Differential stress response to psychological and physical stressors in children using spatial versus response-dependent navigation strategies.

Previous work from our lab has shown that basal cortisol levels are different between healthy young adults who spontaneously use caudate nucleus-dependent response strategies compared to young adults who use hippocampus-dependent spatial navigation strategies. Young adults who use caudate nucleus dependent strategies display lower basal cortisol levels compared to those who use hippocampus-dependent strategies. In the current study, we assessed navigation strategies in children using a virtual navigation task and measured cortisol at baseline as well as cortisol reactivity to both a psychological and to a physical stressor. Replicating what is observed in adults, we found that children who used caudate nucleus-dependent navigation strategies displayed lower cortisol levels at baseline compared to those who used hippocampus-dependent strategies. The psychological stressor, knowledge that a blood draw would be performed by a nurse, caused a significant increase in cortisol uniquely in response learners. The physical stressor, the actual blood draw, produced a significant increase in cortisol amongst spatial learners that was then comparable to levels observed in response learners. Lower baseline cortisol and higher cortisol psychological stress response observed amongst children who used response strategies may therefore reflect early biological changes during development which may have an impact later in life when considering risk for neuropsychiatric disorders.

Opposing effects of cortisol on learning and memory in children using spatial versus response-dependent navigation strategies.

Previous studies showed that healthy young adults who spontaneously use caudate nucleus-dependent strategies on a virtual navigation task, have significantly lower basal levels of cortisol compared with adults who use hippocampus-dependent spatial navigation strategies. In the current paper, we assessed the relation between basal cortisol levels and learning using a virtual navigation task in children. We show that basal cortisol level has a differential effect on learning and memory between children using spatial and response navigation strategies. Specifically, cortisol was found to be beneficial for learning performance in children using spatial strategies, such that higher levels of cortisol were associated with more efficient learning in a virtual maze. In contrast, cortisol had a deleterious effect on learning the virtual maze in children using response strategies, such that higher cortisol levels were associated with increased spatial working memory errors. Based on these results, individual differences in navigation strategy could help explain contradictory results in the literature showing that cortisol can have either a positive or negative association with learning and memory performance.

Neuropsychological Measures that Predict Progression from Mild Cognitive Impairment to Alzheimer's type dementia in Older Adults: a Systematic Review and Meta-Analysis.

This study aimed to determine the extent to which cognitive measures can predict progression from mild cognitive impairment (MCI) to Alzheimer's type dementia (AD), assess the predictive accuracy of different cognitive domain categories, and determine whether accuracy varies as a function of age and length of follow-up. We systematically reviewed and meta-analyzed data from longitudinal studies reporting sensitivity and specificity values for neuropsychological tests to identify individuals with MCI who will develop AD. We searched articles in Medline, Cochrane, EMBASE, PsycINFO, and the Web of Science. Methodological quality was assessed using the STARDem and QUADAS standards. Twenty-eight studies met the eligibility criteria (2365 participants) and reported predictive values from 61 neuropsychological tests with a 31-month mean follow-up. Values were pooled to provide combined accuracy for 14 cognitive domains. Many domains showed very good predictive accuracy with high sensitivity and specificity values (≥ 0.7). Verbal memory measures and many language tests yielded very high predictive accuracy. Other domains (e.g., executive functions, visual memory) showed better specificity than sensitivity. Predictive accuracy was highest when combining memory measures with a small set of other domains or when relying on broad cognitive batteries. Cognitive tests are excellent at predicting MCI individuals who will progress to dementia and should be a critical component of any toolkit intended to identify AD at the pre-dementia stage. Some tasks are remarkable as early indicators, whereas others might be used to suggest imminent progression.

Single-trial properties of place cells in control and CA1 NMDA receptor subunit 1-KO mice.

The NMDA receptor plays a key role in synaptic plasticity and its disruption leads to impaired spatial representation in the CA1 area of the hippocampus, with place cells exhibiting larger place fields (McHugh et al., 1996). Place fields are defined by the spatial and nonspatial inputs of a given place and context, by intrinsic network processes, such as phase precession, but also by the matching of these inputs to a pre-existing spatial representation. Larger place fields may be a consequence of spatially widened firing upon a single crossing of a place field, or of increased variability in place field positions across traversals. We addressed this question by monitoring CA1 place cell activity, with tetrodes, in control and KO mice lacking the NMDA receptor in this region. In individual crossings of the field, we found no difference between genotypes in place field size; the larger, overall place field size turns out to be a consequence of jitter across trials. We suggest that this jitter reflects a deficit in the matching of current spatial inputs to the stored spatial representation of the track. This is supported by the finding that deficits in place field size and spatial information are rescued by extensive exposure of the mouse to the track, which may echo an increased influence of memory retrieval processes in CA3 on firing in CA1.

Detecting early preclinical Alzheimer's disease via cognition, neuropsychiatry, and neuroimaging: qualitative review and recommendations for testing.

In this paper, we review studies that have investigated whether neuropsychological, neuropsychiatric, and neuroimaging measures predict decline to Alzheimer's disease (AD). Prospective neuropsychological studies indicate that cognitive performance may be an excellent indicator of future progression from mild cognitive impairment (MCI) to AD, particularly when episodic memory is combined with tasks relying on executive control and language tasks. Research on neuropsychiatric symptoms reveal that depression, apathy, anxiety, and sleep disturbances can contribute to predictive models, though their sensitivity is typically lower than that found with cognitive measures. Finally, different structural brain imaging markers reveal excellent predictive accuracy. The paper discusses issues that will have to be addressed in future studies. First, it will be necessary to increase the evaluation of combined markers, as this may considerably improve predictive accuracy. Second, it will be necessary to move to earlier stages than MCI in order to expand the detection window. Third, processes of compensation and plasticity will have to be better investigated as research moves into earlier stages. The Consortium for the early identification of AD-Quebec (CIMA-Q) is presented as an instance of this approach, and potential batteries of measures are proposed.

Oscillatory dynamics and place field maps reflect hippocampal ensemble processing of sequence and place memory under NMDA receptor control.

Place coding in the hippocampus requires flexible combination of sensory inputs (e.g., environmental and self-motion information) with memory of past events. We show that mouse CA1 hippocampal spatial representations may either be anchored to external landmarks (place memory) or reflect memorized sequences of cell assemblies depending on the behavioral strategy spontaneously selected. These computational modalities correspond to different CA1 dynamical states, as expressed by theta and low- and high-frequency gamma oscillations, when switching from place to sequence memory-based processing. These changes are consistent with a shift from entorhinal to CA3 input dominance on CA1. In mice with a deletion of forebrain NMDA receptors, the ability of place cells to maintain a map based on sequence memory is selectively impaired and oscillatory dynamics are correspondingly altered, suggesting that oscillations contribute to selecting behaviorally appropriate computations in the hippocampus and that NMDA receptors are crucial for this function.

Complementary Roles of the Hippocampus and the Dorsomedial Striatum during Spatial and Sequence-Based Navigation Behavior.

We investigated the neural bases of navigation based on spatial or sequential egocentric representation during the completion of the starmaze, a complex goal-directed navigation task. In this maze, mice had to swim along a path composed of three choice points to find a hidden platform. As reported previously, this task can be solved by using two hippocampal-dependent strategies encoded in parallel i) the allocentric strategy requiring encoding of the contextual information, and ii) the sequential egocentric strategy requiring temporal encoding of a sequence of successive body movements associated to specific choice points. Mice were trained during one day and tested the following day in a single probe trial to reveal which of the two strategies was spontaneously preferred by each animal. Imaging of the activity-dependent gene c-fos revealed that both strategies are supported by an overlapping network involving the dorsal hippocampus, the dorsomedial striatum (DMS) and the medial prefrontal cortex. A significant higher activation of the ventral CA1 subregion was observed when mice used the sequential egocentric strategy. To investigate the potential different roles of the dorsal hippocampus and the DMS in both types of navigation, we performed region-specific excitotoxic lesions of each of these two structures. Dorsal hippocampus lesioned mice were unable to optimally learn the sequence but improved their performances by developing a serial strategy instead. DMS lesioned mice were severely impaired, failing to learn the task. Our data support the view that the hippocampus organizes information into a spatio-temporal representation, which can then be used by the DMS to perform goal-directed navigation.

A Navigation Analysis Tool (NAT) to assess spatial behavior in open-field and structured mazes.

Spatial navigation calls upon mnemonic capabilities (e.g. remembering the location of a rewarding site) as well as adaptive motor control (e.g. fine tuning of the trajectory according to the ongoing sensory context). To study this complex process by means of behavioral measurements it is necessary to quantify a large set of meaningful parameters on multiple time scales (from milliseconds to several minutes), and to compare them across different paradigms. Moreover, the issue of automating the behavioral analysis is critical to cope with the consequent computational load and the sophistication of the measurements. We developed a general purpose Navigation Analysis Tool (NAT) that provides an integrated architecture consisting of a data management system (implemented in MySQL), a core analysis toolbox (in MATLAB), and a graphical user interface (in JAVA). Its extensive characterization of trajectories over time, from exploratory behavior to goal-oriented navigation with decision points using a wide range of parameters, makes NAT a powerful analysis tool. In particular, NAT supplies a new set of specific measurements assessing performances in multiple intersection mazes and allowing navigation strategies to be discriminated (e.g. in the starmaze). Its user interface enables easy use while its modular organization provides many opportunities of extension and customization. Importantly, the portability of NAT to any type of maze and environment extends its exploitation far beyond the field of spatial navigation.

Virtual navigation strategies from childhood to senescence: evidence for changes across the life span.

This study sought to investigate navigational strategies across the life span, by testing 8-years old children to 80-years old healthy older adults on the 4 on 8 virtual maze (4/8VM). The 4/8VM was previously developed to assess spontaneous navigational strategies, i.e., hippocampal-dependent spatial strategies (navigation by memorizing relationships between landmarks) versus caudate nucleus-dependent response strategies (memorizing a series of left and right turns from a given starting position). With the 4/8VM, we previously demonstrated greater fMRI activity and gray matter in the hippocampus of spatial learners relative to response learners. A sample of 599 healthy participants was tested in the current study. Results showed that 84.4% of children, 46.3% of young adults, and 39.3% of older adults spontaneously used spatial strategies (p < 0.0001). Our results suggest that while children predominantly use spatial strategies, the proportion of participants using spatial strategies decreases across the life span, in favor of response strategies. Factors promoting response strategies include repetition, reward and stress. Since response strategies can result from successful repetition of a behavioral pattern, we propose that the increase in response strategies is a biological adaptive mechanism that allows for the automatization of behavior such as walking in order to free up hippocampal-dependent resources. However, the down-side of this shift from spatial to response strategies occurs if people stop building novel relationships, which occurs with repetition and routine, and thereby stop stimulating their hippocampus. Reduced fMRI activity and gray matter in the hippocampus were shown to correlate with cognitive deficits in normal aging. Therefore, these results have important implications regarding factors involved in healthy and successful aging.

A new approach for modeling episodic memory from rodents to humans: the temporal order memory.

One of the crucial issues in actual research on memory disorders and particularly in Alzheimer's disease is the development of behavioral tasks accurately testing episodic memory, a type of memory sensitive to aging and altered early during neurodegenerative disorders. Translational research allowing comparison of similar memory properties between human and rodent models is a requirement for the finding of behavioral and cognitive biomarkers as well as molecular deficits associated to the pathology. In this review, we propose that the ability to remember an ordered sequence of choices during spatial navigation could be one of the episodic memory properties shared by human and rodent models. The ability to learn the correct sequence of choices depends on the hippocampus, requires flexibility and is particularly sensitive to age-related decline in rodents as in humans. In an innovative approach, we took advantage of a well characterized rodent navigation task, the starmaze, to develop a new model of episodic allowing creating and objective experimental testing of a personal past experience without requiring verbal report which can be transferred to human.

From drought sensing to developmental control: evolution of cyclic AMP signaling in social amoebas.

Amoebas and other protists commonly encyst when faced with environmental stress. Although little is known of the signaling pathways that mediate encystation, the analogous process of spore formation in dictyostelid social amoebas is better understood. In Dictyostelium discoideum, secreted cyclic AMP (cAMP) mediates the aggregation of starving amoebas and induces the differentiation of prespore cells. Intracellular cAMP acting on cAMP-dependent protein kinase (PKA) triggers the maturation of spores and prevents their germination under the prevalent conditions of high osmolality in the spore head. The osmolyte-activated adenylate cyclase, ACG, produces cAMP for prespore differentiation and inhibition of spore germination. To retrace the origin of ACG function, we investigated ACG gene conservation and function in species that span the dictyostelid phylogeny. ACG genes, osmolyte-activated ACG activity, and osmoregulation of spore germination were detected in species that represent the 4 major groups of Dictyostelia. Unlike the derived species D. discoideum, many basal Dictyostelia have retained the ancestral mechanism of encystation from solitary amoebas. In these species and in solitary amoebas, encystation is independently triggered by starvation or by high osmolality. Osmolyte-induced encystation was accompanied by an increase in cAMP and prevented by inhibition of PKA, indicating that ACG and PKA activation mediate this response. We propose that high osmolality signals drought in soil amoebas and that developmental cAMP signaling in the Dictyostelia has evolved from this stress response.

Evolutionary origin of cAMP-based chemoattraction in the social amoebae.

Phenotypic novelties can arise if integrated developmental pathways are expressed at new developmental stages and then recruited to serve new functions. We analyze the origin of a novel developmental trait of Dictyostelid amoebae: the evolution of cAMP as a developmental chemoattractant. We show that cAMP's role of attracting starving amoebae arose through recruitment of a pathway that originally evolved to coordinate fruiting body morphogenesis. Orthologues of the high-affinity cAMP receptor (cAR), cAR1, were identified in a selection of species that span the Dictyostelid phylogeny. The cAR1 orthologue from the basal species Dictyostelium minutum restored aggregation and development when expressed in an aggregation-defective mutant of the derived species Dictyostelium discoideum that lacks high-affinity cARs, thus demonstrating that the D. minutum cAR is a fully functional cAR. cAR1 orthologues from basal species are expressed during fruiting body formation, and only this process, and not aggregation, was disrupted by abrogation of cAR1 function. This is in contrast to derived species, where cAR1 is also expressed during aggregation and critically regulates this process. Our data show that coordination of fruiting body formation is the ancestral function of extracellular cAMP signaling, whereas its derived role in aggregation evolved by recruitment of a preexisting pathway to an earlier stage of development. This most likely occurred by addition of distal cis-regulatory regions to existing cAMP signaling genes.