Impaired quality of life, but not cognition, is linked to a history of chronic hypercortisolism in patients with Cushing's disease in remission.

Context: Impaired cognition and altered quality of life (QoL) may persist despite long-term remission of Cushing's disease (CD). Persistent comorbidities and treatment modalities may account for cognitive impairments. Therefore, the role of hypercortisolism per se on cognitive sequelae remains debatable. Objective: To investigate whether memory and QoL are impaired after long-term remission of CD in patients with no confounding comorbidity. Design and Setting: Cross-sectional case-control study in two tertiary referral centers. Patients: 25 patients (44.5 ± 2.4 years) in remission from CD for 102.7 ± 19.3 Mo and 25 well-matched controls, without comorbidity or treatment liable to impair cognition. Main Outcome Measures: Hippocampus- and prefrontal cortex-dependent memory, including memory flexibility and working memory, were investigated using multiple tests including sensitive locally-developed computerized tasks. Depression and anxiety were evaluated with the MADRS and HADS questionnaires. QoL was evaluated with the SF-36 and CushingQoL questionnaires. The intensity of CD was assessed using mean urinary free cortisol and a score for clinical symptoms. Results: CD patients displayed similar performance to controls in all cognitive tests. In contrast, despite the absence of depression and a minimal residual clinical Cushing score, patients had worse QoL. Most of the SF36 subscales and the CushingQoL score were negatively associated only with the duration of exposure to hypercortisolism (p≤ 0.01 to 0.001). Conclusions: Persistent comorbidities can be a primary cause of long-lasting cognitive impairment and should be actively treated. Persistently altered QoL may reflect irreversible effects of hypercortisolism, highlighting the need to reduce its duration. Clinical Trial Registration number: https://clinicaltrials.gov, identifier NCT02603653.

Gut Microbiota and Mycobiota Evolution Is Linked to Memory Improvement after Bariatric Surgery in Obese Patients: A Pilot Study.

Patients with obesity are known to exhibit gut microbiota dysbiosis and memory deficits. Bariatric surgery (BS) is currently the most efficient anti-obesity treatment and may improve both gut dysbiosis and cognition. However, no study has investigated association between changes of gut microbiota and cognitive function after BS. We prospectively evaluated 13 obese patients on anthropometric data, memory functions, and gut microbiota-mycobiota before and six months after BS. The Rey Auditory Verbal Learning Test (AVLT) and the symbol span (SS) of the Weschler Memory Scale were used to assess verbal and working memory, respectively. Fecal microbiota and mycobiota were longitudinally analyzed by 16S and ITS2 rRNA sequencing respectively. AVLT and SS scores were significantly improved after BS (AVLT scores: 9.7 ± 1.7 vs. 11.2 ± 1.9, p = 0.02, and SS scores: 9.7 ± 23.0 vs. 11.6 ± 2.9, p = 0.05). An increase in bacterial alpha-diversity, and Ruminococcaceae, Prevotella, Agaricus, Rhodotorula, Dipodascus, Malassezia, and Mucor were significantly associated with AVLT score improvement after BS, while an increase in Prevotella and a decrease in Clostridium, Akkermansia, Dipodascus and Candida were linked to SS scores improvement. We identified several changes in the microbial communities that differ according to the improvement of either the verbal or working memories, suggesting a complex gut-brain-axis that evolves after BS.

Polyphenols From Grape and Blueberry Improve Episodic Memory in Healthy Elderly with Lower Level of Memory Performance: A Bicentric Double-Blind, Randomized, Placebo-Controlled Clinical Study.

Polyphenols are promising nutritional bioactives exhibiting beneficial effect on age-related cognitive decline. This study evaluated the effect of a polyphenol-rich extract from grape and blueberry (PEGB) on memory of healthy elderly subjects (60-70 years-old). A bicentric, randomized, double-blind, placebo-controlled trial was conducted with 215 volunteers receiving 600 mg/day of PEGB (containing 258 mg flavonoids) or a placebo for 6 months. The primary outcome was the CANTAB Paired Associate Learning (PAL), a visuospatial learning and episodic memory test. Secondary outcomes included verbal episodic and recognition memory (VRM) and working memory (SSP). There was no significant effect of PEGB on the PAL on the whole cohort. Yet, PEGB supplementation improved VRM-free recall. Stratifying the cohort in quartiles based on PAL at baseline revealed a subgroup with advanced cognitive decline (decliners) who responded positively to the PEGB. In this group, PEGB consumption was also associated with a better VRM-delayed recognition. In addition to a lower polyphenol consumption, the urine metabolomic profile of decliners revealed that they excreted more metabolites. Urinary concentrations of specific flavan-3-ols metabolites were associated, at the end of the intervention, with the memory improvements. Our study demonstrates that PEGB improves age-related episodic memory decline in individuals with the highest cognitive impairments.

Protocols to Study Declarative Memory Formation in Mice and Humans:Optogenetics and Translational Behavioral Approaches.

Declarative memory formation depends on the hippocampus and declines in aging. Two functions of the hippocampus, temporal binding and relational organization (Rawlins and Tsaltas, 1983; Eichenbaum et al., 1992 ; Cohen et al., 1997 ), are known to decline in aging (Leal and Yassa, 2015). However, in the literature distinct procedures have been used to study these two functions. Here, we describe the experimental procedures used to investigate how these two processes are related in the formation of declarative memory and how they are compromised in aging ( Sellami et al., 2017 ). First, we studied temporal binding using a one-trial learning procedure: trace fear conditioning. It is classical Pavlovian conditioning requiring temporal binding since a brief temporal gap separates the conditioned stimulus (CS) and unconditioned stimulus (US) presentations. We combined the trace fear condition procedure with an optogenetic approach, and we showed that the temporal binding relies on dorsal (d)CA1 activity over temporal gaps. Then, we studied the interaction between temporal binding and relational organization in declarative memory formation using a two-phase radial-maze task in mice and its virtual analog in humans. The behavioral procedure comprises an initial learning phase where subjects learned the constant rewarding /no rewarding valence of each arm, followed by a test phase where the reward contingencies among the arms remained unchanged but where the arms were recombined to assess flexibility, a cardinal property of declarative memory. We demonstrated that dCA1-dependent temporal binding is necessary for the development of a relational organization of memories that allows flexible declarative memory expression. Furthermore, in aging, the degradation of declarative memory is due to a reduction of temporal binding capacity that prevents relation organization.

Hippocampus-dependent spatial learning is associated with higher global cognition among healthy older adults.

Cognitive deficits in normal aging have been associated with atrophy of the hippocampus. As such, methods to detect early dysfunction of the hippocampus have become valuable, if not indispensable, to early intervention. The hippocampus is critical for spatial memory and is among the first structures to atrophy with aging. Despite the presence of navigation deficits in aging, few studies have looked at the association between wayfinding ability, navigation strategies, general cognitive function, and hippocampal volume. In the current study we investigated whether better general cognitive function is associated with the use of hippocampal-dependent spatial strategies, better spatial memory, and increased hippocampal volume. We also investigated, within older adults, the effects of aging on spatial memory. Healthy older adults (N = 107) were tested on a virtual wayfinding task and a dual-solution navigation task that can be solved using either a hippocampal-dependent spatial strategy or a caudate nucleus-dependent response strategy. Participants were also administered the Montreal Cognitive Assessment (MoCA), a test that measures general cognition and is sensitive to dementia. A structural MRI was administered to a sub-set of participants (n = 49) and hippocampal volume was calculated using a Multiple Automatically Generated Templates (MAGeT) Brain algorithm. We found that age was negatively associated with wayfinding ability and hippocampal volume. On the wayfinding task, participants with higher MoCA scores found more target locations and travelled shorter distances. We also found a significant association between higher MoCA scores and spatial strategy use. MoCA scores, spatial memory ability, and spatial strategy use all positively correlated with a larger hippocampal volume. These results confirm that with age there is a decrease in spatial memory, which is consistent with decreased volume in the hippocampus with aging. Furthermore, better general cognitive function is associated with better wayfinding ability and increased use of hippocampal-dependent spatial strategies.

Temporal binding function of dorsal CA1 is critical for declarative memory formation.

Temporal binding, the process that enables association between discontiguous stimuli in memory, and relational organization, a process that enables the flexibility of declarative memories, are both hippocampus-dependent and decline in aging. However, how these two processes are related in supporting declarative memory formation and how they are compromised in age-related memory loss remain hypothetical. We here identify a causal link between these two features of declarative memory: Temporal binding is a necessary condition for the relational organization of discontiguous events. We demonstrate that the formation of a relational memory is limited by the capability of temporal binding, which depends on dorsal (d)CA1 activity over time intervals and diminishes in aging. Conversely, relational representation is successful even in aged individuals when the demand on temporal binding is minimized, showing that relational/declarative memory per se is not impaired in aging. Thus, bridging temporal intervals by dCA1 activity is a critical foundation of relational representation, and a deterioration of this mechanism is responsible for the age-associated memory impairment.

Decreased functional magnetic resonance imaging activity in the hippocampus in favor of the caudate nucleus in older adults tested in a virtual navigation task.

The neuroimaging literature has shown consistent decreases in functional magnetic resonance imaging (fMRI) activity in the hippocampus of healthy older adults engaged in a navigation task. However, navigation in a virtual maze relies on spatial or response strategies known to depend on the hippocampus and caudate nucleus, respectively. Therefore, since the proportion of people using spatial strategies decreases with normal aging, we hypothesized that it was responsible for the observed decreases in fMRI activity in the hippocampus reported in the literature. The aim of this study was to examine the effects of aging on the hippocampus and caudate nucleus during navigation while taking into account individual navigational strategies. Young (N = 23) and older adults (N = 29) were tested using fMRI on the Concurrent Spatial Discrimination Learning Task, a radial task that dissociates between spatial and response strategies (in Stage 2) after participants reached criteria (in Stage 1). Success on Stage 2 requires that participants have encoded the spatial relationship between the target object and environmental landmarks, that is, the spatial strategy. While older adults required more trials, all participants reached criterion. fMRI results showed that, as a group, young adults had significant activity in the hippocampus as opposed to older adults who instead had significant activity in the caudate nucleus. Importantly, individual differences showed that the older participants who used a spatial strategy to solve the task had significant activity in the hippocampus. These findings suggest that the aging process involves a shift from using the hippocampus toward the caudate nucleus during navigation but that activity in the hippocampus is sustained in a subset of healthy older adults engaged in spatial strategies.

Juvenile, but not adult exposure to high-fat diet impairs relational memory and hippocampal neurogenesis in mice.

Increased consumption of high-fat diet (HFD) leads to obesity and adverse neurocognitive outcomes. Childhood and adolescence are important periods of brain maturation shaping cognitive function. These periods could consequently be particularly sensitive to the detrimental effects of HFD intake. In mice, juvenile and adulthood consumption of HFD induce similar morphometric and metabolic changes. However, only juvenile exposure to HFD abolishes relational memory flexibility, assessed after initial radial-maze concurrent spatial discrimination learning, and decreases neurogenesis. Our results identify a critical period of development covering adolescence with higher sensitivity to HFD-induced hippocampal dysfunction at both behavioral and cellular levels.

Studying the impact of aging on memory systems: contribution of two behavioral models in the mouse.

In the present chapter, we describe our own attempts to improve our understanding of the pathophysiology of memory in aging. First, we tried to improve animal models of memory degradations occurring in aging, and develop common behavioral tools between mice and humans. Second, we began to use these behavioral tools to identify the molecular/intracellular changes occurring within the integrate network of memory systems in order to bridge the gap between the molecular and system level of analysis. The chapter is divided into three parts (i) modeling aging-related degradation in declarative memory (DM) in mice, (ii) assessing the main components of working memory (WM) with a common radial-maze task in mice and humans and (iii) studying the role of the retinoid cellular signaling path in aging-related changes in memory systems.

Evidence for a virtual human analog of a rodent relational memory task: a study of aging and fMRI in young adults.

A radial maze concurrent spatial discrimination learning paradigm consisting of two stages was previously designed to assess the flexibility property of relational memory in mice, as a model of human declarative memory. Aged mice and young adult mice with damage to the hippocampus, learned accurately Stage 1 of the task which required them to learn a constant reward location in a specific set of arms (i.e., learning phase). In contrast, they were impaired relative to healthy young adult mice in a second stage when faced with rearrangements of the same arms (i.e., flexibility probes). This mnemonic inflexibility in Stage 2 is thought to derive from insufficient relational processing by the hippocampus during initial learning (Stage 1) which favors stimulus-response learning, a form of procedural learning. This was proposed as a model of the selective declarative and relational memory decline classically described in elderly people. As a first step to examine the validity of this model, we adapted this protocol to humans using a virtual radial-maze. (1) We showed that performance in the flexibility probes in young and older adults positively correlated with performance in a wayfinding task, suggesting that our paradigm assesses relational memory. (2) We demonstrated that older healthy participants displayed a deficit in the performance of the flexibility probes (Stage 2), similar to the one previously seen in aged mice. This was associated with a decline in the wayfinding task. (3) Our fMRI data in young adults confirmed that hippocampal activation during early discrimination learning in Stage 1 correlated with memory flexibility in Stage 2, whereas caudate nucleus activation in Stage 1 negatively correlated with subsequent flexibility. By enabling relational memory assessment in mice and humans, our radial-maze paradigm provides a valuable tool for translational research.

The brain-derived neurotrophic factor Val66Met polymorphism is associated with reduced functional magnetic resonance imaging activity in the hippocampus and increased use of caudate nucleus-dependent strategies in a human virtual navigation task.

Multiple memory systems are involved in parallel processing of spatial information during navigation. A series of studies have distinguished between hippocampus-dependent 'spatial' navigation, which relies on knowledge of the relationship between landmarks in one's environment to build a cognitive map, and habit-based 'response' learning, which requires the memorization of a series of actions and is mediated by the caudate nucleus. Studies have demonstrated that people spontaneously use one of these two alternative navigational strategies with almost equal frequency to solve a given navigation task, and that strategy correlates with functional magnetic resonance imaging (fMRI) activity and grey matter density. Although there is evidence for experience modulating grey matter in the hippocampus, genetic contributions may also play an important role in the hippocampus and caudate nucleus. Recently, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene has emerged as a possible inhibitor of hippocampal function. We have investigated the role of the BDNF Val66Met polymorphism on virtual navigation behaviour and brain activation during an fMRI navigation task. Our results demonstrate a genetic contribution to spontaneous strategies, where 'Met' carriers use a response strategy more frequently than individuals homozygous for the 'Val' allele. Additionally, we found increased hippocampal activation in the Val group relative to the Met group during performance of a virtual navigation task. Our results support the idea that the BDNF gene with the Val66Met polymorphism is a novel candidate gene involved in determining spontaneous strategies during navigation behaviour.

Retinoid hyposignaling contributes to aging-related decline in hippocampal function in short-term/working memory organization and long-term declarative memory encoding in mice.

An increasing body of evidence indicates that the vitamin A metabolite retinoic acid (RA) plays a role in adult brain plasticity by activating gene transcription through nuclear receptors. Our previous studies in mice have shown that a moderate downregulation of retinoid-mediated transcription contributed to aging-related deficits in hippocampal long-term potentiation and long-term declarative memory (LTDM). Here, knock-out, pharmacological, and nutritional approaches were used in a series of radial-arm maze experiments with mice to further assess the hypothesis that retinoid-mediated nuclear events are causally involved in preferential degradation of hippocampal function in aging. Molecular and behavioral findings confirmed our hypothesis. First, a lifelong vitamin A supplementation, like short-term RA administration, was shown to counteract the aging-related hippocampal (but not striatal) hypoexpression of a plasticity-related retinoid target-gene, GAP43 (reverse transcription-PCR analyses, experiment 1), as well as short-term/working memory (STWM) deterioration seen particularly in organization demanding trials (STWM task, experiment 2). Second, using a two-stage paradigm of LTDM, we demonstrated that the vitamin A supplementation normalized memory encoding-induced recruitment of (hippocampo-prefrontal) declarative memory circuits, without affecting (striatal) procedural memory system activity in aged mice (Fos neuroimaging, experiment 3A) and alleviated their LTDM impairment (experiment 3B). Finally, we showed that (knock-out, experiment 4) RA receptor beta and retinoid X receptor gamma, known to be involved in STWM (Wietrzych et al., 2005), are also required for LTDM. Hence, aging-related retinoid signaling hypoexpression disrupts hippocampal cellular properties critically required for STWM organization and LTDM formation, and nutritional vitamin A supplementation represents a preventive strategy. These findings are discussed within current neurobiological perspectives questioning the historical consensus on STWM and LTDM system partition.

Spontaneous navigational strategies and performance in the virtual town.

The 4-on-8 virtual maze provides evidence for variability in spontaneous strategy use during navigation. Functional magnetic resonance imaging (MRI) confirmed that these spatial and response strategies rely on the hippocampus and caudate nucleus memory systems, respectively. We asked whether the spontaneous use of a particular navigational strategy was associated with a particular ability to navigate in one's environment. We tested 30 young participants on the 4-on-8 virtual maze and we assessed their way finding ability in a virtual town. As expected, spatial learners performed well in the virtual town and the response learners, who never used external landmarks and relied purely on an egocentric strategy, performed poorly. Interestingly, a group who used the most efficient response strategy based on external landmarks in the 4-on-8 virtual maze, switched to the most efficient spatial strategy in the virtual town. Our data suggest that the best navigators are those who appropriately use spatial or response strategies depending on the demands of the task.

The hippocampus plays a critical role at encoding discontiguous events for subsequent declarative memory expression in mice.

The hypothesis that hippocampal activity at encoding is causally related to subsequent declarative memory expression is tested in the mouse, by using lidocaine inactivation of the hippocampus in combination with c-fos neuroimaging analysis. We employed a two-stage radial maze paradigm of spatial discrimination, which was previously shown to dissociate between declarative and nondeclarative expression of memory related to the same acquired material. In Stage 1 (encoding), mice learnt the constant location of food among a set of six arms (three baited, three unbaited) by being submitted repeatedly to discontiguous experiences with each arm separately ("go/no-go" discrimination). In Stage 2 (test-session), they are challenged with novel presentations of the arms, which are either combined into pairs of opposite valence ("two-choice" discrimination), or opened all six together ("six-choice" discrimination). Previous experiments have demonstrated that the "two-choice" situation is a critical test for declarative memory while "six-choice" discrimination may rely on procedural memory. We observed that (i) hippocampal activity measured by c-fos mRNA expression was increased by "go/no-go" learning, and this activation was blocked by pre-training local infusions of lidocaine; (ii) when performed just before each session of Stage 1, such inactivation spared the acquisition of "go/no-go" discrimination but produced, subsequently, a selective deficit in the "two-choice" test (not in the "six-choice" test). This study indicates that the hippocampus is "spontaneously" engaged in encoding processes necessary for long-term storage of discontiguous experiences under a form enabling flexible declarative memory expression.

Vitamin A deficiency and relational memory deficit in adult mice: relationships with changes in brain retinoid signalling.

Vitamin A and its derivatives, the retinoids, have recently been reported to be implicated in the synaptic plasticity of the hippocampus and in cognitive functions. Acting via transcription factors, retinoids can regulate gene expression via their nuclear receptors [retinoic acid receptors (RARs) and retinoid X receptors (RXRs)]. We recently showed that a moderate (about 30%) hypoexpression of brain (and hippocampal) retinoid signalling, like that naturally occurring in the aged brain of mice, might be related to a selective relational memory deficit. To further assess this hypothesis, the present study investigated the effects of Vitamin A deprivation of varying duration both on the brain expression of retinoid receptors (RARbeta and RXRbeta/gamma) and two associated target genes [tissue-type transglutaminase (tTG) and neurogranin, (RC3)], and on radial maze discrimination learning using young adult mice as subjects. We observed that irrespective of its duration (i.e. 31 or 39 weeks), Vitamin A deprivation resulted in a significant reduction (25-30%) in the expression of brain RARbeta, RXRbeta/gamma and tTG mRNAs. Conversely, only the 39-week condition was found to induce a significant decrease in brain RC3 mRNAs contents and a selective relational memory impairment. Finally, daily administration of retinoic acid (RA) failed to reverse the 39-week Vitamin A deficiency (VAD)-related cognitive deficit and to fully normalise the associated brain retinoid hyposignalling. In particular, there was no evidence for an up-regulating effect of RA on whole brain (and hippocampal) RC3 mRNAs of the 39-week-depleted mice. The results show that post-natal VAD may induce a selective memory impairment and give further support to the hypothesis that the fine regulation of retinoid-mediated gene expression is important for optimal brain functioning and higher cognition.

Hippocampal lesions and discrimination performance of mice in the radial maze: sparing or impairment depending on the representational demands of the task.

The effects of ibotenate hippocampal lesions on discrimination performance in an eight-arm radial maze were investigated in mice, using a three-stage paradigm in which the only parameter that varied among stages was the way the arms were presented. In the initial learning phase (stage 1), animals learned the valence or reward contingency associated with six (three positive and three negative) adjacent arms of the maze using a successive (go/no-go) discrimination procedure. In the first test phase (stage 2), the six arms were grouped into three pairs, so that on each trial, the subject was faced with a choice between two adjacent arms of opposite valence (concurrent two-choice discrimination). In the second test phase (stage 3), the subject was faced with all six arms simultaneously (six-choice discrimination). Hippocampal-lesioned mice acquired the initial learning phase at a near-normal rate but behaved as if they had learned nothing when challenged with the two-choice discriminations at stage 2. In contrast, they behaved normally when confronted with the six-choice discrimination at stage 3. Detailed examination of within- and between-stage performance suggests that hippocampal-lesioned mice perform as intact mice when presentation of the discriminanda encourages the storage and use of separate representations (i.e., in initial learning and six-choice discrimination testing), but that they fail in test situations that involve explicit comparisons between such separate representations (two-choice discriminations), hence requiring the use of relational representations.