Pattern Separation Task Research Articles

Acute Treatment with the Nootropic CILTEP® Does Not Improve Cognitive Performance in Healthy Middle-Aged Participants

This study investigated the acute effects of the dietary nootropic stack CILTEP®. It contains a combination of ingredients that have been individually reported to improve cognitive performance. Especially, the ingredients luteolin, which is considered a phosphodiesterase type 4 (PDE4) inhibitor, and forskolin, an adenylate cyclase stimulator, were of interest since they can increase the second messenger cAMP and thus also intracellular signaling. Numerous studies have shown that inhibition of PDE4 can improve memory in animals and humans. We examined whether acute dosing of 3 capsules of CILTEP® would improve cognitive function in healthy participants aged 30 to 40 (n = 33). We used a randomized, double-blind, placebo-controlled, two-way cross-over design. Our test battery was aimed at measuring memory performance, attention, and sensorimotor speed. The primary outcome measures were the performance on the verbal learning task and the spatial pattern separation task. Secondary outcomes included other cognitive tests, event-related potentials (ERPs), and assessment of the activity of the enzyme beta-glucuronidase and its effect on the bioavailability of luteolin, heart rate, and blood pressure. No relevant effects of acute CILTEP® treatment were found on any measure of the test battery or ERPs. Blood plasma concentrations of luteolin increased, yet about 2000 times too low to likely exert any PDE4 inhibition. CILTEP® treatment did neither affect heart rate nor blood pressure. In summary, there is no evidence that a single standardized dose of 3 capsules of CILTEP® can improve cognitive function in healthy middle-aged participants.

Environmental enrichment in middle age rats improves spatial and object memory discrimination deficits.

Changes in memory performance are one of the main symptoms of normal aging. The storage of similar experiences as different memories (ie. behavioral pattern separation), becomes less efficient as aging progresses. Studies have focused on hippocampus dependent spatial memories and their role in the aging related deficits in behavioral pattern separation (BPS) by targeting high similarity interference conditions. However, parahippocampal cortices such as the perirhinal cortex are also particularly vulnerable to aging. Middle age is thought to be the stage where mild mnemonic deficits begin to emerge. Therefore, a better understanding of the timing of the spatial and object domain memory impairment could shed light over how plasticity changes in the parahipocampal-hippocampal system affects mnemonic function in early aging. In the present work, we compared the performance of young and middle-aged rats in both spatial (spontaneous location recognition) and non-spatial (spontaneous object recognition) behavioral pattern separation tasks to understand the comparative progression of these deficits from early stages of aging. Moreover, we explored the impact of environmental enrichment (EE) as an intervention with important translational value. Although a bulk of studies have examined the contribution of EE for preventing age related memory decline in diverse cognitive domains, there is limited knowledge of how this intervention could specifically impact on BPS function in middle-aged animals. Here we evaluate the effects of EE as modulator of BPS, and its ability to revert the deficits caused by normal aging at early stages. We reveal a domain-dependent impairment in behavioral pattern separation in middle-aged rats, with spatial memories affected independently of the similarity of the experiences and object memories only affected when the stimuli are similar, an effect that could be linked to the higher interference seen in this group. Moreover, we found that EE significantly enhanced behavioral performance in middle-aged rats in the spatial and object domain, and this improvement is specific of the high similarity load condition. In conclusion, these results suggest that memory is differentially affected by aging in the object and spatial domains, but that BPS function is responsive to an EE intervention in a multidomain manner.

33 The Impact of Context on Memory for Short Stories Among Older and Younger Adults

Objective:On traditional pattern separation tasks, older adults perform worse than younger adults when identifying similar objects but perform equally well when recognizing repeated objects. When objects are superimposed on semantically related scenes, older adults are influenced by the context to a greater degree than younger adults, leading to errors when identifying similar objects. However, in everyday life, people rarely need to differentiate between two perceptually similar objects. Therefore, we developed a task using short stories to represent similar events people may experience in daily life. Our goal was to investigate the influence of context, detail-type, and age on memory performance.Participants and Methods:Twenty-one older and 18 younger adults listened to 20 short stories taking place in either a coffee shop or library, each paired with a unique picture (i.e., context). Participants were asked to imagine the story taking place within the picture. Approximately 20 minutes later, participants answered a yes/no question about a detail from a story superimposed on different contexts. The different context conditions were (1) the same picture from the original story, (2) a similar picture (i.e., a different library or coffee shop picture), (3) a dissimilar picture (i.e., a library picture instead of a coffee shop picture), or (4) a control using a Fourier-transform (FT) image without any spatial-context information. Questions either asked about an identical or similar detail from the story.Results:Correct answers were analyzed using a 4x2x2 repeated measures ANOVA including context (same, similar, dissimilar, and FT), detail type (identical and similar), and age (younger and older adults). Overall, younger adults were more accurate than older adults, F(1,37)=23.4, p<0.001. However, surprisingly, the context and detail-type made no difference in accuracy, (F’s<1.1) A similar model was used to analyze reaction times. Younger adults were faster than older adults, F(1,37)=23.4, p<0.001. Participants of both ages were faster at correctly responding to the identical detail than the similar detail, F(1,114)=62.87, p<0.001. Context also impacted reaction time, F(3,114)=7.97, p<0.001. All participants were faster while viewing same and similar contexts compared to both the dissimilar and FT contexts (t(39)’s>2.20, p’s<0.05).Conclusions:We did not find the kinds of age-related effects normally observed on traditional pattern separation tasks. Although younger adults performed better overall, older adults were not any worse when responding to a similar detail compared to an identical detail, which is inconsistent with performance on pattern separation tasks where older adults perform worse when identifying similar objects compared to younger adults. Additionally, older and younger adults were influenced by context in the same way. Previous studies from our laboratory demonstrated that older adults are biased toward the context when recognizing similar objects, but the context in this paradigm did not differentially influence accuracy for either older or younger adults. Potentially, this task relies on more semantic similarity rather than the perceptual similarity of objects. Semantic similarity from the short stories may incorporate more information to better orthogonalize similar memories, rendering retrieval less susceptible to interference.

High estradiol reduces adult neurogenesis but strengthens functional connectivity within the hippocampus during spatial pattern separation in adult female rats

Adult neurogenesis in the dentate gyrus plays an important role for pattern separation, the process of separating similar inputs and forming distinct neural representations. Estradiol modulates neurogenesis and hippocampus function, but to date no examination of estradiol's effects on pattern separation have been conducted. Here, we examined estrogenic regulation of adult neurogenesis and functional connectivity in the hippocampus after the spatial pattern separation task in female rats. Ovariectomized Sprague-Dawley rats received daily injections of vehicle, 0.32 μg (Low) or 5 μg (High) of estradiol benzoate until the end of experiment. A single bromodeoxyuridine (BrdU) was injected one day after initiation of hormone or vehicle treatment and rats were tested in the delayed nonmatching to position spatial pattern separation task in the 8-arm radial maze for 12 days beginning two weeks after BrdU injection. Rats were perfused 90 min after the final trial and brain sections were immunohistochemically stained for BrdU/neuronal nuclei (NeuN) (new neurons), Ki67 (cell proliferation), and the immediate early gene, zif268 (activation). Results showed that high, but not low, estradiol reduced the density of BrdU/NeuN-ir cells and had significant inter-regional correlations of zif268-ir cell density in the hippocampus following pattern separation. Estradiol treatment did not influence pattern separation performance or strategy use. These results show that higher doses of estradiol can reduce neurogenesis but at the same time increases correlations of activity of neurons within the hippocampus during spatial pattern separation.

High-fat-sugar diet is associated with impaired hippocampus-dependent memory in humans

Overconsumption of high-fat and high-sugar (HFS) diet may affect the hippocampus, and consequently, memory functions. Yet, converging evidence is needed to demonstrate that the type of memory affected by HFS diet consumption is indeed hippocampus dependent. Moreover, the extent to which HFS diet can also affect executive functioning, and indirectly affect memory requires further examination. In this online study, we asked 349 young adults to report their HFS diet consumption and complete a word memory task, the Everyday Memory Questionnaire, and importantly two memory tasks that have been shown to robustly engage the hippocampus, i.e., the Pattern Separation and Associative Memory Tasks. Participants also completed two executive functioning tasks, the Trail Making Task (TMT) and the Stroop Task. These measures assess attention/cognitive flexibility and the ability to inhibit cognitive interference, respectively. After controlling for confounding variables, we found that participants who reported higher level consumption of a HFS diet performed worse on the Pattern Separation Task and that higher HFS intake was significantly associated with poorer TMT task performance and longer Stroop average reaction time (RT). TMT and Stroop RT scores indicative of reduced executive function also partially mediated the relationship between HFS diet and memory performance on the pattern separation task. Taken together, our results provide converging evidence that HFS diet may impair hippocampus-dependent memory. HFS diet may also affect executive functioning and indirectly impair memory function. The findings are consistent with human subject and animal studies and call for further investigations on the psychological and neural mechanisms underlying the dietary effects on cognitive processes.

Morphometric and microstructural characteristics of hippocampal subfields in mesial temporal lobe epilepsy and their correlates with mnemonic discrimination.

Pattern separation (PS) is a fundamental aspect of memory creation that defines the ability to transform similar memory representations into distinct ones, so they do not overlap when storing and retrieving them. Experimental evidence in animal models and the study of other human pathologies have demonstrated the role of the hippocampus in PS, in particular of the dentate gyrus (DG) and CA3. Patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HE) commonly report mnemonic deficits that have been associated with failures in PS. However, the link between these impairments and the integrity of the hippocampal subfields in these patients has not yet been determined. The aim of this work is to explore the association between the ability to perform mnemonic functions and the integrity of hippocampal CA1, CA3, and DG in patients with unilateral MTLE-HE. To reach this goal we evaluated the memory of patients with an improved object mnemonic similarity test. We then analyzed the hippocampal complex structural and microstructural integrity using diffusion weighted imaging. Our results indicate that patients with unilateral MTLE-HE present alterations in both volume and microstructural properties at the level of the hippocampal subfields DG, CA1, CA3, and the subiculum, that sometimes depend on the lateralization of their epileptic focus. However, none of the specific changes was found to be directly related to the performance of the patients in a pattern separation task, which might indicate a contribution of various alterations to the mnemonic deficits or the key contribution of other structures to the function. we established for the first time the alterations in both the volume and the microstructure at the level of the hippocampal subfields in a group of unilateral MTLE patients. We observed that these changes are greater in the DG and CA1 at the macrostructural level, and in CA3 and CA1 in the microstructural level. None of these changes had a direct relation to the performance of the patients in a pattern separation task, which suggests a contribution of various alterations to the loss of function.

Temozolomide treatment inhibits spontaneous motivation for exploring a complex object in mice: A potential role of adult hippocampal neurogenesis in "curiosity".

Intrinsic exploratory biases are an innate motivation for exploring certain types of stimuli or environments over others, and they may be associated with cognitive, emotional, and even personality-like traits. However, their neurobiological basis has been scarcely investigated. Considering the involvement of the hippocampus in novelty recognition and in spatial and pattern separation tasks, this work researched the role of adult hippocampal neurogenesis (AHN) in intrinsic exploratory bias for a perceptually complex object in mice. Spontaneous object preference tasks revealed that both male and female C57BL/6J mice showed a consistent unconditioned preference for exploring "complex"-irregular-objects over simpler ones. Furthermore, increasing objects' complexity resulted in an augmented time of object exploration. In a different experiment, male mice received either vehicle or the DNA alkylating agent temozolomide (TMZ) for 4 weeks, a pharmacological treatment that reduced AHN as evidenced by immunohistochemistry. After assessment in a behavioral test battery, the TMZ-treated mice did not show any alterations in general exploratory and anxiety-like responses. However, when tested in the spontaneous object preference task, the TMZ-treated mice did not display enhanced exploration of the complex object, as evidenced both by a reduced exploration time-specifically for the complex object-and a lack of preference for the complex object over the simple one. This study supports a novel role of AHN in intrinsic exploratory bias for perceptual complexity. Moreover, the spontaneous complex object preference task as a rodent model of "curiosity" is discussed.

Pharmacodynamics Assessment of Aducanumab in 5XFAD mice: A MODEL‐AD PTC Study

AbstractBackgroundThe Preclinical Testing Core (PTC) of the Model Organism Development for Evaluation of Late Onset Alzheimer’s Disease (MODEL‐AD) consortium established a rigorous preclinical drug testing strategy with go/no‐go decision points that permits unbiased assessments of therapeutic agents. As part of the pipeline validation, the chimeric murinized therapeutic antibody aducanumab (chAducanumab), was selected for evaluation in 5XFAD mice.MethodsInitial PK modeling and simulation was guided by literature and Aβ reductions from a pilot cohort of 9 month aged 5XFAD mice following 1x/week treatment of 30 mg/kg chAducanumab for 4 weeks. These pilot data were used to inform the chronic dosing regimen for the PD study which started at an age in 5XFAD mice where significant amyloid plaque accumulation was present (9 mos). PD endpoints (n=10‐12/sex/genotype/treatment) were assessed at the conclusion of chronic treatment, and included: 18‐FDG and 18F‐AV45 PET/CT, autoradiography, immunohistochemistry, AB40 and AB42 in plasma and brain fractions, and a behavioral battery. An additional cohort was enrolled for comprehensive cognitive testing using touchscreen learning and pattern separation tasks and evaluated for electroencephalography (EEG) activity using wireless telemetry.ResultsPK/PD modeling revealed slow clearance of chAducanumab following IP dosing with a T1/2 of ∼2.5 days. Therefore, the dose regimen for chronic PD studies included 0.1, 1.56, and 30 mg/kg administered 1x weekly for 12 weeks. Treatment with chAducanumab resulted in dose‐ and sex‐dependent reduction in amyloid deposition via 18F‐AV45 PET. Glucose uptake via 18F‐FDG PET similarly showed a dose dependent reversal of glycolytic loss in key brain regions. Cognitive assessments indicated no effect on learning however an improvement in pattern separation was observed with chAducanumab in females but not males. EEG analysis revealed improvements in delta, alpha, and beta oscillations with chAducanumab treatment. Multi‐omics analysis are in progress.ConclusionschAducanumab treatment in 5XFAD mice resulted in the expected reductions in brain amyloid consistent with clinical findings. Moreover, chAducanumab showed a unique glycolytic restoration profile in 5XFAD mice and improvements in some aspects of cognitive function. Together these data positively support pipeline validation of the MODEL‐AD PTC for evaluating therapeutic antibodies.

The impact of context on pattern separation for objects among younger and older apolipoprotein ϵ4 carriers and noncarriers.

On continuous recognition tasks, changing the context objects are embedded in impairs memory. Older adults are worse on pattern separation tasks requiring identification of similar objects compared to younger adults. However, how contexts impact pattern separation in aging is unclear. The apolipoprotein (APOE) ϵ4 allele may exacerbate possible age-related changes due to early, elevated neuropathology. The goal of this study is to determine how context and APOE status affect pattern separation among younger and older adults. Older and younger ϵ4 carriers and noncarriers were given a continuous object recognition task. Participants indicated if objects on a Repeated White background, Repeated Scene, or a Novel Scene were old, similar, or new. The proportions of correct responses and the types of errors made were calculated. Novel scenes lowered recognition scores compared to all other contexts for everyone. Younger adults outperformed older adults on identifying similar objects. Older adults misidentified similar objects as old more than new, and the repeated scene exacerbated this error. APOE status interacted with scene and age such that in repeated scenes, younger carriers produced less false alarms, and this trend switched for older adults where carriers made more false alarms. Context impacted recognition memory in the same way for both age groups. Older adults underutilized details and over relied on holistic information during pattern separation compared to younger adults. The triple interaction in false alarms may indicate an even greater reliance on holistic information among older adults with increased risk for Alzheimer's disease.

Effects Of Acute Aerobic Exercise On Behavioral Pattern Separation Performance In Older Adults

PURPOSE: Ample evidence suggests moderate-intensity aerobic exercise is beneficial for hippocampal structure and function. Furthermore, recent studies in younger adults suggest a single session of aerobic exercise provides immediate benefits to behavioral pattern separation performance, a highly hippocampal-specific memory task. However, no work has explored how a single session of aerobic exercise might alter pattern separation performance in older adults, who generally exhibit deficits in pattern separation performance and hippocampal deterioration in relation to younger adults. METHODS: To address this question, we conducted a within-subject acute exercise study in 31 cognitively healthy and physically active older adults (70.1 (±6.1) years). Participants performed baseline testing and then completed two experimental day visits in counterbalanced order. On the experimental days, they performed different iterations of a behavioral pattern separation task on the computer before and after 30 minutes of moderate intensity aerobic exercise on a cycle ergometer or 30 minutes of quiet seated rest. Linear mixed-effects model analysis was employed in which condition order was controlled for, time (pre vs. post) and condition (exercise vs. rest) were modeled as fixed effects, and subject was modeled as a random effect. RESULTS: No significant time by condition interaction effect was found for general object recognition (F(1,31) = 1.25, p = .267, η2 = .01) and a positive, but non-significant interaction effect was found for pattern separation performance following the exercise condition (F(1,31) = 3.56, p = .062, η2 = .04). Furthermore, a post-intervention only analysis indicated that there was no significant difference between the exercise and rest condition for general object recognition (F(1,31) = 1.46, p = .236, η2 = .05), but that participants performed significantly better on the pattern separation task (F(1,31) = 8.86, p = .006, η2 = .22) following the exercise condition. CONCLUSIONS: Our results suggest a single session of moderate-intensity aerobic exercise may lead to reduced interference and better pattern separation performance in healthy older adults, suggesting immediate benefits for hippocampal-specific memory function.

Monocyte Polarization As A Biomarker Of Cardiorespiratory And Cognitive Health In Active Older Adults: A Pilot Study.

The aging process is characterized by a chronic, low-grade pro-inflammatory state that may contribute to age-related conditions such as Alzheimer’s Disease (AD). Recent frameworks suggest monocyte phenotypes play key roles in the aging immune response that may exacerbate AD pathology and contribute to cognitive decline. Lifestyle behaviors, such as aerobic exercise training, can be neuroprotective and immunoprotective but the relationships between monocyte phenotypes, cardiorespiratory fitness, and cognitive function are poorly understood.PURPOSE:To explore the associations between monocyte phenotypes, cardiorespiratory fitness (VO2max), and performance in a hippocampal-dependent pattern separation task. METHODS:Active older adults (70 ± 6.7y, n = 24) were recruited for this study. Baseline VO2max was obtained via graded exercise test and pattern separation performance with a previously validated computerized test. Following a 12 h fast, Peripheral blood mononuclear cells (PBMCs) were isolated via Ficoll-gradient and immunostained with cell surface markers CD14 and CD16 to sort monocytes via flow cytometry. Spearman’s rank-order correlations (rs) were employed to determine the associations between monocyte phenotypes, VO2max, and cognitive outcomes. A multiple linear regression analysis was used to determine the association between monocyte polarization and outcomes of interest. RESULTS:No significant associations were found between classical (rs = -0.09, p > .05), intermediate (rs = 0.18, p > .05), or non-classical (rs = 0.10, p > .05) monocytes and pattern separation performance. Classical monocytes showed a direct correlation with VO2max (rs = 0.26, p = .01) while intermediate (rs = -0.18, p = .01) and non-classical (rs = -0.24, p = .01) monocytes showed inverse correlations with VO2max. A multiple regression model predicting VO2max from all monocyte phenotypes, controlling for age and sex, was significant (F(5,18) = 9.38, p = <.001, R2 = 0.64); follow-up contrasts indicated only intermediate monocytes were a significant predictor of VO2max (t(18) = -2.25, p = 0.03).CONCLUSIONS:Our results suggest pro-inflammatory monocyte phenotypes may negatively relate to VO2max in active older adults, but monocyte phenotypes did not relate to cognitive outcomes.

Influence of Effort-based Reward Training on Neuroadaptive Cognitive Responses: Implications for Preclinical Behavioral Approaches for Depressive Symptoms

Despite the presence of multiple pharmacotherapeutic options, incidence rates for depressive disorders continue to rise. Nonpharmacological approaches (e.g., cognitive and behavioral therapies) exhibit encouraging efficacy rates; however, a lack of preclinical models has prevented progress in the identification of relevant neurobiological mechanisms of these approaches. Accordingly, the effort-based reward (EBR) preclinical model exposes rats to response-outcome (R-O) contingencies and provides an opportunity to investigate behavioral clinical approaches. In the current study, male and female rats were assigned to either an EBR contingent- or noncontingent-trained group and exposed to 7 weeks of training. Neuroadaptive cognitive responses were assessed in a cognitive uncertainty task (UT) and an object pattern separation task (OPST). Although no significant effects of EBR were observed in the UT, EBR contingent-trained rats approached the novel panel in the most difficult trial of the OPST faster than the noncontingent-trained group. Additionally, female EBR contingent-trained rats exhibited increased engagement with the novel stimulus panel across all trials. Examination of brain-derived neurotrophic factor (BDNF) in the lateral habenula (LHb), a putative neurobiological target for depressive symptoms, revealed lower BDNF immunoreactivity in EBR contingent-trained rats. Females in both training groups exhibited higher dehydroepiandrosterone/cortisol (DHEA/CORT) ratios, suggesting, along with the increased engagement with novel stimulus panels, that female rats may be more responsive to EBR contingency training than males. Together, these results suggest that EBR contingency training offers promise as a preclinical rat model for behavioral therapeutic interventions for depressive symptoms leading to a clearer understanding of putative neurobiological mechanisms.

Artificial neural network performance based on correlation analysis qualitatively comparable with human performance in behavioral signal detection experiments.

Standard Gaussian signal detection theory (SDT) is a widely used approach to assess the detection performance of living organisms or technical systems without looking at the inner workings of these systems like neural or electronic mechanisms. Nevertheless, a consideration of the inner mechanisms of a system and how they produce observed behaviors should help to better understand the functioning. It might even offer the possibility to demonstrate isolated pattern separation processes directly in the model. To do so, modeling the interaction between the entorhinal cortex (EC) and the hippocampal subnetwork dentate gyrus (DG) via the perforant path reveals the decorrelation network's mode of operation. We show that the ability to do pattern separation is crucial for high-performance pattern recognition, but also for lure discrimination, and depends on the proportionality between input and output network. NEW & NOTEWORTHY We elucidate the interplay of the entorhinal cortex and the hippocampal dentate gyrus during pattern separation tasks by providing a new simulation model. Functional memory formation and processing of similar memory content is illuminated from within the system. For the first time orthogonalized spiking patterns are evaluated with signal detection theory methods, and the results are applied to clinically established and novel tests.

How to account for hallucinations in the interpretation of the antidepressant effects of psychedelics: a translational framework

RationaleRecent trials with psychedelics in major depressive disorder and treatment-resistant depression showed remarkable improvements in depressive symptoms that can last for up to several months after even a single administration. The lack of an appropriate placebo control group—as patients are often able to discriminate the subjective effects of the drug—and an incomplete understanding of the role of the hallucinogenic and mystical experience, hampers the interpretation of these therapeutic effects.ObjectivesTo control for these factors, we developed a translational framework based on establishing pharmacokinetic/pharmacodynamic (PK/PD) relationships in rodents and humans for hallucinogenic (i.e., discriminative stimulus effects in rodents and humans; head twitch responses in rodents; questionnaires in humans) and therapeutic effects. For the latter, we selected the pattern separation and attentional set-shifting tasks as measures for cognitive flexibility because of their high translational value. We predict that these PK/PD analyses will lead to a more objective evaluation of improvements in patients compared to relying only on the currently used self-reported questionnaires. We hypothesize that—if the role of the hallucinogenic experience is not central in the antidepressant effects of psychedelics—the ED50’s for the therapeutic effects will be significantly lower than for the hallucinogenic and mystical effects.ConclusionOur framework will help to inform future studies that aim at the elucidation of the mechanism(s) of action of psychedelics in depression, and the role of the acute subjective and/or hallucinogenic experience in their effects.

Meditation and Aerobic Exercise Enhance Mental Health Outcomes and Pattern Separation Learning Without Changing Heart Rate Variability in Women with HIV.

Mental and physical (MAP) training targets the brain and the body through a combination of focused-attention meditation and aerobic exercise. The following feasibility pilot study tested whether 6 weeks of MAP training improves mental health outcomes, while enhancing discrimination learning and heart rate variability (HRV) in a group of women living with human immunodeficiency virus (HIV) and other stress-related conditions. Participants were assigned to training (n = 18) or no-training control (n = 8) groups depending on their ability and willingness to participate, and if their schedule allowed. Training sessions were held once a week for 6 weeks with 30 min of meditation followed by 30 min of aerobic exercise. Before and after 6 weeks of training, participants completed the Behavioral Pattern Separation Task as a measure of discrimination learning, self-report questionnaires of ruminative and trauma-related thoughts, depression, anxiety, and perceived stress, and an assessment of HRV at rest. After training, participants reported fewer ruminative and trauma-related thoughts, fewer depressive and anxiety symptoms, and less perceived stress (p’s < 0.05). The positive impact on ruminative thoughts and depressive symptoms persisted 6 months after training. They also demonstrated enhanced discrimination of similar patterns of information (p < 0.05). HRV did not change after training (p > 0.05). Combining mental and physical training is an effective program for enhancing mental health and aspects of cognition in women living with HIV, although not necessarily through variance in heart rate.

Regular aerobic exercise is positively associated with hippocampal structure and function in young and middle-aged adults.

Regular exercise has numerous benefits for brain health, including the structure and function of the hippocampus. The hippocampus plays a critical role in memory function, and is altered in a number of psychiatric disorders associated with memory impairments (e.g., depression and schizophrenia), as well as healthy aging. While many studies have focused on how regular exercise may improve hippocampal integrity in older individuals, less is known about these effects in young to middle-aged adults. Therefore, we assessed the associations of regular exercise and cardiorespiratory fitness with hippocampal structure and function in these age groups. We recruited 40 healthy young to middle-aged adults, comprised of two groups (n=20) who self-reported either high or low levels of exercise, according to World Health Organization guidelines. We assessed cardiorespiratory fitness using a graded exercise test (VO2 max) and hippocampal structure via manual tracing of T1-weighted magnetic resonance images. We also assessed hippocampal function using magnetic resonance spectroscopy to derive estimates of N-acetyl-aspartate concentration and hippocampal-dependent associative memory and pattern separation tasks. We observed evidence of increased N-acetyl-aspartate concentration and associative memory performance in individuals engaging in high levels of exercise. However, no differences in hippocampal volume or pattern separation capacity were observed between groups. Cardiorespiratory fitness was positively associated with left and right hippocampal volume and N-acetyl-aspartate concentration. However, no associations were observed between cardiorespiratory fitness and associative memory or pattern separation. Therefore, we provide evidence that higher levels of exercise and cardiorespiratory fitness are associated with improved hippocampal structure and function. Exercise may provide a low-risk, effective method of improving hippocampal integrity in an early-to-mid-life stage.

The spontaneous location recognition task for assessing spatial pattern separation and memory across a delay in rats and mice.

Keeping similar memories distinct from one another is a critical cognitive process without which we would have difficulty functioning in everyday life. Memories are thought to be kept distinct through the computational mechanism of pattern separation, which reduces overlap between similar input patterns to amplify differences among stored representations. At the behavioral level, impaired pattern separation has been shown to contribute to memory deficits seen in neuropsychiatric and neurodegenerative diseases, including Alzheimer's disease, and in normal aging. This protocol describes the use of the spontaneous location recognition (SLR) task in mice and rats to behaviorally assess spatial pattern separation ability. This two-phase spontaneous memory task assesses the extent to which animals can discriminate and remember object locations presented during the encoding phase. Using three configurations of the task, the similarity of the to-be-remembered locations can be parametrically manipulated by altering the spatial positions of objects-dissimilar, similar or extra similar-to vary the load on pattern separation. Unlike other pattern separation tasks, SLR varies the load on pattern separation during encoding, when pattern separation is thought to occur. Furthermore, SLR can be used in standard rodent behavioral facilities with basic expertise in rodent handling. The entire protocol takes ~20 d from habituation to testing of the animals on all three task configurations. By incorporating breaks between testing, and varying the objects used as landmarks, animals can be tested repeatedly, increasing experimental power by allowing for within-subjects manipulations.

Strenuous Exercise Habits and Spatial Mnemonic Discrimination Ability in Young Adult Men and Women.

Increased physical activity has shown positive effects on various hippocampal memory functions through accumulating evidence that physical exercise and higher cardiorespiratory fitness can enhance human performance on nonspatial mnemonic discrimination tasks that rely on hippocampal pattern separation. However, there is less direct evidence of exercise effects on spatial pattern separation in humans, despite evidence for this association in rodent models. We examined the influence of strenuous exercise habits on spatial mnemonic discrimination among 176 young adults. We used a delayed match-/non-match-to-sample (same/different) task to assess pattern separation for spatial locations across varying degrees of similarity. Participants who reported regularly engaging in strenuous exercise three or more times per week performed significantly better than those who reported engaging in strenuous exercise fewer than three times per week, even when pattern separation tasks involved higher spatial similarity. These apparent exercise effects were observed for female, but not male, participants. These findings support likely benefits of strenuous exercise habits for human spatial pattern separation skills, and they suggest a need to explore potential interaction effects of exercise and gender.

Leucine-rich repeats and immunoglobulin-like domains 1 deficiency affects hippocampal dendrite complexity and impairs cognitive function.

Leucine-rich repeat (LRR) transmembrane proteins have been directly linked to neurodevelopmental and cognitive disorders. We have previously shown that the LRR transmembrane protein, leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1), is a physiological regulator of dendrite complexity of hippocampal pyramidal neurons and social behavior. In this study, we performed a battery of behavioral tests to evaluate spatial memory and cognitive capabilities in Lrig1 mutant mice. The cognitive assessment demonstrated deficits in recognition and spatial memory, evaluated by novel object recognition and object location tests. Moreover, we found that Lrig1-deficient mice present specific impairments in the processing of similar but not dissimilar locations in a spatial pattern separation task, which was correlated with an enhanced dendritic growth and branching of Doublecortin-positive immature granule cells of the dentate gyrus. Altogether, these findings indicate that Lrig1 plays an essential role in controlling morphological and functional plasticity in the hippocampus.

Prophylactic ( R,S )‐ketamine Protects Against Fear Overgeneralization 8.5.5

The adolescent stage is a sensitive time period for brain development. During this phase, the brain's high plasticity makes adolescents more susceptible to external factors, one of these being stress. Anxiety and mood disorders such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) mainly stem from exposure to stress. Studies have shown that a single injection of (R,S)-ketamine, an NMDA antagonist, prior to stress protects against the development of depressive-like behavior and attenuates learned fear. However, most of these studies were conducted in post-natal day 60 (P60) adult mice. We sought to identify the neural correlates of fear in post-natal day 35 (P35) adolescent mice and which neural alterations correlate to fear generalization. In the experiment, ArcCreERT2 P60 and P35 mice were administered a pattern separation (PS) paradigm. The mice were then sacrificed, and their brains were processed on either day 3 (D3) or day 10 (D10) following context A or B exposures, respectively. Through cell quantification and hippocampal analysis, we saw that during the PS task, both groups of mice exhibited comparable levels of freezing following one-shock in the aversive context A. However, when compared to P60 mice, the P35 mice tend to over-generalize fear. P35 mice distinguish between the two contexts on Day 8, whereas P60 mice distinguish between the two contexts starting on Day 6. This behavioral phenotype seems to be mainly mediated by CA3 but not the Dentate Gyrus in the hippocampus. Our data indicate that P35 adolescent mice over-generalize fear when compared to P60 adult mice. It also reveals that the CA3 in the hippocampus is what mediates contextual discrimination in these adolescent mice. In the future, these results encourage us to introduce ketamine to P35 adolescent mice. This would allow us to explore the mechanisms involved in fear generalization between P35 and P60 mice and if ketamine would have the same effect on them. 8.5.5