromes, confirming that good screening procedures are necessary to optimize management of hospitalized olders. Most of faller patients have an ISAR score > or = 3 and should benefit a comprehensive geriatric assessment.

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. Donepezil alleviated age-related memory deficits, however, by increasing pCREB in the CA1, while pCREB in PL remained unaffected. Finally, whereas neuronal inhibition by lidocaine infusion in the PL appeared deleterious in young mice, the infusion of Rp-cAMPS (a compound known to inhibit CREB phosphorylation) or S 38232 rescued WM in aged animals. Thus, by targeting the α4β2*-nicotinic receptor of the PL, S 38232 alleviates PL CREB overphosphorylation and restores WM in aged mice, which opens new pharmacologic perspectives of therapeutic strategy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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.

Contingency learning is essential for establishing predictive or causal judgements. Retrospective revaluation captures essential aspects of the updating of this knowledge, according to new experience. In the present study, retrospective revaluation and its neural substrate was investigated in a rat conditioned magazine approach. One element of a previously food-reinforced Tone-Light compound stimulus was either further reinforced (inflation) or extinguished (extinction). These treatments affected the predictive value of the alternate stimulus (target), but only when the target was a weakly salient stimulus such as a Light, and the inflation/extinction procedure concerned the more salient element, that is the Tone. As the predictive value of the Light was decreased in comparison with a relevant control group, this revaluation was interpreted as backward blocking, and not unovershadowing. This observation challenges retrospective revaluation models focused on acquisition and prediction error detection, and is better accounted for by retrieval-based associative theories such as the comparator model (Miller and Matzel) [5]. Immunohistochemical detection of the Fos protein after the test phase revealed activation of the orbitofrontal and infralimbic cortices as well as nucleus accumbens core and shell, in rats that exhibited retrospective revaluation. Our results suggest that rats integrate successive experiences at the retrieval stage of retrospective revaluation, and that prefronto-accumbal interactions are involved in this function., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Current transgenic mouse models of Alzheimer disease constitute a relevant tool to examine the relationships between neuropathological lesions, neurodegeneration and clinical syndromes. Nevertheless, addressing the relation between Abeta deposition and cognition deterioration requires careful adjustment for age to decipher underlying mechanisms of impairments and identify potential therapeutic targets. In the present work we have carried out a detailed behavioral analysis of the APP(751SL) transgenic mouse model testing 6 age-points (from 2 to 19-20 months) and estimating in parallel the cerebral Abeta deposition. The immunohistochemistry study indicated a fast progression of Abeta(17-24) staining in several brain structures that reached for most of them, a maximal level at 7-8 months of age. Behavioral experiments showed that APP(751SL) mice displayed alterations in some general functions (muscular strength, motor activity) whereas other functions are preserved (anxiety, exploration). Acquisition and extinction of an appetitive operant conditioning were used to assess early learning deficits. Hippocampal but not dorso-lateral striatal lesion was shown to delay extinction. Although some learning deficits were detected at 5-6 months in the acquisition of the operant conditioning task, more robust impairments in extinction were observed in 7-8-month-old mice. Indeed, spatial memory deficit was associated to a selective hippocampal CA1 impairment of learning-induced Zif268 activation. Because this mouse model displayed gradual memory deficits it gives the opportunity to investigate the temporal progression of molecular and cellular mechanisms that induce cognitive decline.

Rationale: Reinforcement in the medial septal division (MSDB) might involve local GABAergic mechanisms., Objectives: We used intracranial self-administration to determine whether the GABAA agonist muscimol or antagonist bicuculline might have rewarding effects when infused into the MSDB. We assessed the anatomical specificity of muscimol intra-MSDB self-administration by injecting this molecule into the nucleus accumbens (NAc). Finally, we evaluated the involvement of dopaminergic mechanisms in muscimol self-administration., Materials and Methods: BALB/c mice were implanted with a guide cannula targeting the MSDB or the NAc. They were trained to discriminate between the two arms of a Y-maze, one arm being reinforced by muscimol or bicuculline injections. Another group of MSDB implanted mice was pre-treated intraperitoneally before muscimol self-administration with a D1 (SCH23390) or D2/D3 (sulpiride) receptor antagonist or vehicle. A last group of MSDB mice received additional bilateral guide cannulae targeting the ventral tegmental area (VTA) or a more dorsal region to assess the effects of intra-VTA injection of SCH23390 on intra-MSDB muscimol self-administration., Results: Mice self-administered intra-MSDB muscimol (0.6, 1.2, or 12 ng/50 nl), but not bicuculline (1.5 or 3 ng/50 nl). Systemic pre-treatment with SCH23390 (25 microg/kg) or sulpiride (50 mg/kg) or bilateral injection of SCH23390 (0.25 microg/0.1 microl) into the VTA prevented acquisition of intra-MSDB muscimol self-administration., Conclusion: The activation of GABAA receptors in the MSDB supports self-administration, and dopamine release from the VTA may be involved in the acquisition of this behaviour. The MSDB could represent a common brain substrate for the rewarding properties of drugs facilitating GABAA tone.

Both mu-opioid receptors (MORs) and delta-opioid receptors (DORs) are expressed in the ventral tegmental area (VTA) and are thought to be involved in the addictive properties of opiates. However, their respective contributions to opiate reward remain unclear. We used intracranial self-administration (ICSA) to study the rewarding effects of morphine microinjections into the VTA of male and female MOR-/- and DOR-/- mice. In brains of mice tested for intra-VTA morphine self-administration, we analyzed regional Fos protein expression to investigate the neural circuitry underlying this behavior. Male and female WT and DOR-/- mice exhibited similar self-administration performances, whereas knockout of the MOR gene abolished intra-VTA morphine self-administration at all doses tested. Naloxone (4 mg/kg) disrupted this behavior in WT and DOR mutants, without triggering physical signs of withdrawal. Morphine ICSA was associated with an increase in Fos within the nucleus accumbens, striatum, limbic cortices, amygdala, hippocampus, the lateral mammillary nucleus (LM), and the ventral posteromedial thalamus (VPM). This latter structure was found to express high levels of Fos exclusively in self-administering WT and DOR-/- mice. Abolition of morphine reward in MOR-/- mice was associated with a decrease in Fos-positive neurons in the mesocorticolimbic dopamine system, amygdala, hippocampus (CA1), LM, and a complete absence within the VPM. We conclude that (i) VTA MORs, but not DORs, are critical for morphine reward and (ii) the role of VTA-thalamic projections in opiate reward deserves to be further explored.

Convergent data suggest dissociated roles for the lateral (LA) and basolateral (BLA) amygdaloid nuclei in fear conditioning, depending on whether a discrete conditioned stimulus (CS)-unconditional stimulus (US) or context-US association is considered. Here, we show that pretraining inactivation of the BLA selectively impaired conditioning to context. In contrast, inactivation of the LA disrupted conditioning to the discrete tone CS, but also either impaired or enhanced contextual conditioning, depending on whether the context was in the foreground or in the background. Hence, these findings refine the current model of the amygdala function in emotional learning by showing that the BLA and the LA not only differentially contribute to elemental and context-US association, but also promote, through their interaction, the most relevant of these two associations.

This study was aimed at determining (i) whether or not bilateral subtotal lesions of the anterior thalamic nuclei (ATH) in rodents produced memory deficits for spatial and/or non-spatial information and of auditory fear conditioning, and (ii) if these eventual deficits resemble those produced by chronic alcohol consumption (CAC). Working memory was assessed using both spatial (spontaneous alternation) and non-spatial (temporal alternation) delayed response tasks. Results showed that ATH lesions induced delay-dependent memory impairments in both spatial and non-spatial alternation tasks, as well as a decreased level of auditory and background contextual fear conditioning compared with respective controls. CAC did not induce accelerated rate of forgetting in the spatial and non-spatial tasks, but increased the vulnerability to interference in the spatial task. CAC impaired only background contextual fear conditioning. We conclude that ATH nuclei are involved in the maintenance of information over time, regardless of the nature (spatial vs. non-spatial) of the information, and play a role in associative processes for both unimodal (the tone) and polymodal (contextual) information. In contrast, ATH dysfunction does not account for the memory disorders induced by the CAC treatment. Our results contribute to showing that the functional overlap between the structures comprising the hippocampo-mamillo-thalamic pathway is only partial.

A total of 791 spindle poles was analysed with regard to intrafusal fibre composition in the first and second superficial lumbrical muscles from the right and left hindfeet of 9 male and 5 female adult cats. Bag and chain muscle fibres were identified by their myofibrillar ATPase staining profile in the B region, after either acid or alkaline preincubation. A high proportion of the spindle pole population (43.2%) was observed to contain three or more (up to 5) bag fibres; those poles were classified as multiple-bag spindle poles. In the 334 muscle spindles in which both poles were studied, 42 bag fibres (12.6%) were found to be of the 'mixed' type, that is a fibre in which the two poles differ in their ATPase staining profile (either bag1/bag2 or bag/chain). The variability of the intrafusal fibre content observed in spindles of these muscles has been studied in relation to individual characteristics such as sex, weight and side of the animal. In general, multiple-bag spindles are more frequent in male than in female cats and in right as compared to left side muscles. Nearly all 'mixed' bag intrafusal fibres (38 out of 42) were observed in spindles containing 3 or more bag fibres. In 3-bag spindles the proportion of 'mixed' bag spindles is approximately the same in male and female cats. The ratio of 'dynamic' (mean polar bag1 content) to 'static' (mean polar bag2 plus chain fibre content) intrafusal effectors per muscle tends to increase in spindles of right side muscles and to decrease in the heaviest animals. The quantitative and qualitative differences in fibre content of spindles observed in first lumbrical muscles of different animals suggest that the spindle fibre composition, especially that of the 'dynamic' bag1 fibre, may be related to individual predetermined and/or acquired factors.

The glycogen content of the three types of intrafusal muscle fibre was studied with histochemical techniques in cat muscle spindles of superficial lumbrical muscles after a very large number of brief large stretches. Zones of glycogen depletion were observed in a high proportion of nuclear bag fibres, notably in bag 1 fibres, but not in chain fibres. These observations suggest that stretching of bag fibres by itself may activate these fibres.