Spatial Navigation Learning Research Articles

태극삼의 장기투여가 인지기능향상과 기억력증진에 미치는 영향

To investigate effects of cognitive function improvement whether against Taegeuk ginseng on scopolamine-induced memory impairment in rats. All experiments were conducted in three groups: the control group (CTR), the scopolamine 0.4mg/kg (SCP), and the scopolamine (SCP+T) treated with Taegeuk ginseng 100 mg/kg. Taegeuk ginseng 100 mg/kg daily was orally administered for one month and treated with scopolamine was only for 7 consecutive days on the Morris water maze task. 3 weeks after oral administration of Taegeuk ginseng, subjects were performed the Morris water maze test for 8 days and then the open-field exploration test which to assessed for cognitive function improvement. After behavioral testing, subjects were sacrificed and microdissected brains for neurochemical analysis. In the cognitive-behavioral test, long-term administration of Taegeuk ginseng improved spatial navigation learning task compared with the impeded by scopolamine treatment. In neurochemistry, the expression of the synaptic marker PSD95 (postsynaptic density protein 95) was increased in the hippocampus compared to the scopolamine group. Also, brain-derived neurotrophic factor (BDNF) expression was significantly increased in the taegeuk ginseng administration group. These data suggested that long-term administration of taegeuk ginseng might improve cognitive-behavioral functions on hippocampal related spatial learning memory, and it was correlated with neurotropic and synaptic reinforcement. In conclusion, treatment with taegeuk ginseng may positive outcome on learning and memory deficit disorders.

Impact of forest fire smoke on the state of the central nervous system of rats

Introduction. The adverse negative effect of forest fire smoke on human health represents a unique interdisciplinary challenge to the scientific community. The influence of forest fire smoke on locomotor activity, cognitive indices, and brain bioelectrical activity parameters in exposed rats is presented. Materials and methods. Experimental studies were carried out on outbred white male rats. The animals of the experimental group were exposed to smoke inhalation forest fire for one day. Immediately after the end of the exposure, the animals were examined, including testing in an open field and Morris water maze, as well as an electroencephalographic examination. Results. At twenty-four-hour exposure to wildfire smoke in the model, conditions showed increasing motor and research activity of male rats against the backdrop of growing anxiety. Disorders of indicators of spatial memory and navigation learning were not revealed. On the encephalogram of the exposed animals, in comparison with the control group, the δ-rhythm range predominated, more pronounced in the leads of the right hemisphere. A decrease in the power spectrum and the average amplitude β1-rhythm, as well as a tendency to decrease the average amplitude of θ-rhythm, were revealed. The indices of the primary EEG rhythms did not have statistically significant differences when compared with the control group. Conclusion. The results showed that forest fire smoke leads to changes in the bioelectric activity of brain structures and dysregulation of individual behaviour in animals, all of which may indicate the formation of increased levels of stressing beyond physiological adaptation.

Post-Training Sleep Modulates Topographical Relearning-Dependent Resting State Activity.

Continuation of experience-dependent neural activity during offline sleep and wakefulness episodes is a critical component of memory consolidation. Using functional magnetic resonance imaging (fMRI), offline consolidation effects have been evidenced probing behavioural and neurophysiological changes during memory retrieval, i.e., in the context of task practice. Resting state fMRI (rsfMRI) further allows investigating the offline evolution of recently learned information without the confounds of online task-related effects. We used rsfMRI to investigate sleep-related changes in seed-based resting functional connectivity (FC) and amplitude of low frequency fluctuations (ALFF) after spatial navigation learning and relearning. On Day 1, offline resting state activity was measured immediately before and after topographical learning in a virtual town. On Day 4, it was measured again before and after relearning in an extended version of the town. Navigation-related activity was also recorded during target retrieval, i.e., online. Participants spent the first post-training night under regular sleep (RS) or sleep deprivation (SD) conditions. Results evidence FC and ALFF changes in task-related neural networks, indicating the continuation of navigation-related activity in the resting state. Although post-training sleep did not modulate behavioural performance, connectivity analyses evidenced increased FC after post-training SD between navigation-related brain structures during relearning in the extended environment. These results suggest that memory traces were less efficiently consolidated after post-learning SD, eventually resulting in the use of compensatory brain resources to link previously stored spatial elements with the newly presented information.

Adolescent Alcohol Exposure Produces Protracted Cognitive-Behavioral Impairments in Adult Male and Female Rats.

Binge drinking is common in adolescence. Rodent studies modeling adolescent binge drinking find persistent effects on the brain’s physiology, including increased expression of neuroimmune genes, impaired neurogenesis, and changes in behavioral flexibility. This study used females and males to investigate the effects of adolescent intermittent ethanol (AIE) on a battery of behaviors assessing spatial navigation using a radial arm water maze, working memory using the Hebb-Williams maze, non-spatial long-term memory using novel object recognition, and dominance using a tube dominance test. Results indicate that AIE impairs adult acquisition in spatial navigational learning with deficits predominantly driven by females. Surprisingly, AIE slowed the transition from random to serial search strategies in both sexes, suggesting AIE impairs flexibility in problem-solving processing. In the Hebb-Williams maze working memory task, adult AIE rats exhibited deficits in problem solving, resulting in more errors across the 12 maze configurations, independent of sex. Conversely, AIE decreased dominance behaviors in female rats, and at 7 months post-alcohol, female AIE rats continued to exhibit deficits in novel object recognition. These results suggest that cognitive-behavioral alterations after adolescent binge drinking persist well into middle age, despite abstinence. Future studies should focus on intervening treatment strategies in both females and males.

An immune stress test for resilience to aging: Pneumococcal vaccine response.

The idea that the degree of response to physical stress in early life can be used to measure health in later life is a novel approach to better define resilience to aging. To investigate this, middle-age (15 months) mice were stressed by vaccination with a commercial pneumococcal vaccine (Prevnar 13), and 30 days later separated into a high antibody response group and a low antibody response group using Elisa to detect IgG serum antibody levels. After 4 months, mice were evaluated for physiological performance and learning ability. The high antibody response group was able to stay on a rotating rod longer than the low antibody response group and were more quickly able to find the escape hole in a spatial navigation learning task. This observation suggests Prevnar 13 antibody response in midlife could be a useful stress test to predict healthy aging.

Short-term plasticity following motor sequence learning revealed by diffusion magnetic resonance imaging.

Current noninvasive methods to detect structural plasticity in humans are mainly used to study long‐term changes. Diffusion magnetic resonance imaging (MRI) was recently proposed as a novel approach to reveal gray matter changes following spatial navigation learning and object‐location memory tasks. In the present work, we used diffusion MRI to investigate the short‐term neuroplasticity that accompanies motor sequence learning. Following a 45‐min training session in which participants learned to accurately play a short sequence on a piano keyboard, changes in diffusion properties were revealed mainly in motor system regions such as the premotor cortex and cerebellum. In a second learning session taking place immediately afterward, feedback was given on the timing of key pressing instead of accuracy, while participants continued to learn. This second session induced a different plasticity pattern, demonstrating the dynamic nature of learning‐induced plasticity, formerly thought to require months of training in order to be detectable. These results provide us with an important reminder that the brain is an extremely dynamic structure. Furthermore, diffusion MRI offers a novel measure to follow tissue plasticity particularly over short timescales, allowing new insights into the dynamics of structural brain plasticity.

Subchronic cerebrolysin treatment alleviates cognitive impairments and dendritic arborization alterations of granular neurons in the hippocampal dentate gyrus of rats with temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is one of the most frequent forms of focal epilepsy; patients with this condition, in addition to exhibiting complex seizures, also exhibit cognitive deficits. In the temporal lobe, the hippocampus, a structure relevant to learning and memory processes, is particularly affected by epilepsy. In animal models of TLE induced by pilocarpine, learning and memory deficiencies associated with changes in synaptic plasticity of the hippocampus have been reported. Cerebrolysin (CBL) is a biologically active mixture of low molecular weight peptides with neuroprotective and neurotrophic effects. The objective of the present study was to determine whether subchronic CBL treatment of rats in the chronic phase of TLE reduces the number and intensity of seizures, and whether CBL treatment can improve cognitive deficits (learning and spatial memory) and dendritic morphology in granular dentate neurons of the hippocampus. Temporal lobe epilepsy (lithium–pilocarpine model) was induced in male Wistar rats (weight, 250–300 g). Two epileptic groups were studied, in which CBL (538 mg/kg) or vehicle was administered intraperitoneally for 5 consecutive days per week for 3 weeks. Respective controls were also included in the study. At the end of treatment, the Barnes maze test (BMT) was used to assess spatial navigational learning and memory. The dendritic morphology of the dentate gyrus was also evaluated using the Golgi–Cox staining method. Results of this study did not support an antiepileptic effect of CBL. Epileptic animals treated with this agent exhibited secondarily generalized seizures similar in frequency and intensity to those of epileptic animals treated only with vehicle. However, when analyzing dendritic morphology of hippocampal granular neurons in these animals, CBL appeared to attenuate dendritic deterioration caused by epilepsy, which was associated with improved cognitive performance of the CBL-treated animals in the BMT compared with vehicle-treated epileptic rats. In conclusion, although CBL did not exert an anticonvulsant effect against secondarily generalized seizures, it can be proposed for use as an add-on therapy in epilepsy management to prevent neuronal alterations, and to improve memory and learning processes.

MazeSuite 3: A design, presentation and analysis platform for spatial navigation, cognitive neuroscience and neuroengineering applications

MazeSuite 3: A design, presentation and analysis platform for spatial navigation, cognitive neuroscience and neuroengineering applications

Effects of sex and HIV serostatus on spatial navigational learning and memory among cocaine users.

Spatial learning and memory are critically dependent on the integrity of hippocampal systems. Functional MRI and neuropathological studies show that hippocampal circuitry is prominently affected among HIV-seropositive individuals, but potential spatial learning and memory deficits have not been studied in detail in this population. We investigated the independent and interactive effects of sex and HIV serostatus on performance of a spatial learning and memory task in a sample of 181 individuals with a history of cocaine dependence. We found that men showed faster times to completion on immediate recall trials compared with women and that delayed recall was significantly poorer among HIV-infected compared with HIV-uninfected participants. Additionally, a sex × serostatus effect was found on the total number of completed learning trials. Specifically, HIV-infected men successfully completed more learning trials compared with HIV-infected women. Results are discussed in the context of recent reports of sex and HIV serostatus effects on episodic memory performance.

Effects of developmental exposure to bisphenol A and ethinyl estradiol on spatial navigational learning and memory in painted turtles (Chrysemys picta)

Developmental exposure of turtles and other reptiles to endocrine disrupting chemicals (EDCs), including bisphenol A (BPA) and ethinyl estradiol (EE2, estrogen present in birth control pills), can induce partial to full gonadal sex-reversal in males. No prior studies have considered whether in ovo exposure to EDCs disrupts normal brain sexual differentiation. Yet, rodent model studies indicate early exposure to these chemicals disturbs sexually selected behavioral traits, including spatial navigational learning and memory. Thus, we sought to determine whether developmental exposure of painted turtles (Chrysemys picta) to BPA and EE2 results in sex-dependent behavioral changes. At developmental stage 17, turtles incubated at 26⁰C (male-inducing temperature) were treated with 1) BPA High (100μg /mL), 2) BPA Low (0.01μg/mL), 3) EE2 (0.2μg/mL), or 4) vehicle or no vehicle control groups. Five months after hatching, turtles were tested with a spatial navigational test that included four food containers, only one of which was baited with food. Each turtle was randomly assigned one container that did not change over the trial period. Each individual was tested for 14 consecutive days. Results show developmental exposure to BPA High and EE2 improved spatial navigational learning and memory, as evidenced by increased number of times spent in the correct target zone and greater likelihood of solving the maze compared to control turtles. This study is the first to show that in addition to overriding temperature sex determination (TSD) of the male gonad, these EDCs may induce sex-dependent behavioral changes in turtles.

Keep Calm and Comp. Cog. On. Commentary: A crisis in comparative psychology: where have all the undergraduates gone?

Full Disclosure: We have recently authored an undergraduate textbook entitled Comparative Cognition (Olmstead and Kuhlmeier, 2015). Our motivation to write this book did not result from a perceived lack of undergraduate interest in the topic, but rather overenrolled courses for which we did not have a textbook. A key difference between our approach—largely shared by fellow commenters Brodbeck and Brodbeck (2015) and McMillan and Sturdy (2015)—and that of Abramson (2015), is our willingness to work under the title “comparative cognition.” We have been trained under various titles (e.g., biological anthropology, behavioral ecology, ethology, cognitive psychology, developmental psychology, and behavioral neuroscience) and have witnessed the continued emergence of comparative cognition as the logical intersection of these disciplines. Though, still considered a narrowly focused field by Abramson, we propose instead that comparative cognition has broadened (or perhaps always was broad, see Hulse et al., 1978; Wasserman, 1981), and encompasses, without conflict, Abramson's defining features of comparative psychology. Our point here goes beyond an argument about semantics, though it is important to be clear about our use of “comparative cognition,” Take, for example, a statement in the commentary by Bielert and Gallup (2015): “In particular, comparative cognition is quite similar to comparative psychology aside from restricting its research questions and measures to those specific to information processing (Shettleworth, 2010).” We do not see this “restriction” in scope in the modern practice of comparative cognition research. Instead, researchers consider the ways that general learning mechanisms may be constrained by early developing (perhaps innate) behavioral or perceptual biases, conceptual abilities, and/or non-conceptual processes. So yes, comparative cognition is open to the possibility of cognitive processes, but it actively tests for them. It also goes far beyond comparing behavioral responses of “species X” to that of humans (an anthropocentric approach that only a subset of researchers adopt, often with appropriate consideration of phylogenetics), and gone are the days of studying only a few, unrelated species. To use one metric: at the 2015 meeting of the Comparative Cognition Society, research with over 20 different species was presented. Shettleworth (2009), a pioneer and leader in the field, noted that comparative cognition research in the first decade of the twenty-first century was characterized by an increasing number of species examined and more synergy with related fields, such as behavioral ecology. A scholar of comparative cognition—and we think Shettleworth would agree with this based on her 2010 book—should be knowledgeable about sensory systems, behavioral tenets including general associative learning mechanisms, memory, and proposed cognitive mechanisms that are implicated in such areas as categorization, spatial navigation, number, timing, prosocial behavior, communication, and social learning, all the while considering an evolutionary, developmental, and neuroscientific framework. It's a tall order, but what an exciting field! In our experience, undergraduates agree. Like fellow commenters Furlong et al. (2015), we see the “missing” undergraduates every week—200 of them this term alone in a second year survey course: Introduction to Comparative Cognition. Many of these students will take our upper level laboratory courses that focus on specialized topics within the field of comparative cognition. The majority of these students specialize in other areas of psychology such as developmental, clinical, or cognitive psychology, a number are biology or life science majors, and a handful come from complementary disciplines such as computer science or philosophy. And yes, occasionally students seek out graduate study in laboratories specifically focused on comparative cognition. Regardless, we trust that they all pursue their chosen area of study with a greater appreciation and engagement in the basic, comparative science that informs so many fields of study.

Aprendizaje espacial y geometría. Los anfibios en la evolución de los sistemas cognitivos cerebrales

This article presents a comparative review of the works that have studied the spatial learning in vertebrates using geometry information and visual cues from the environment. We describe experiments conducted in our laboratory showing spatial navigation learning in amphibians and their dependence on a functional medial pallium (homologous area to the mammalian hippocampus). The results indicate that these animals use both the information provided by the geometry as visual cues, but when both types of reference are presented in conflict they prefer geometry to orient (as results found in amniotes). Broadly, these findings suggest that the ability to orient in space is a characteristic evolutionarily preserved and support the idea that the role of the hippocampus in spatial cognition precedes the evolution of fully terrestrial vertebrates.

Effects of developmental exposure to bisphenol A on spatial navigational learning and memory in rats: A CLARITY-BPA study

Bisphenol A (BPA) is a ubiquitous industrial chemical used in the production of a wide variety of items. Previous studies suggest BPA exposure may result in neuro-disruptive effects; however, data are inconsistent across animal and human studies. As part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA), we sought to determine whether female and male rats developmentally exposed to BPA demonstrated later spatial navigational learning and memory deficits. Pregnant NCTR Sprague–Dawley rats were orally dosed from gestational day 6 to parturition, and offspring were directly orally dosed until weaning (postnatal day 21). Treatment groups included a vehicle control, three BPA doses (2.5μg/kg body weight (bw)/day—[2.5], 25μg/kg bw/day—[25], and 2500μg/kg bw/day—[2500]) and a 0.5μg/kg/day ethinyl estradiol (EE)-reference estrogen dose. At adulthood, 1/sex/litter was tested for seven days in the Barnes maze. The 2500 BPA group sniffed more incorrect holes on day 7 than those in the control, 2.5 BPA, and EE groups. The 2500 BPA females were less likely than control females to locate the escape box in the allotted time (p value=0.04). Although 2.5 BPA females exhibited a prolonged latency, the effect did not reach significance (p value=0.06), whereas 2.5 BPA males showed improved latency compared to control males (p value=0.04), although the significance of this result is uncertain. No differences in serum testosterone concentration were detected in any male or female treatment groups. Current findings suggest developmental exposure of rats to BPA may disrupt aspects of spatial navigational learning and memory.

Increased anxiety-like behavior and selective learning impairments are concomitant to loss of hippocampal interneurons in the presymptomatic SOD1(G93A) ALS mouse model.

Amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease primarily characterized by motor neuron death, causes damages beyond motor-related areas. In particular, cognitive impairments and hippocampal damage have been reported in ALS patients. We investigated spatial navigation learning and hippocampal interneurons in a mutant SOD1(G93A) mouse (mSOD1) model of ALS. Behavioral tests were performed by using presymptomatic mSOD1 mice. General motor activity was comparable to that of wild-type mice in the open-field test, in which, however mSOD1 exhibited increased anxiety-like behavior. In the Barnes maze test, mSOD1 mice displayed a delay in learning, outperformed wild-type mice during the first probe trial, and exhibited impaired long-term memory. Stereological counts of parvalbumin-positive interneurons, which are crucial for hippocampal physiology and known to be altered in other central nervous system regions of mSOD1 mice, were also performed. At postnatal day (P) 56, the population of parvalbumin-positive interneurons in mSOD1 mice was already reduced in CA1 and in CA3, and at P90 the reduction extended to the dentate gyrus. Loss of parvalbumin-positive hippocampal interneurons occurred mostly during the presymptomatic stage. Western blot analysis showed that hippocampal parvalbumin expression levels were already reduced in mSOD1 mice at P56. The hippocampal alterations in mSOD1 mice could at least partly account for the increased anxiety-like behavior and deficits in spatial navigation learning. Our study provides evidence for cognitive alterations and damage to the γ-aminobutyric acid (GABA)ergic system in the hippocampus of murine ALS, thereby revealing selective deficits antecedent to the onset of motor symptoms.

The neural stem cell fate determinant TRIM32 regulates complex behavioral traits.

In mammals, new neurons are generated throughout the entire lifespan in two restricted areas of the brain, the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ)—olfactory bulb (OB) system. In both regions newborn neurons display unique properties that clearly distinguish them from mature neurons. Enhanced excitability and increased synaptic plasticity enables them to add specific properties to information processing by modulating the existing local circuitry of already established mature neurons. Hippocampal neurogenesis has been suggested to play a role in spatial-navigation learning, spatial memory, and spatial pattern separation. Cumulative evidences implicate that adult-born OB neurons contribute to learning processes and odor memory. We recently demonstrated that the cell fate determinant TRIM32 is upregulated in differentiating neuroblasts of the SVZ-OB system in the adult mouse brain. The absence of TRIM32 leads to increased progenitor cell proliferation and less cell death. Both effects accumulate in an overproduction of adult-generated OB neurons. Here, we present novel data from behavioral studies showing that such an enhancement of OB neurogenesis not necessarily leads to increased olfactory performance but in contrast even results in impaired olfactory capabilities. In addition, we show at the cellular level that TRIM32 protein levels increase during differentiation of neural stem cells (NSCs). At the molecular level, several metabolic intermediates that are connected to glycolysis, glycine, or cysteine metabolism are deregulated in TRIM32 knockout mice brain tissue. These metabolomics pathways are directly or indirectly linked to anxiety or depression like behavior. In summary, our study provides comprehensive data on how the impairment of neurogenesis caused by the loss of the cell fate determinant TRIM32 causes a decrease of olfactory performance as well as a deregulation of metabolomic pathways that are linked to mood disorders.

Virtual water maze learning in human increases functional connectivity between posterior hippocampus and dorsal caudate.

Recent work has demonstrated that functional connectivity between remote brain regions can be modulated by task learning or the performance of an already well-learned task. Here, we investigated the extent to which initial learning and stable performance of a spatial navigation task modulates functional connectivity between subregions of hippocampus and striatum. Subjects actively navigated through a virtual water maze environment and used visual cues to learn the position of a fixed spatial location. Resting-state functional magnetic resonance imaging scans were collected before and after virtual water maze navigation in two scan sessions conducted 1 week apart, with a behavior-only training session in between. There was a large significant reduction in the time taken to intercept the target location during scan session 1 and a small significant reduction during the behavior-only training session. No further reduction was observed during scan session 2. This indicates that scan session 1 represented initial learning and scan session 2 represented stable performance. We observed an increase in functional connectivity between left posterior hippocampus and left dorsal caudate that was specific to scan session 1. Importantly, the magnitude of the increase in functional connectivity was correlated with offline gains in task performance. Our findings suggest cooperative interaction occurs between posterior hippocampus and dorsal caudate during awake rest following the initial phase of spatial navigation learning. Furthermore, we speculate that the increase in functional connectivity observed during awake rest after initial learning might reflect consolidation-related processing.

Abstract T P68: Delayed Progesterone Treatment Improves Long-Term Recovery of Function Following Permanent Stroke in Older Rats

BACKGROUND: Less is known about the long-term sustained effects of PROG on recovery of function following stroke. Two objectives were evaluated, First, whether functional deficits caused by pMCAO persist and if repeated testing in itself reduce the extent of injury over long periods (8 weeks). Second, determine PROG's effects on a panel of behavioral tests performed several weeks post-pMCAO Methods: Male Sprague-Dawley rats (12 months old) underwent pMCAO by electrocoagulation or sham surgery. For the first study, repeated long term group with pMCAO began a battery of tests at repeated intervals (during the 3rd, 6th, and 8th weeks post-pMCAO), while long term with pMCAO group testing began during the 8 th week post-pMCAO. For the second study, beginning 3 h post-occlusion, rats were given IP injections of 8 mg/kg of PROG or vehicle, followed by SC injections at 8 h and then every 24 h for 9 days with tapering of final 2 treatments. All animals received: motor, sensory and cognitive tests; grip strength, rotarod, sensory neglect tests and spatial navigation learning and memory test; and computerized analysis of gait impairment. Results: Functional deficits caused by pMCAO showed modest improvement over time but were still persistent in older rats. Repeated testing (3 times over 8 weeks) did not reduce the effects of injury. Despite modest recovery in vehicle treated rats at eight weeks post-pMCAO, PROG treatment given 3 h after stroke and compared with vehicle group, showed improvement in grip strength by 59.28%, rotarod stability by 46.36 %, reduced sensory neglect by 28.69% and memory deficits by 38.56%. Automated gait assessment showed that PROG treatments significantly improved motor deficits in the affected limb on parameters like stride length, strand, paw print, and swing cycle. Conclusions: 1. The above tested behavioral assays over long-term assessment period, can be used for evaluating therapeutic agents in models of ischemic stroke in older rats. 2 . PROG was found to have sustained effect up to 8 weeks post stroke. PROG shows pre-clinical promise and should be examined for safety and efficacy in a clinical trial for ischemic stroke.

Abstract 3101: Post-ischemic Development and Resolution of Infarct and Behavioral Deficits Induced by Permanent Middle Cerebral Artery Occlusion in Middle-aged Rats: A Progesterone Dose-response Study

BACKGROUND: There is currently no safe, effective, widely applicable post-stroke treatment for ischemic stroke, especially when treatment is delayed beyond a few hours. Our group and others have shown progesterone (PROG) to be beneficial after brain injury in several injury models. A systematic pre-clinical PROG dose-response study in ischemic stroke models is lacking. Since focal pMCAO models better simulate the typical human stroke injury without reperfusion, our study sought to determine PROG's dose-response effects on behavioral performance after pMCAO. We used a clinically relevant, middle-aged rat model and long-term sensory, motor, and cognitive outcome measures. METHODS: Male Sprague-Dawley rats (12 months old) underwent pMCAO by electrocoagulation or sham operation. At 1h post-pMCAO, the animals were given an intraperitoneal injection of one of three doses of PROG (8, 16, or 32 mg/kg), followed by subcutaneous injections 6h post-injury and then once every 24h for the next 7 days. The dose was tapered over the final 2 treatments. Behavioral recovery was evaluated at repeated intervals for locomotor activity, grip strength, rotarod performance, sensory neglect, gait impairment and spatial navigation learning and memory. Rats were killed at 22 days post-stroke and brains perfused for evaluation of infarct volume. RESULTS: Repeated measures ANOVA showed significant group ( F (4,88) = 17.15, p <0.001) effects in grip strength, significant group ( F (4,41) = 3.5, p < 0.05) and time ( F (4,164) = 2.6, p < 0.05) effects on rotarod, significant group ( F (4,41) = 2.94, p < 0.05) effects on latency to remove sticky paper from the affected contralateral forepaw, and significant group ( F (4,41) = 14.63, p < 0.0001) effects on total distance traveled. The best recovery in grip strength, rotarod and sensory neglect was seen in the 8mg/kg PROG group. In spatial learning memory, percent time spent in the platform quadrant of the MWM showed that progesterone improved performance ( F (4, 40) =2.7, p <0.05). Automated, computer-assisted, gait assessment showed that PROG significantly improved gait deficits in the affected limb. Significant decreases in stride length, print area and swing speed were observed. Both 8mg/kg ansd 16mg/kg of PROG treatment produced significant attenuation in infarct volume compared to the vehicle-alone group ( F (3, 19) = 4.38, p < 0.05). CONCLUSION: All doses of PROG improved functional deficits in a clinically relevant model of stroke. The 8mg/kg dose was optimal in improving motor, sensory and memory function. PROG shows pre-clinical promise as a potential therapeutic agent and should be examined for safety and efficacy in a clinical trial for ischemic stroke.

Estradiol alters Fos-immunoreactivity in the hippocampus and dorsal striatum during place and response learning in middle-aged but not young adult female rats.

Evidence from lesion and inactivation studies suggests that the hippocampus (HPC) and dorsal striatum compete for control over navigation behavior, and there is some evidence in males that the structure with greater relative activation controls behavior. Estradiol has been shown to enhance HPC-dependent place learning and impair dorsal striatum-dependent response learning in female rats, possibly by increasing hippocampal activation and/or decreasing striatal activation. We used Fos-immunoreactivity (Fos-IR) to examine the activation of several subregions of the HPC and striatum in ovariectomized female rats with or without estradiol replacement 30 min after place or response learning. In 4-month-old rats, neither task nor estradiol increased Fos-IR above explore control levels in any subregion analyzed, even though estradiol impaired response learning. In 12-month-old rats, estradiol increased Fos-IR in the dentate gyrus, dorsal medial striatum, and dorsal lateral striatum in place task learners, while the absence of estradiol increased Fos-IR in these regions in response task learners. However, learning rate was not affected by estradiol in either task. We also included a group of long-term ovariectomized 12-month-old rats that displayed impaired place learning and altered Fos-IR in CA1 of the HPC. These results suggest that task-specific effects of estradiol on hippocampal and striatal activation emerge across age but that relative hippocampal and striatal activation are not related to learning rate during spatial navigation learning.

Spatial Navigation and APOE in Amnestic Mild Cognitive Impairment

Background: The effect of APOE Ε4 allele (Ε4) on spatial navigation in amnestic mild cognitive impairment (aMCI) is unknown. Objective: Our purpose was to examine the characteristics of spatial navigation impairment in Ε4-positive (Ε4+) and Ε4-negative (Ε4–) aMCI subgroups. Methods: Blood samples were collected to determine the APOE genotype. A total of 34 aMCI patients were stratified into aMCI-Ε4– (n = 23) and aMCI-Ε4+ (n = 11) groups. Control (n = 28) and mild Alzheimer’s disease (AD; n = 16) groups were also used. We used a human analogue of the Morris water maze (enclosed arena 2.9 m in diameter) to examine body-centered (egocentric) and world-centered (allocentric) spatial navigation. Results: The aMCI-Ε4+ group performed poorer on spatial navigation than the aMCI-Ε4– group in both egocentric and allocentric tasks even though these 2 groups did not differ in global cognitive functioning or neuropsychological tests. The aMCI-Ε4+ and mild AD groups performed similarly on all Morris Water Maze tasks and were outperformed by the aMCI-Ε4– group, which also resembled the control group in performance on the egocentric tasks. The aMCI groups showed poor spatial navigation learning regardless of their Ε4 positivity. Conclusion: We found more profound deficits in spatial navigation in aMCI-Ε4+ relative to aMCI-Ε4– patients. The aMCI-Ε4+ group resembled the mild AD group in spatial navigation performance. Although the Ε4 genotype was indicative of spatial navigation performance, it was not indicative of the aMCI patients’ ability to learn the tasks. Spatial navigation testing represents a promising area with respect to identifying individuals at higher risk for AD among the heterogeneous MCI population.