Maze Performance Research Articles

Spatial Learning and Memory in the Naked Mole-Rat: Evolutionary Adaptations to a Subterranean Niche

Evolutionary adaptation to a subterranean habitat consisting of extensive underground tunnel systems would presumably require adept spatial learning and memory, however, such capabilities have not been characterized to date in naked mole-rats (Heterocephalus glaber) which, like other members of Bathyergidae, are subterranean rodents. The goal of this study was to develop a method for effectively assessing spatial learning and memory by modifying a Hebb-Williams maze for use with these subterranean rodents. Established behavioral tests to assess spatial learning and memory have primarily focused on, and have been optimized for, more typical laboratory rodent species such as mice and rats. In the current study, we utilized species-appropriate motivators, analyzed learning curves associated with maze performance, and tested memory retention in naked mole-rats. Using a modified Hebb-Williams maze, naked mole-rats underwent 3 days of training, consisting of five trials per day wherein they could freely explore the maze in search of the reward chamber. Memory retention was then tested 1 day, 1 week, and 1 month following the last day of training. Performance was analyzed based on latency to the reward chamber, errors made, and distance traveled to reach the reward chamber. Overall, this study established a behavioral paradigm for assessing maze navigation, spatial learning, and spatial memory in subterranean rodents, including optimization of rewards and environmental motivators.

Alcohol-Drinking Under Limited-Access Procedures During Mature Adulthood Accelerates the Onset of Cognitive Impairment in Mice.

A history of heavy drinking increases vulnerability to, and the severity of, Alzheimer’s disease (AD) and related dementias, with alcohol use disorder identified as the strongest modifiable risk factor for early-onset dementia. Heavy drinking has increased markedly in women over the past 10 years, particularly in mature adult women during the coronavirus (COVID-19) pandemic. This is concerning as women are more sensitive to many alcohol-related disease states, including AD and related dementias. Herein, we conducted two studies to determine if a 1-month period of binge drinking during mature adulthood (i.e., 5–9 months of age) impairs spatial and working memory to a greater extent in female vs. male C57BL/6J (B6J) mice. The anxiogenic and cognitive-impairing effects of binge drinking were also compared between mature adult and old B6J mice (18 months of age) in a third study. Throughout, females consumed more alcohol than males, indicating that a sex difference in binge drinking persists into old age. Despite the sex difference in intake, we detected no consistent sex difference in our measures of alcohol withdrawal-induced anxiety during a behavioral test battery. Although mature adult females exhibited more cognitive deficits than males, the precise outcome exhibiting a female-selective effect varied across studies. Old mice drank lower amounts of alcohol than mature adult mice, yet their blood ethanol concentrations (BECs) were within error of the 80 mg/dl criterion for binge drinking, indicative of an age-related slowing of alcohol metabolism. As expected, 18-month-old controls exhibited more signs of cognitive impairment than their 6-month-old counterparts, and binge drinking history impaired the Morris water maze performance of mice of both ages. In contrast, binge drinking history impaired the radial arm maze performance of 6-month-old mice only, and the extent of the impairment was comparable to the behavior exhibited by the older mice. We conclude from our studies that: (1) both biological sex and the age of drinking onset are subject factors that impact voluntary alcohol consumption by mice into old age; (2) binge drinking during later life elicits a negative affective state that is relatively sex-independent; (3) binge drinking during both mature adulthood and old age impairs spatial learning and memory; (4) binge drinking during mature adulthood accelerates deficits in working memory; and (5) mature adult females tend to exhibit more alcohol-induced cognitive impairments than males. If relevant to humans, these findings suggest that binge-like drinking by older adult men and women induces a negative affective state and cognitive decline, but that mature adult women, in particular, may be more sensitive to both the immediate and persistent cognitive-impairing effects of heavy drinking.

The effect of exercise on early sensorimotor performance alterations in the 3xTg-AD model of Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by a progressive decline in cognitive function; however, recent evidence suggests that non-cognitive sensorimotor and psychomotor symptoms accompany early stages of the disease in humans and AD models. Although exercise is emerging as an important therapeutic to combat AD progression, little is known about the effect of exercise on sensorimotor domain functions. The purpose of this study was to determine if early sensorimotor symptoms accompany deficits in Morris water maze (MWM) performance in the 3xTg-AD model, and investigate if exercise could protect against early behavioral decline. 3xTg-AD and wild-type (WT) control mice were subjected to 12 weeks of moderate intensity wheel running or remained sedentary. At 6 months of age, animals underwent a series of sensorimotor and MWM testing. 3xTg-AD mice displayed deficits in sensorimotor function (beam traversal, spontaneous activity, and adhesive removal) and MWM performance. Interestingly, 3xTg-AD animals exhibited increased freezing and unusual shaking/tremoring behaviors not displayed by WT controls. Exercise improved beam traversal, adhesive removal, and reduced the unusual motor-related behaviors in 3xTg-AD mice. Our study shows that sensorimotor symptoms coincide with deficits in MWM performance, and suggest that exercise may mitigate deficits associated with early disease in 3xTg-AD mice.

Novel measures of Morris water maze performance that use vector field maps to assess accuracy, uncertainty, and intention of navigational searches.

Most commonly used behavioral measures for testing learning and memory in the Morris water maze (MWM) involve comparisons of an animal's residence time in different quadrants of the pool. Such measures are limited in their ability to test different aspects of the animal's performance. Here, we describe novel measures of performance in the MWM that use vector fields to capture the motion of mice as well as their search pattern in the maze. Using these vector fields, we develop quantitative measures of performance that are intuitive and more sensitive than classical measures. First, we describe search patterns in terms of vector field properties and use these properties to define three metrics of spatial memory namely Spatial Accuracy, Uncertainty and, Intensity of Search. We demonstrate the usefulness of these measures using four different data sets including comparisons between different strains of mice, an analysis of two mouse models of Noonan syndrome (NS; Ptpn11 D61G and Ptpn11 N308D/+), and a study of goal reversal training. Importantly, besides highlighting novel aspects of performance in this widely used spatial task, our measures were able to uncover previously undetected differences, including in an animal model of NS, which we rescued with the mitogen activated protein kinase kinase (MEK) inhibitor SL327. Thus, our results show that our approach breaks down performance in the MWM into sensitive measurable independent components that highlight differences in spatial learning and memory in the MWM that were undetected by conventional measures.

Correlation studies on pathological changes in brain with neurotransmitters and behavioural changes in Balb/c mice

Aim: To determine the plasma neurotransmitters simultaneously and to find any correlation with pathological changes in the hippocampus and Purkinje cells and their relation with behavioral changes in Balb/c mice. Methodology: In the present study, both sexes of Balb /C mice were divided into two groups (4 males and 4 females; n = 8): Both the groups were given a single dose of either saline or sodium valproate (400mg kg-1) respectively through subcutaneous injection on PND 14. Behavioural tests were conducted on mice pups on various postnatal days till 40th day. On PND 41, blood samples were collected from all the animals for quantification of the neurotransmitters (serotonin, dopamine, and noradrenalin) in plasma, animals were sacrificed by cervical dislocation and whole brain was isolated for histological examination of the Purkinje cells and hippocampus. Results: Sodium valproate exposed animals showed loss of motor skill development (delayed negative geotaxic response), increased locomotor activity, increased anxiety, and retardation in water maze performance, and lower social interaction. Histopathological evolutions of cerebellum purkinje cells and hippocampus showed 40-50% atrophic cells in sodium valproate animals compared to control animals. Interpretation: The results of the present study indicate that Sodium valproate changes specific brain cell population in Balb/C mice, which might be the reason for the altered neurotransmitter levels, leading to behavioural changes in these animals.

Transport in mazes; simple geometric representations to guide the design of engineered systems

Although engineers can control the internal geometry of materials down to the micro-scale, it is unclear what configuration is ideal for a given transport process. We explore the use of mazes as abstract representations of two-phase systems. Mazes can be easily generated using many different algorithms and then represented as graphs for analysis. The three, dimensionless graph parameters of effective tortuous resistance, average tortuosity, and minimum-cut-size were derived and then correlated to the maze’s effective transport property (e.g., permeability), average residence time, and robustness, respectively. It was shown that by tuning the settings of the maze algorithm, one can obtain desired maze performance. Finally, a composite maze was constructed and shown to mimic the geometry and permeability of a real commercial membrane. In principle, a surrogate maze geometry can be optimized/tuned for a given transport process and then used to guide the rational design of the engineered system it represents.

Effects of possible odor cue on radial arm maze performance over long-term intervals in rats

Effects of possible odor cue on radial arm maze performance over long-term intervals in rats

β-hydroxybutyrate Alleviates Learning and Memory Impairment Through the SIRT1 Pathway in D-Galactose-Injured Mice.

Learning and memory impairment is a common clinical symptom of aging and nervous system injuries, and seriously affects quality of life. Memory impairment is associated with increased oxidative stress (OS) and inflammatory response. β-hydroxybutyrate (BHBA) is a water-soluble endogenous small-molecule ketone body that easily crosses the blood-brain barrier and has shown neuroprotection activities. In this study, we investigated the effects and mechanisms of BHBA on D-galactose (D-gal)-induced memory impairment in mice by in vitro and in vivo experiments. BHBA was administered intragastrically to D-gal-injured C57BL/6 mice for 42 days. Water maze performance, the morphology of the hippocampus with Nissl staining, the ACh content, OS, and inflammation status were examined. To further investigate the mechanism, hippocampal neuronal cells (HT22) were treated with BHBA with or without the SIRT1 inhibitor or small interfering RNAs against sirt1 (si-SIRT1) before incubation with D-gal. BHBA significantly improved water maze performance; increased the ACh content, SOD activity, and SIRT1 expression; and decreased AChE and LDH activity, ROS, MDA, IL-1β, TNF-α contents, and NLRP3 expression. Further studies with the SIRT inhibitor or siRNAs against sirt1 reversed the above effects of BHBA. Collectively, BHBA inhibited hippocampal OS and the inflammation process to alleviate learning and memory impairment through activating the SIRT1 pathway in D-gal-injured mice, suggesting that BHBA could be a potential option for drug development of learning and memory impairment induced by nervous system injuries.

Effects of Toll-like receptor 4 inhibition on spatial memory and cell proliferation in male and female adult and aged mice

Toll-like receptors (TLRs) participate in the response to infection, stress, and injury by initiating an innate immune response. In addition, these receptors are expressed in many neural cell types and under physiological conditions are implicated in modulating cognitive function and neural plasticity in the adult and aged brain. Knockout of the Toll-like receptor 4 (TLR4) subtype enhances spatial memory and adult hippocampal neurogenesis through increasing proliferation and neuronal differentiation. Currently unknown is whether pharmacological inhibition of TLR4 produces similar enhancements in cognitive function and cell proliferation. The present study evaluated water maze performance, cytokine expression, and cell proliferation in the hippocampus of young and aged male and female C57BL6/J mice following treatment with the TLR4 antagonist, TAK-242. Further, alterations in the response to an acute stressor were evaluated in TAK-242-treated mice. Results showed that TAK-242 selectively enhanced spatial learning and memory in young females. Additionally, TAK-242 treatment reduced thigmotaxis in the water maze and lowered corticosterone levels following acute stress in females. TAK-242 decreased hippocampal interleukin (IL)-1β expression but had no effect on IL-6 or tumor necrosis factor-α (TNFα). Aged mice showed decreased cell proliferation compared to young mice, but TAK-242 administration had minimal effects on estimated Ki67 positive cell numbers. Findings indicate that pharmacological inhibition of TLR4 improves cognitive function in young females likely through attenuating stress reactivity.

Defining the absolute risk of maternal infections on offspring neurodevelopmental outcomes: How to ensure your model is not lost in translation

Toll-like receptors (TLRs) participate in the response to infection, stress, and injury by initiating an innate immune response. In addition, these receptors are expressed in many neural cell types and under physiological conditions are implicated in modulating cognitive function and neural plasticity in the adult and aged brain. Knockout of the Toll-like receptor 4 (TLR4) subtype enhances spatial memory and adult hippocampal neurogenesis through increasing proliferation and neuronal differentiation. Currently unknown is whether pharmacological inhibition of TLR4 produces similar enhancements in cognitive function and cell proliferation. The present study evaluated water maze performance, cytokine expression, and cell proliferation in the hippocampus of young and aged male and female C57BL6/J mice following treatment with the TLR4 antagonist, TAK-242. Further, alterations in the response to an acute stressor were evaluated in TAK-242-treated mice. Results showed that TAK-242 selectively enhanced spatial learning and memory in young females. Additionally, TAK-242 treatment reduced thigmotaxis in the water maze and lowered corticosterone levels following acute stress in females. TAK-242 decreased hippocampal interleukin (IL)-1β expression but had no effect on IL-6 or tumor necrosis factor-α (TNFα). Aged mice showed decreased cell proliferation compared to young mice, but TAK-242 administration had minimal effects on estimated Ki67 positive cell numbers. Findings indicate that pharmacological inhibition of TLR4 improves cognitive function in young females likely through attenuating stress reactivity.

The effects of aging and dopaminergic inhibition on large scale maze learning in rhesus monkeys

Studies have shown that both aging and dopaminergic dysfunction affected spatial learning and memory. Systematic dopaminergic inhibition, by dopamine receptor (DR) antagonist treatment, impaired spatial delayed-response (SDR) performance, which mostly requires self/body centered egocentric reference frame, in rhesus monkeys. However, the influence of DR blocking on large scale maze learning, which mainly involves world centered allocentric reference frame, remains unclear. Moreover, the effects of aging on the process also remain unknown. Present study investigated the issues, using large scale mazes composed of 8 maze units. Maze No. 1 was used for adaptation and training. Mazes No. 2-4 were used to investigate influence of aging, by comparing learning performance between young and aged rhesus monkeys. Mazes No. 5-8 were used to investigate the effects of DR antagonist treatment, SKF-83566 (0.02, 0.2 mg/kg) and haloperidol (0.001, 0.01 mg/kg). The result showed similar learning performance between young and aged monkeys in mazes No. 2-4. In mazes No. 5-8, we also found similar learning performance after acute DR antagonist injection, compared with pre-treatment baseline performance in mazes No. 2-4, in both young and aged groups. The result showed similar maze learning performance between young and aged monkeys in mazes (No. 2-4), suggesting no significant influence of aging on allocentric spatial learning. We also found similar maze performance in both groups, after dopamine receptor antagonist treatment in mazes (No. 5-8) compared with pre-treatment baseline performance in mazes (No. 2-4), suggesting no significant influence of dopaminergic inhibition on allocentric spatial learning. Together, the present study potentially suggested insensitivity of allocentric spatial learning to cognitive aging and acute systematic dopaminergic inhibition.

Increasing dietary choline attenuates spatial memory deficits resulting from exposure to the chemotherapeutic agents cyclophosphamide and doxorubicin.

Choline supplementation (+Ch) improves cognitive function in impaired animals and humans. Chemotherapy-related cognitive deficits (CRCDs) occur in cancer patients, and these deficits persist following treatment, adversely impacting quality of life. To date, there are no approved treatments for this condition. Because +Ch improves impaired memory, it was of interest to determine whether +Ch can attenuate spatial memory deficits induced by the chemotherapeutic agents doxorubicin (DOX) and cyclophosphamide (CYP). Female BALB/C mice, 64 days of age, were trained in the Morris water maze and baseline performance determined on day 15. Following baseline assessment, mice were placed on +Ch diet (2.0% Ch) or remained on standard diet (0.12% Ch). Mice received intravenous injections of DOX (2.5 mg/kg) and CYP (25 mg/kg), or equivalent volumes of saline (0.9% NaCl), on days 16, 23, 30, and 37, and spatial memory was assessed weekly from day 22 to 71. DOX and CYP produced a prolonged impairment in spatial memory as indicated by an increased latency to the correct zone (p < 0.05), and a decrease in time in the correct zone (p < 0.05), % of total swim distance in the correct zone (p < 0.05) and % entries to the correct zone (p < 0.05). These effects were attenuated by +Ch. Although it remains to be determined whether this effect extends to other cognitive domains and whether +Ch is prophylactic or therapeutic, these findings suggest that +Ch may be an effective intervention for CRCDs.

Dimethyl fumarate does not mitigate cognitive decline and β-amyloidosis in female APPPS1 mice

IntroductionAlzheimer’s disease (AD) is the leading cause of dementia and a major global health issue. Currently, only limited treatment options are available to patients. One possibility to expand the treatment repertoire is repurposing of existing drugs such as dimethyl fumarate (DMF). DMF is approved for treatment of multiple sclerosis and previous animal studies have suggested that DMF may also have a beneficial effect for the treatment of AD. MethodsWe used an APPPS1 transgenic model of senile β-amyloidosis and treated female mice orally with DMF in two treatment paradigms (pre and post onset). We quantified learning and memory parameters, β-amyloidosis, and neuroinflammation to determine the potential of DMF as AD therapeutics. ResultsTreatment with DMF had no influence on water maze performance, β-amyloid accumulation, plaque formation, microglia activation, and recruitment of immune cells to the brain. Compared to vehicle-treated animals, oral DMF treatment could not halt or retard disease progression in the mice. DiscussionOur results do not favour the use of DMF as treatment for AD. While our results stand in contrast to previous findings in other models, they emphasize the importance of animal model selection and suggest further studies to elucidate the mechanisms leading to conflicting results.

Cognitive impairment in obese rat model: role of glial cells.

Obesity is a worldwide problem. Some studies revealed that it leads to deterioration of the cognitive function, regardless of age. explore the effect of obesity on cognitive function in a rat model of obesity highlighting the role of glial cells. twenty adult male albino rats were assigned to two groups: group I: consumed normal diet, group II: consumed high-fat diet. Body Mass Index (BMI), serum glucose, insulin, HOMA IR and lipid profile were measured. Also, hippocampal expression of Brain derived neurotrophic factor (Bdnf), synapsin, Ionized calcium binding adaptor molecule 1 (Iba), nuclear factor erythroid -related factor 2 (Nrf2), Myelin basic protein (Mbp) were measured by real-time polymerase chain reaction. The Morris Water Maze is a test used to assess spatial learning and memory capacities of rats. There was a high significant increase in lipid profile, serum glucose, insulin serum levels and HOMA-IR in obese groups with impaired Morris water maze performance compared to control group. There was a significant downregulation in hippocampal Bdnf and synapsin mRNA expression. In addition to decrease in Mbp mRNA expression (P < 0.001). This could be explained by oxidative stress through significant downregulation of Nrf2 mRNA, and inflammation observed in significant upregulation Iba mRNA gene expression in the obese group. Many factors contribute to obesity associated cognitive impairment. In our study, we figured out the crucial roles of glial cells including microglial activation and oligodendrocytes affection with other underlying mechanisms including oxidative stress and hippocampal inflammation.

Q134R: Small chemical compound with NFAT inhibitory properties improves behavioral performance and synapse function in mouse models of amyloid pathology.

Inhibition of the protein phosphatase calcineurin (CN) ameliorates pathophysiologic and cognitive changes in aging rodents and mice with aging‐related Alzheimer's disease (AD)‐like pathology. However, concerns over adverse effects have slowed the transition of common CN‐inhibiting drugs to the clinic for the treatment of AD and AD‐related disorders. Targeting substrates of CN, like the nuclear factor of activated T cells (NFATs), has been suggested as an alternative, safer approach to CN inhibitors. However, small chemical inhibitors of NFATs have only rarely been described. Here, we investigate a newly developed neuroprotective hydroxyquinoline derivative (Q134R) that suppresses NFAT signaling, without inhibiting CN activity. Q134R partially inhibited NFAT activity in primary rat astrocytes, but did not prevent CN‐mediated dephosphorylation of a non‐NFAT target, either in vivo, or in vitro. Acute (≤1 week) oral delivery of Q134R to APP/PS1 (12 months old) or wild‐type mice (3–4 months old) infused with oligomeric Aβ peptides led to improved Y maze performance. Chronic (≥3 months) oral delivery of Q134R appeared to be safe, and, in fact, promoted survival in wild‐type (WT) mice when given for many months beyond middle age. Finally, chronic delivery of Q134R to APP/PS1 mice during the early stages of amyloid pathology (i.e., between 6 and 9 months) tended to reduce signs of glial reactivity, prevented the upregulation of astrocytic NFAT4, and ameliorated deficits in synaptic strength and plasticity, without noticeably altering parenchymal Aβ plaque pathology. The results suggest that Q134R is a promising drug for treating AD and aging‐related disorders.

Sustained Dysbiosis and Decreased Fecal Short-Chain Fatty Acids after Traumatic Brain Injury and Impact on Neurologic Outcome.

Traumatic brain injury (TBI) alters microbial populations present in the gut, which may impact healing and tissue recovery. However, the duration and impact of these changes on outcome from TBI are unknown. Short-chain fatty acids (SCFAs), produced by bacterial fermentation of dietary fiber, are important signaling molecules in the microbiota gut-brain axis. We hypothesized that TBI would lead to a sustained reduction in SCFA producing bacteria, fecal SCFAs concentration, and administration of soluble SCFAs would improve functional outcome after TBI. Adult mice (n = 10) had the controlled cortical impact (CCI) model of TBI performed (6 m/sec, 2-mm depth, 50-msec dwell). Stool samples were collected serially until 28 days after CCI and analyzed for SCFA concentration by high-performance liquid chromatography-mass spectrometry/mass spectrometry and microbiome analyzed by 16S gene sequencing. In a separate experiment, mice (n = 10/group) were randomized 2 weeks before CCI to standard drinking water or water supplemented with the SCFAs acetate (67.5 mM), propionate (25.9 mM), and butyrate (40 mM). Morris water maze performance was assessed on post-injury Days 14-19. Alpha diversity remained stable until 72 h, at which point a decline in diversity was observed without recovery out to 28 days. The taxonomic composition of post-TBI fecal samples demonstrated depletion of bacteria from Lachnospiraceae, Ruminococcaceae, and Bacteroidaceae families, and enrichment of bacteria from the Verrucomicrobiaceae family. Analysis from paired fecal samples revealed a reduction in total SCFAs at 24 h and 28 days after TBI. Acetate, the most abundant SCFA detected in the fecal samples, was reduced at 7 days and 28 days after TBI. SCFA administration improved spatial learning after TBI versus standard drinking water. In conclusion, TBI is associated with reduced richness and diversity of commensal microbiota in the gut and a reduction in SCFAs detected in stool. Supplementation of soluble SCFAs improves spatial learning after TBI.

Non-selective COX inhibitors impair memory formation and short-term but not long-term synaptic plasticity.

Cyclooxygenase (COX) plays a critical role in synaptic plasticity. Therefore, long-term administration of acetylsalicylic acid (ASA) and its main metabolite, salicylate, as a COX inhibitor may impair synaptic plasticity and subsequently memory formation. Although different studies have tried to explain the effects of ASA and sodium salicylate (SS) on learning and memory, the results are contradictory and the mechanisms are not exactly known. The present study was designed to investigate the effects of long-term low-dose (equivalent to prophylactic dose) and short-term high-dose (equivalent to analgesic dose) administration of ASA and SS respectively, on spatial learning and memory and hippocampal synaptic plasticity. Animals were treated with a low dose of ASA (2mg/mlsolvated in drinking water, 6weeks) or a high dose of SS, a metabolite of ASA, (300mg/kg, 3days, twice-daily, i.p). Spatial memory and synaptic plasticity were assessed by water maze performance and in vivo field potential recording from CA1, respectively. Animals treated with ASA but not SS showed a significant increase in escape latency and distance moved. Furthermore, in the probe test, animals treated with both drugs spent less time in the target quadrant zone. The paired-pulse ratio (PPR) at 20-ms inter-pulse intervals (IPI) as an index of short-term plasticity in both treated groups was significantly higher than of the control group. Interestingly, none of the administered drugs affected long-term potentiation (LTP). These data suggested that long-term inhibition of COX disrupted memory acquisition and retrieval. Interestingly, cognitive impairments happened along with short-term but not long-term synaptic plasticity disturbance.

Spatial Learning Is Impaired in Male Pubertal Rats Following Neonatal Daily but Not Randomly Spaced Maternal Deprivation.

Severe early life stress has long been associated with neuropsychological disorders in adulthood, including depression, schizophrenia, post-traumatic stress disorder, and memory dysfunction. To some extent, all of these conditions involve dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and reduced negative feedback inhibition of cortisol release in adulthood. However, the time course for mental health and hormonal outcomes across life stages and the attributes of early life stress that direct the behavioral and biological alterations is not fully understood. We designed our studies to compare outcomes of the two most common maternal deprivation schedules on cognitive ability prior to adulthood. We exposed rat pups to daily or randomly spaced maternal separation bouts within the first 3 weeks of life and examined cognitive performance, neurotrophic signaling, and stress and immune system markers during puberty. We found that the daily separation schedule impaired spatial learning while the randomly spaced schedule did not alter maze performance relative to normally reared control animals. Animals that underwent daily separation showed a tendency for reduced body weight compared to the randomly spaced condition, but there were no differences in adrenal weight. Thymus weight normalized by body weight was increased following daily separation compared to random separation and control conditions. Plasma corticosterone levels measured after behavior testing did not differ amongst experimental groups and there was no impact of TrKB receptor inhibition. Combined, the results show that different early life stress schedules produce different behavioral and biological outcomes when measured at puberty. Combined with prior findings from more mature animals, the results presented here suggest that daily neonatal stress produces varied alterations in spatial cognition at different life stages with a transient learning deficit at puberty preceding a more persistent and a progressive memory impairment through adulthood and into aging.

Caenorhabditis elegans learning in a structured maze is a multisensory behavior

SummaryWe show that C. elegans nematodes learn to associate food with a combination of proprioceptive cues and information on the structure of their surroundings (maze), perceived through mechanosensation. By using the custom-made Worm-Maze platform, we demonstrate that C. elegans young adults can locate food in T-shaped mazes and, following that experience, learn to reach a specific maze arm. C. elegans learning inside the maze is possible after a single training session, it resembles working memory, and it prevails over conflicting environmental cues. We provide evidence that the observed learning is a food-triggered multisensory behavior, which requires mechanosensory and proprioceptive input, and utilizes cues about the structural features of nematodes' environment and their body actions. The CREB-like transcription factor and dopamine signaling are also involved in maze performance. Lastly, we show that the observed aging-driven decline of C. elegans learning ability in the maze can be reversed by starvation.

Age Impacts the Burden That Reference Memory Imparts on an Increasing Working Memory Load and Modifies Relationships With Cholinergic Activity

Rodent aging research often utilizes spatial mazes, such as the water radial-arm-maze (WRAM), to evaluate cognition. The WRAM can simultaneously measure spatial working and reference memory, wherein these two memory types are often represented as orthogonal. There is evidence, however, that these two memory forms yield interference at a high working memory load. The current study systematically evaluated whether the presence of a reference memory component impacts handling of an increasing working memory load. Young and aged female rats were tested to assess whether aging impacts this relationship. Cholinergic projections from the basal forebrain to the hippocampus and cortex can affect cognitive outcomes, and are negatively impacted by aging. To evaluate whether age-related changes in working and reference memory profiles are associated with cholinergic functioning, we assessed choline acetyltransferase activity in these behaviorally-tested rats. Results showed that young rats outperformed aged rats on a task testing solely working memory. The addition of a reference memory component deteriorated the ability to handle an increasing working memory load, such that young rats performed similar to their aged counterparts. Aged rats also had challenges when reference memory was present, but in a different context. Specifically, aged rats had difficulty remembering which reference memory arms they had entered within a session, compared to young rats. Further, aged rats that excelled in reference memory also excelled in working memory when working memory demand was high, a relationship not seen in young rats. Relationships between cholinergic activity and maze performance differed by age in direction and brain region, reflecting the complex role that the cholinergic system plays in memory and attentional processes across the female lifespan. Overall, the addition of a reference memory requirement detrimentally impacted the ability to handle working memory information across young and aged timepoints, especially when the working memory challenge was high; these age-related deficits manifested differently with the addition of a reference memory component. This interplay between working and reference memory provides insight into the multiple domains necessary to solve complex cognitive tasks, potentially improving the understanding of complexities of age- and disease- related memory failures and optimizing their respective treatments.