Diversifying faculty recruitment in biomedical sciences.

A wealth of data has consistently demonstrated that a diverse faculty maximizes productivity and innovation in the research enterprise and increases the persistence and success of groups that are underrepresented in STEM. While the diversity of students in graduate programs has steadily increased, faculty diversity, particularly in the biomedical sciences, continues to remain relatively flat. Several issues contribute to this mismatch between the pipeline and the professoriate including biases in search and hiring practices, lack of equity and equal opportunities for individuals from underrepresented backgrounds, and unwelcoming campus climates that lead to marginalization and isolation in academic life. A comprehensive approach that addresses these challenges is necessary for institutions of higher education to achieve their faculty diversity goals and create a climate where individuals from all groups feel welcomed and succeed. This article focuses on the first step in this approach-diversifying faculty recruitment through adopting search practices that generate an applicant pool that matches national availability, ensures equity in evaluation and hiring practices, and promotes inclusion and belonging in the hiring experience. These strategies have been recently used at the University of California, Irvine's School of Biological Sciences and while the long-term impact remains unknown, short-term outcomes in recruitment and hiring have demonstrated significant improvement over previous years.

Parsing memory and nonmemory contributions to age-related declines in mnemonic discrimination performance: a hierarchical Bayesian diffusion decision modeling approach.

The mnemonic discrimination task (MDT) is a widely used cognitive assessment tool. Performance in this task is believed to indicate an age-related deficit in episodic memory stemming from a decreased ability to pattern-separate among similar experiences. However, cognitive processes other than memory ability might impact task performance. In this study, we investigated whether nonmnemonic decision-making processes contribute to the age-related deficit in the MDT. We applied a hierarchical Bayesian version of the Ratcliff diffusion model to the MDT performance of 26 younger and 31 cognitively normal older adults. It allowed us to decompose decision behavior in the MDT into different underlying cognitive processes, represented by specific model parameters. Model parameters were compared between groups, and differences were evaluated using the Bayes factor. Our results suggest that the age-related decline in MDT performance indicates a predominantly mnemonic deficit rather than differences in nonmnemonic decision-making processes. In addition, this mnemonic deficit might also involve a slowing in processes related to encoding and retrieval strategies, which are relevant for successful memory as well. These findings help to better understand what cognitive processes contribute to the age-related decline in MDT performance and may help to improve the diagnostic value of this popular task.

Entorhinal-Hippocampal Circuit Integrity Is Related to Mnemonic Discrimination and Amyloid-ß Pathology in Older Adults.

Mnemonic discrimination, a cognitive process that relies on hippocampal pattern separation, is one of the first memory domains to decline in aging and preclinical Alzheimer's disease. We tested whether functional connectivity (FC) within the entorhinal-hippocampal circuit, measured with high-resolution resting state fMRI, is associated with mnemonic discrimination and amyloid-ß (Aß) pathology in a sample of 64 cognitively normal human older adults (mean age, 71.3 ± 6.4 years; 67% female). FC was measured between entorhinal-hippocampal circuit nodes with known anatomical connectivity, as well as within cortical memory networks. Aß pathology was measured with 18F-florbetapir-PET, and neurodegeneration was assessed with subregional volume from structural MRI. Participants performed both object and spatial versions of a mnemonic discrimination task outside of the scanner and were classified into low-performing and high-performing groups on each task using a median split. Low object mnemonic discrimination performance was specifically associated with increased FC between anterolateral entorhinal cortex (alEC) and dentate gyrus (DG)/CA3, supporting the importance of this connection to object memory. This hyperconnectivity between alEC and DG/CA3 was related to Aß pathology and decreased entorhinal cortex volume. In contrast, spatial mnemonic discrimination was not associated with altered FC. Aß was further associated with dysfunction within hippocampal subfields, particularly with decreased FC between CA1 and subiculum as well as reduced volume in these regions. Our findings suggest that Aß may indirectly lead to memory impairment through entorhinal-hippocampal circuit dysfunction and neurodegeneration and provide a mechanism for increased vulnerability of object mnemonic discrimination.SIGNIFICANCE STATEMENT Mnemonic discrimination is a critical episodic memory process that is performed in the dentate gyrus (DG) and CA3 subfield of the hippocampus, relying on input from entorhinal cortex. Mnemonic discrimination is particularly vulnerable to decline in older adults; however, the mechanisms behind this vulnerability are still unknown. We demonstrate that object mnemonic discrimination impairment is related to hyperconnectivity between the anterolateral entorhinal cortex and DG/CA3. This hyperconnectivity was associated with amyloid-ß pathology and neurodegeneration in entorhinal cortex, suggesting aberrantly increased network activity is a pathological process. Our findings provide a mechanistic explanation of the vulnerability of object compared to spatial mnemonic discrimination in older adults and has translational implications for choice of outcome measures in clinical trials for Alzheimer's disease.

Pupil dynamics during very light exercise predict benefits to prefrontal cognition.

Physical exercise, even stress-free very-light-intensity exercise such as yoga and very slow running, can have beneficial effects on executive function, possibly by potentiating prefrontal cortical activity. However, the exact mechanisms underlying this potentiation have not been identified. Evidence from studies using pupillometry demonstrates that pupil changes track the real-time dynamics of activity linked to arousal and attention, including neural circuits from the locus coeruleus to the cortex. This makes it possible to examine whether pupil-linked brain dynamics induced during very-light-intensity exercise mediate benefits to prefrontal executive function in healthy young adults. In this experiment, pupil diameter was measured during 10 min of very-light-intensity exercise (30% V˙o2peak). A Stroop task was used to assess executive function before and after exercise. Prefrontal cortical activation during the task was assessed using multichannel functional near-infrared spectroscopy (fNIRS). We observed that very-light-intensity exercise significantly elicited pupil dilation, reduction of Stroop interference, and task-related left dorsolateral prefrontal cortex activation compared with the resting-control condition. The magnitude of change in pupil dilation predicted the magnitude of improvement in Stroop performance. In addition, causal mediation analysis showed that pupil dilation during very-light-intensity exercise robustly determined subsequent enhancement of Stroop performance. This finding supports our hypothesis that the pupil-linked mechanisms, which may be tied to locus coeruleus activation, are a potential mechanism by which very light exercise enhances prefrontal cortex activation and executive function. It also suggests that pupillometry may be a useful tool to interpret the beneficial impact of exercise on boosting cognition.

Associations between saliva and plasma cytokines in cognitively normal, older adults.

BACKGROUND: Inflammatory responses play key roles in the development and progression of many pathological conditions, including neurodegenerative diseases. Accurate quantification of inflammatory factors in saliva would be highly advantageous, given its convenience and non-invasive nature, especially in elderly populations. METHODS: In this study, we measured levels of 10 cytokines, and the pro-inflammatory factor, YKL-40, in plasma and saliva samples from a cohort of nondemented older adults (n = 71; 62% female; 70.3 ± 6.4 years) using sensitive electrochemiluminescence-based immunoassays. RESULTS: We found that the mean levels of all cytokines were higher in saliva compared to plasma and that strong sex differences were observed for both saliva and plasma cytokines in this population. Comparing each cytokine between the two biofluids, we found that levels of interferon-gamma (IFNγ), interleukin (IL)-6 and tumor necrosis factor-alpha (TNFα) in blood were significantly correlated with their respective levels in saliva. We further observed that levels of these cytokines in blood were significantly correlated with additional cytokines in saliva, including IL-1ß, IL-10, IL-8, IL12p70 and IL-13. CONCLUSIONS: These findings show that inflammatory markers in saliva are associated with those found in circulation, suggesting shared inflammatory mechanisms between these two fluids. The higher levels of cytokines measured in saliva suggest that it might represent a better peripheral fluid to gauge inflammatory processes. Finally, our findings of robust sex differences in several salivary cytokines could have important implications for their potential use as disease biomarkers in the elderly and might be related to sex differences in the prevalence of age-related conditions.

Aberrant Maturation of the Uncinate Fasciculus Follows Exposure to Unpredictable Patterns of Maternal Signals.

Across species, unpredictable patterns of maternal behavior are emerging as novel predictors of aberrant cognitive and emotional outcomes later in life. In animal models, exposure to unpredictable patterns of maternal behavior alters brain circuit maturation and cognitive and emotional outcomes. However, whether exposure to such signals in humans alters the development of brain pathways is unknown. In mother-child dyads, we tested the hypothesis that exposure to more unpredictable maternal signals in infancy is associated with aberrant maturation of corticolimbic pathways. We focused on the uncinate fasciculus, the primary fiber bundle connecting the amygdala to the orbitofrontal cortex and a key component of the medial temporal lobe-prefrontal cortex circuit. Infant exposure to unpredictable maternal sensory signals was assessed at 6 and 12 months. Using high angular resolution diffusion imaging, we quantified the integrity of the uncinate fasciculus using generalized fractional anisotropy (GFA). Higher maternal unpredictability during infancy presaged greater uncinate fasciculus GFA in children 9-11 years of age (n = 69, 29 female). In contrast to the uncinate, GFA of a second corticolimbic projection, the hippocampal cingulum, was not associated with maternal unpredictability. Addressing the overall functional significance of the uncinate and cingulum relationships, we found that the resulting imbalance of medial temporal lobe-prefrontal cortex connectivity partially mediated the association between unpredictable maternal sensory signals and impaired episodic memory function. These results suggest that unbalanced maturation of corticolimbic circuits is a mechanism by which early unpredictable sensory signals may impact cognition later in life.SIGNIFICANCE STATEMENT Our prior work across species demonstrated that unpredictable patterns of maternal care are associated with compromised memory function. However, the neurobiological mechanisms by which this occurs in humans remain unknown. Here, we identify an association of exposure to unpredictable patterns of maternal sensory signals with the integrity of corticolimbic circuits involved in emotion and cognition using state-of-the-art diffusion imaging techniques and analyses. We find that exposure to early unpredictability is associated with higher integrity of the uncinate fasciculus with no effect on a second corticolimbic pathway, the cingulum. The resulting imbalance of corticolimbic circuit development is a novel mediator of the association between unpredictable patterns of maternal care and poorer episodic memory.

Hippocampal dentate gyrus integrity revealed with ultrahigh resolution diffusion imaging predicts memory performance in older adults.

Medial temporal lobe (MTL) atrophy is a core feature of age-related cognitive decline and Alzheimer's disease (AD). While regional volumes and thickness are often used as a proxy for neurodegeneration, they lack the sensitivity to serve as an accurate diagnostic test and indicate advanced neurodegeneration. Here, we used a submillimeter resolution diffusion weighted MRI sequence (ZOOMit) to quantify microstructural properties of hippocampal subfields in older adults (63-98 years old) using tensor derived measures: fractional anisotropy (FA) and mean diffusivity (MD). We demonstrate that the high-resolution sequence, and not a standard resolution sequence, identifies dissociable profiles for CA1, dentate gyrus (DG), and the collateral sulcus. Using ZOOMit, we show that advanced age is associated with increased MD of the CA1 and DG as well as decreased FA of the DG. Increased MD of the DG, reflecting decreased cellular density, mediated the relationship between age and word list recall. Further, increased MD in the DG, but not DG volume, was linked to worse spatial pattern separation. Our results demonstrate that ultrahigh-resolution diffusion imaging enables the detection of microstructural differences in hippocampal subfield integrity and will lead to novel insights into the mechanisms of age-related memory loss.

Probing the proteome to explore potential correlates of increased Alzheimer's-related cerebrovascular disease in adults with Down syndrome.

Cerebrovascular disease is associated with symptoms and pathogenesis of Alzheimer's disease (AD) among adults with Down syndrome (DS). The cause of increased dementia-related cerebrovascular disease in DS is unknown. We explored whether protein markers of neuroinflammation are associated with markers of cerebrovascular disease among adults with DS. Participants from the Alzheimer's disease in Down syndrome (ADDS) study with magnetic resonance imaging (MRI) scans and blood biomarker data were included. Support vector machine (SVM) analyses examined the relationship of blood-based proteomic biomarkers with MRI-defined cerebrovascular disease among participants characterized as having cognitive decline (n = 36, mean age ± SD = 53 ± 6.2) and as being cognitively stable (n = 78, mean age = 49 ± 6.4). Inflammatory and AD markers were associated with cerebrovascular disease, particularly among symptomatic individuals. The pattern suggested relatively greater inflammatory involvement among cognitively stable individuals and greater AD involvement among those with cognitively decline. The findings help to generate hypotheses that both inflammatory and AD markers are implicated in cerebrovascular disease among those with DS and point to potential mechanistic pathways for further examination.

Pattern Separation and Source Memory Engage Distinct Hippocampal and Neocortical Regions during Retrieval.

Detailed representations of past events rely on the ability to form associations between items and their contextual features (i.e., source memory), as well as the ability to distinctly represent a new event from a similar one stored in memory (i.e., pattern separation). These processes are both known to engage the hippocampus, although whether they share similar mechanisms remains unclear. It is also unknown if, and in which region(s), activity related to these processes overlaps and/or interacts. Here, we used high-resolution fMRI to examine the contributions of hippocampal subfields and neocortical areas to pattern separation and source memory with an experimental paradigm that concurrently tested both. During encoding, male and female human subjects incidentally studied items in one of four quadrants on the screen. During test, they viewed repeated items (targets), similar items (lures), and new items (foils) and were asked to indicate whether each item was old, similar, or new. Following each item judgment, subjects were asked to indicate the quadrant in which the original stimulus was presented. Thus, each lure trial had a lure discrimination component (taxing pattern separation) and a location judgment (source memory). We found two main response profiles: (1) pattern separation-related signals in DG/CA3 and perirhinal cortex and (2) source memory signals in posterior CA1, parahippocampal cortex, and angular gyrus. Whole-brain voxelwise analysis revealed that activity related to lure discrimination and source memory was largely nonoverlapping. These findings suggest that distinct processes underlie the retrieval of pattern separated item representations and recollection of source information.SIGNIFICANCE STATEMENT Recalling past events with detail and accuracy depends on the ability to remember the contextual features of an event (i.e., source memory) as well as the ability to distinguish among similar events in memory (i.e., pattern separation). Previous work has shown that these processes are behaviorally dissociable (e.g., people can have clear memory for context but misidentify people or items). However, both processes engage the hippocampus, and it is unclear whether they rely on shared or distinct neural mechanisms. Here, we used high-resolution fMRI to concurrently assess hippocampal and neocortical activity related to source memory and pattern separation. We found that activity related to these processes was largely nonoverlapping, shedding light on two complementary but distinct mechanisms supporting episodic memory.

APOE moderates the effect of hippocampal blood flow on memory pattern separation in clinically normal older adults.

Pattern separation, the ability to differentiate new information from previously experienced similar information, is highly sensitive to hippocampal structure and function and declines with age. Functional MRI studies have demonstrated hippocampal hyperactivation in older adults compared to young, with greater task-related activation associated with worse pattern separation performance. The current study was designed to determine whether pattern separation was sensitive to differences in task-free hippocampal cerebral blood flow (CBF) in 130 functionally intact older adults. Given prior evidence that apolipoprotein E e4 (APOE e4) status moderates the relationship between CBF and episodic memory, we predicted a stronger negative relationship between hippocampal CBF and pattern separation in APOE e4 carriers. An interaction between APOE group and right hippocampal CBF was present, such that greater right hippocampal CBF was related to better lure discrimination in noncarriers, whereas the effect reversed directionality in e4 carriers. These findings suggest that neurovascular changes in the medial temporal lobe may underlie memory deficits in cognitively normal older adults who are APOE e4 carriers.

Alzheimer-Related Cerebrovascular Disease in Down Syndrome.

OBJECTIVE: Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology by their 5th decade. Compared with the general population, traditional vascular risks in adults with DS are rare, allowing examination of cerebrovascular disease in this population and insight into its role in AD without the confound of vascular risk factors. We examined in vivo magnetic resonance imaging (MRI)-based biomarkers of cerebrovascular pathology in adults with DS, and determined their cross-sectional relationship with age, beta-amyloid pathology, and mild cognitive impairment or clinical AD diagnostic status. METHODS: Participants from the Biomarkers of Alzheimer's Disease in Down Syndrome study (n = 138, 50 ± 7 years, 39% women) with MRI data and a subset (n = 90) with amyloid positron emission tomography (PET) were included. We derived MRI-based biomarkers of cerebrovascular pathology, including white matter hyperintensities (WMH), infarcts, cerebral microbleeds, and enlarged perivascular spaces (PVS), as well as PET-based biomarkers of amyloid burden. Participants were characterized as cognitively stable (CS), mild cognitive impairment-DS (MCI-DS), possible AD dementia, or definite AD dementia based on in-depth assessments of cognition, function, and health status. RESULTS: There were detectable WMH, enlarged PVS, infarcts, and microbleeds as early as the 5th decade of life. There was a monotonic increase in WMH volume, enlarged PVS, and presence of infarcts across diagnostic groups (CS < MCI-DS < possible AD dementia < definite AD dementia). Higher amyloid burden was associated with a higher likelihood of an infarct. INTERPRETATION: The findings highlight the prevalence of cerebrovascular disease in adults with DS and add to a growing body of evidence that implicates cerebrovascular disease as a core feature of AD and not simply a comorbidity. ANN NEUROL 2020;88:1165-1177.

Increased dynamic flexibility in the medial temporal lobe network following an exercise intervention mediates generalization of prior learning.

Recent work has conceptualized the brain as a network comprised of groups of sub-networks or modules. "Flexibility" of brain network(s) indexes the dynamic reconfiguration of comprising modules. Using novel techniques from dynamic network neuroscience applied to high-resolution resting-state functional magnetic resonance imaging (fMRI), the present study investigated the effects of an aerobic exercise intervention on the dynamic rearrangement of modular community structure-a measure of neural flexibility-within the medial temporal lobe (MTL) network. The MTL is one of the earliest brain regions impacted by Alzheimer's disease. It is also a major site of neuroplasticity that is sensitive to the effects of exercise. In a two-group non-randomized, repeated measures and matched control design with 34 healthy older adults, we observed an exercise-related increase in flexibility within the MTL network. Furthermore, MTL network flexibility mediated the beneficial effect aerobic exercise had on mnemonic flexibility, as measured by the ability to generalize past learning to novel task demands. Our results suggest that exercise exerts a rehabilitative and protective effect on MTL function, resulting in dynamically evolving networks of regions that interact in complex communication patterns. These reconfigurations may underlie exercise-induced improvements on cognitive measures of generalization, which are sensitive to subtle changes in the MTL.

Integrity of the uncinate fasciculus is associated with emotional pattern separation-related fMRI signals in the hippocampal dentate and CA3.

Alterations in white matter integrity have been demonstrated in a number of psychiatric disorders involving emotional disruptions. One such pathway - the uncinate fasciculus - connects the orbitofrontal cortex (OFC) to the medial temporal lobes (MTL) and has been associated with early life adversity, maltreatment, anxiety, and depression. While it is purported to play a role in episodic memory and discrimination, its exact function remains poorly understood. We have previously described the role of the amygdala and dentate (DG)/CA3 fields of the hippocampus in the mnemonic discrimination of emotional experiences (i.e. emotional pattern separation). However, how this computation may be modulated by connectivity with the orbitofrontal cortex remains unknown. Here we asked if the uncinate fasciculus plays a role in influencing MTL subregional activity during emotional pattern separation. By combining diffusion imaging with high-resolution fMRI, we found that reduced integrity of the UF is related to elevated BOLD fMRI activation of the DG/CA3 subregions of the hippocampus during emotional lure discrimination. We additionally report that higher levels of DG/CA3 activity are associated with poorer memory performance, suggesting that greater activation in this network (possibly driven by CA3 recurrent collaterals) is associated with memory errors. Based on this work we suggest that the UF is one pathway that may allow the OFC to exert control on this network and improve discrimination of emotional experiences, although further work is necessary to fully evaluate this possibility. This work provides novel insight into the role of prefrontal interactions with the MTL, particularly in the context of emotional memory.

Hippocampal CA1 gamma power predicts the precision of spatial memory judgments.

The hippocampus plays a critical role in spatial memory. However, the exact neural mechanisms underlying high-fidelity spatial memory representations are unknown. We report findings from presurgical epilepsy patients with bilateral hippocampal depth electrodes performing an object-location memory task that provided a broad range of spatial memory precision. During encoding, patients were shown a series of objects along the circumference of an invisible circle. At test, the same objects were shown at the top of the circle (0°), and patients used a dial to move the object to its location shown during encoding. Angular error between the correct location and the indicated location was recorded as a continuous measure of performance. By registering pre- and postimplantation MRI scans, we were able to localize the electrodes to specific hippocampal subfields. We found a correlation between increased gamma power, thought to reflect local excitatory activity, and the precision of spatial memory retrieval in hippocampal CA1 electrodes. Additionally, we found a similar relationship between gamma power and memory precision in the dorsolateral prefrontal cortex and a directional relationship between activity in this region and in the CA1, suggesting that the dorsolateral prefrontal cortex is involved in postretrieval processing. These results indicate that local processing in hippocampal CA1 and dorsolateral prefrontal cortex supports high-fidelity spatial memory representations.

Rapid stimulation of human dentate gyrus function with acute mild exercise.

Physical exercise has beneficial effects on neurocognitive function, including hippocampus-dependent episodic memory. Exercise intensity level can be assessed according to whether it induces a stress response; the most effective exercise for improving hippocampal function remains unclear. Our prior work using a special treadmill running model in animals has shown that stress-free mild exercise increases hippocampal neuronal activity and promotes adult neurogenesis in the dentate gyrus (DG) of the hippocampus, improving spatial memory performance. However, the rapid modification, from mild exercise, on hippocampal memory function and the exact mechanisms for these changes, in particular the impact on pattern separation acting in the DG and CA3 regions, are yet to be elucidated. To this end, we adopted an acute-exercise design in humans, coupled with high-resolution functional MRI techniques, capable of resolving hippocampal subfields. A single 10-min bout of very light-intensity exercise (30%[Formula: see text]) results in rapid enhancement in pattern separation and an increase in functional connectivity between hippocampal DG/CA3 and cortical regions (i.e., parahippocampal, angular, and fusiform gyri). Importantly, the magnitude of the enhanced functional connectivity predicted the extent of memory improvement at an individual subject level. These results suggest that brief, very light exercise rapidly enhances hippocampal memory function, possibly by increasing DG/CA3-neocortical functional connectivity.

ABCA7 risk variant in healthy older African Americans is associated with a functionally isolated entorhinal cortex mediating deficient generalization of prior discrimination training.

Using high-resolution resting state functional magnetic resonance imaging (fMRI), the present study tested the hypothesis that ABCA7 genetic risk differentially affects intra-medial temporal lobe (MTL) functional connectivity between MTL subfields, versus internetwork connectivity of the MTL with the medial prefrontal cortex (mPFC), in nondemented older African Americans. Although the association of ABCA7 risk variants with Alzheimer's disease (AD) has been confirmed worldwide, its effect size on the relative odds of being diagnosed with AD is significantly higher in African Americans. However, little is known about the neural correlates of cognitive function in older African Americans and how they relate to AD risk conferred by ABCA7. In a case-control fMRI study of 36 healthy African Americans, we observed ABCA7 related impairments in behavioral generalization that was mediated by dissociation in entorhinal cortex (EC) resting state functional connectivity. Specifically, ABCA7 risk variant was associated with EC-hippocampus hyper-synchronization and EC-mPFC hypo-synchronization. Carriers of the risk genotype also had a significantly smaller anterolateral EC, despite our finding no group differences on standardized neuropsychological tests. Our findings suggest a model where impaired cortical connectivity leads to a more functionally isolated EC at rest, which translates into aberrant EC-hippocampus hyper-synchronization resulting in generalization deficits. While we cannot identify the exact mechanism underlying the observed alterations in EC structure and network function, considering the relevance of Aß in ABCA7 related AD pathogenesis, the results of our study may reflect the synergistic reinforcement between amyloid and tau pathology in the EC, which significantly increases tau-induced neuronal loss and accelerates synaptic alterations. Finally, our results add to a growing literature suggesting that generalization of learning may be a useful tool for assessing the mild cognitive deficits seen in the earliest phases of prodromal AD, even before the more commonly reported deficits in episodic memory arise.

The Relationship Between Cumulative Exogenous Corticosteroid Exposure and Volumes of Hippocampal Subfields and Surrounding Structures.

PURPOSE/BACKGROUND: Glucocorticoids are a class of hormones that include naturally occurring cortisol and corticosterone, as well as prescription drugs commonly used to manage inflammatory, autoimmune, and allergic conditions. Adverse effects, including neuropsychiatric symptoms, are common. The hippocampus appears to be especially sensitive to the effects of glucocorticoids. However, to our knowledge, no studies to date have examined hippocampal subfields in humans receiving glucocorticoids. We examined patients on chronic glucocorticoid regimens to determine relationships between dose and duration of treatment, and hippocampal subfields, and related regions volumes. METHODS/PROCEDURES: The study included adult men and women receiving at least 5 mg daily of prednisone equivalents for at least 6 months. Volumes of brain regions were measured via magnetic resonance imaging. A multivariate general linear model was used for analysis, with brain volumes as dependent variables and age, sex, and cumulative corticosteroid exposure, as predictors. FINDINGS/RESULTS: The study population consisted of 81 adult outpatients (43 male) on corticosteroids (mean dose, 7.88 mg; mean duration, 76.75 months). Cumulative glucocorticoid exposure was negatively associated with left and right hippocampal dentate gyrus/CA3 volume. In subsequent subgroup analysis, this association held true for the age group older than the median age of 46 years but not for the younger age group. IMPLICATIONS/CONCLUSIONS: This finding is consistent with previous studies showing detrimental effects of elevated glucocorticoids on the hippocampus but further suggests that the dentate gyrus and CA3 regions are particularly vulnerable to those effects, which is consistent with animal models of chronic stress but has not been previously demonstrated in humans.

Post-encoding stress enhances mnemonic discrimination of negative stimuli.

Stress influences how we remember emotional events and how these events shape future behaviors. However, the impact of stress on memory specificity for emotional events has yet to be examined. To this end, the present study utilized a mnemonic discrimination task that taxes hippocampal pattern separation, the process of distinguishing between overlapping experiences, thereby allowing us to better understand the mechanisms by which stress affects gist versus detail memory of emotional events. Participants encoded scenes composed of negative or neutral objects placed on neutral backgrounds and then underwent a psychosocial stressor or matched control task. Twenty-four hours later during testing, objects were presented separately, with some identical old objects (targets), some new objects (foils), and some similar but not identical objects (lures). Target recognition was enhanced for negative compared to neutral objects in both the stress and control groups. Interestingly, post-encoding stress selectively enhanced mnemonic discrimination of negative versus neutral objects, which was not the case in the control group. Measures of salivary cortisol revealed a quadratic inverted U relationship between negative mnemonic discrimination and cortisol increase. These findings suggest that moderate cortisol release following stress is associated with enhanced memory precision for negative information.

Pattern separation and goal-directed behavior in the aged canine.

The pattern separation task has recently emerged as a behavioral model of hippocampus function and has been used in several pharmaceutical trials. The canine is a useful model to evaluate a multitude of hippocampal-dependent cognitive tasks that parallel those in humans. Thus, this study was designed to evaluate the suitability of pattern separation task(s) for detecting age-related changes in canines. We also assessed the dogs' ability to show pattern separation and discrimination reversal, which provides a novel extension of the pattern separation learning literature. Our data show that aged dogs are impaired on a complex pattern separation task (six-well task) relative to easier tasks (four-well or six-well pattern discrimination task), and that the age-related deficits are due to loss of perceptual and inhibitory control in addition to the loss of spatial discrimination and pattern separation ability. Our data also suggest that aged animals show pattern separation deficits when the objects are brought progressively closer together while changing the location of both correct and incorrect objects. However, if the location of any one object is fixed the animals tend to use alternate strategies. Overall, these data provide important insight into age-related pattern separation deficits in a higher animal model and offers additional means for evaluating the impact of lifestyle and pharmaceutical interventions on episodic memory in preclinical trials.

Repetition reveals ups and downs of hippocampal, thalamic, and neocortical engagement during mnemonic decisions.

The extent to which current information is consistent with past experiences and our capacity to recognize or discriminate accordingly are key factors in flexible memory-guided behavior. Despite a wealth of evidence linking hippocampal and neocortical computations to these phenomena, many important factors remain poorly understood. One such factor is repeated encoding of learned information. In this experiment, participants completed a task in which study stimuli were incidentally encoded either once or three separate times during high-resolution fMRI scanning. We asked how repetition influenced recognition and discrimination memory judgments, and how this affects engagement of hippocampal and neocortical regions. Repetition revealed shifts in engagement in an anterior (ventral) CA1-thalamic-medial prefrontal network related to true and false recognition. Conversely, repetition revealed shifts in a posterior (dorsal) dentate/CA3-parahippocampal-restrosplenial network related to accurate discrimination. These differences in engagement were accompanied by task-related correlations in respective anterior and posterior networks. In particular, the anterior thalamic region observed during recognition judgments is functionally and anatomically consistent with nucleus reuniens in humans, and was found to mediate correlations between the anterior CA1 and medial prefrontal cortex. These findings offer new insights into how repeated experience affects memory and its neural substrates in hippocampal-neocortical networks. © 2016 Wiley Periodicals, Inc.