Age-related impairment of declarative memory: linking memorization of temporal associations to GluN2B redistribution in dorsal CA1.

GluN2B subunits of NMDA receptors have been proposed as a target for treating age-related memory decline. They are indeed considered as crucial for hippocampal synaptic plasticity and hippocampus-dependent memory formation, which are both altered in aging. Because a synaptic enrichment in GluN2B is associated with hippocampal LTP in vitro, a similar mechanism is expected to occur during memory formation. We show instead that a reduction of GluN2B synaptic localization induced by a single-session learning in dorsal CA1 apical dendrites is predictive of efficient memorization of a temporal association. Furthermore, synaptic accumulation of GluN2B, rather than insufficient synaptic localization of these subunits, is causally involved in the age-related impairment of memory. These challenging data identify extra-synaptic redistribution of GluN2B-containing NMDAR induced by learning as a molecular signature of memory formation and indicate that modulating GluN2B synaptic localization might represent a useful therapeutic strategy in cognitive aging.

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.

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.

Estradiol enhances retention but not organization of hippocampus-dependent memory in intact male mice.

Because estrogens have mostly been studied in gonadectomized females, effects of chronic exposure to environmental estrogens in the general population are underestimated. Estrogens can enhance hippocampus-dependent memory through the modulation of information storage. However, declarative memory, the hippocampus-dependent memory of facts and events, demands more than abilities to retain information. Specifically, memory of repetitive events of everyday life such as "where I parked" requires abilities to organize/update memories to prevent proactive interference from similar memories of previous "parking events". Whether such organizational processes are estrogen-sensitive is unknown. We here studied, in intact young and aged adult mice, drinking-water (1µM) estradiol effects on both retention and organizational components of hippocampus-dependent memory, using a radial-maze task of everyday-like memory. Demand on retention vs organization was manipulated by varying the time-interval separating repetitions of similar events. Estradiol increased performance in young and aged mice under minimized organizational demand, but failed to improve the age-associated memory impairment and diminished performance in young mice under high organizational demand. In fact, estradiol prolonged mnemonic retention of successive events without improving organization abilities, hence resulted in more proactive interference from irrelevant memories. c-Fos imaging of testing-induced brain activations showed that the deterioration of young memory was associated with dentate gyrus dysconnectivity, reminiscent of that seen in aged mice. Our findings support the view that estradiol is promnesic but also reveal that such property can paradoxically impair memory. These findings have important outcomes regarding health issues relative to the impact of environmental estrogens in the general population.

Temporal Memory and Its Enhancement by Estradiol Requires Surface Dynamics of Hippocampal CA1 N-Methyl-D-Aspartate Receptors.

BACKGROUND: Identifying the underlying cellular mechanisms of episodic memory is an important challenge, since this memory, based on temporal and contextual associations among events, undergoes preferential degradation in aging and various neuropsychiatric disorders. Memory storage of temporal and contextual associations is known to rely on hippocampal N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity, which depends ex vivo on dynamic organization of surface NMDARs. Whether NMDAR surface trafficking sustains the formation of associative memory, however, remains unknown. METHODS: We tested this hypothesis, using single nanoparticle imaging, electrophysiology, and behavioral approaches, in hippocampal networks challenged with a potent modulator of NMDAR-dependent synaptic plasticity and memory, 17ß-estradiol (E2). RESULTS: We demonstrate that E2 modulates NMDAR surface trafficking, a necessary condition for E2-induced potentiation at hippocampal cornu ammonis 1 synapses. Strikingly, cornu ammonis 1 NMDAR surface trafficking controls basal and E2-enhanced mnemonic retention of temporal, but not contextual, associations. CONCLUSIONS: NMDAR surface trafficking and its modulation by the sex hormone E2 is a cellular mechanism critical for a major component of episodic memory, opening a new and noncanonical research avenue in the physiopathology of cognition.

Partial loss in septo-hippocampal cholinergic neurons alters memory-dependent measures of brain connectivity without overt memory deficits.

The functional relevance of septo-hippocampal cholinergic (SHC) degeneration to the degradation of hippocampus-dependent declarative memory (DM) in aging and Alzheimer's disease (AD) remains ill-defined. Specifically, selective SHC lesions often fail to induce overt memory impairments in animal models. In spite of apparent normal performance, however, neuronal activity within relevant brain structures might be altered by SHC disruption. We hypothesized that partial SHC degeneration may contribute to functional alterations within memory circuits occurring in aging before DM decline. In young adult mice, we studied the effects of behaviorally ineffective (saporin-induced) SHC lesions - similar in extent to that seen in aged animals - on activity patterns and functional connectivity between three main neural memory systems: the septo-hippocampal system, the striatum and the amygdala that sustain declarative, procedural and emotional memory, respectively. Animals were trained in a radial maze procedure dissociating the human equivalents of relational/DM and non-R/DM expressions in animals. Test-induced Fos activation pattern revealed that the partial SHC lesion significantly altered the brain's functional activities and connectivity (co-activation pattern) despite the absence of overt behavioral deficit. Specifically, hippocampal CA3 hyperactivity and abnormal septo-hippocampo-amygdalar inter-connectivity resemble those observed in aging and prodromal AD. Hence, SHC neurons critically coordinate hippocampal function in concert with extra-hippocampal structures in accordance with specific mnemonic demand. Although partial SHC degeneration is not sufficient to impact DM performance by itself, the connectivity change might predispose the emergence of subsequent DM loss when, due to additional age-related insults, the brain can no longer compensate the holistic imbalance caused by cholinergic loss.

Glucocorticoids can induce PTSD-like memory impairments in mice.

Posttraumatic stress disorder (PTSD) is characterized by a hypermnesia of the trauma and by a memory impairment that decreases the ability to restrict fear to the appropriate context. Infusion of glucocorticoids in the hippocampus after fear conditioning induces PTSD-like memory impairments and an altered pattern of neural activation in the hippocampal-amygdalar circuit. Mice become unable to identify the context as the correct predictor of the threat and show fear responses to a discrete cue not predicting the threat in normal conditions. These data demonstrate PTSD-like memory impairments in rodents and identify a potential pathophysiological mechanism of this condition.

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.

Detection of age-dependent working memory deterioration in APP751SL mice.

Despite huge advances on Alzheimer's disease (AD) etiology, the clinical diagnosis remains the unique commonly used tool to detect the onset of the disease. For instance, epidemiological studies report that the combination of episodic and working memory disorders represents the most consistent sign of progression from mild cognitive impairment to AD. However, such working memory disorders failed to be observed early in transgenic mouse models of AD because the behavioral procedures used do not tackle properly crucial components of working memory. The aim of the present work was to assess early occurrence of working memory impairments in APP(751SL) mice. Therefore, we designed a new behavioral task in the water-maze, based on the principle of a delayed matching to place task, where spatial recognition was assessed for four different platform locations within a single session. First, we showed that dorsal hippocampal but not medial prefrontal cortex lesions in C57Bl6 mice induced a time-dependent impairment of spatial recognition. Then, the hippocampal-like memory alterations were reproduced in 7-8-month-old APP(751SL) mice but not in younger animals (5-6-month-old). We also demonstrated that these working memory deficits are related to progressive Aß accumulation in the hippocampus, but not in the other selected brain structures.

Chronic treatment with Delta(9)-tetrahydrocannabinol impairs spatial memory and reduces zif268 expression in the mouse forebrain.

Few studies have investigated the effects of chronic cannabinoid exposure on memory performance and whether tolerance occurs to cannabinoid-induced memory impairment. Here, we studied the effects of repeated exposure to Delta-tetrahydrocannabinol (THC: 1 mg/kg) on spatial memory and zif268 expression in mice. One group of animals was not pretreated with THC, whereas another group was injected with 13 daily injections of THC before memory testing in the Morris water maze. Both groups were administered with THC throughout the memory-testing phase of the experiment. THC decreased spatial memory and reversal learning, even in animals that received the THC pretreatment and were tolerant to the locomotor suppressant effects of the drug. Zif268 immunoreactivity was reduced in the CA3 of the hippocampus and in the prefrontal cortex only in non-pretreated animals, indicating that although tolerance to the effects of THC on neuronal activity was evident, cannabinoid-induced memory impairment in these animals persisted even after 24 days of exposure. This study shows that after extended administration of THC, its spatial memory-impairing effects are resistant to tolerance.