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Object-location memory (OLM) is a type of declarative memory for spatial information and consists of the individual's ability to establish accurate associations between objects and their spatial locations. Long-COVID describes the long-term effects of the COVID-19 disease. Long-COVID patients show medial temporal lobe dysfunction and neuropsychological alterations affecting memory. This study aimed to assess OLM in a group of Long-COVID patients, n=66, and a Control group of healthy individuals with similar age and sex composition, n=21, using an immersive virtual reality (iVR)-based OLM task. We also explored associations between the performance in the iVR-based OLM task and general cognitive function (MoCA), and both verbal (VSTM) and visuospatial (SSTM) span. The Long-COVID group showed fewer correct responses, made more task attempts, and invested more time in the iVR-based OLM task than the Control group. Delayed memory was more severely altered than immediate memory in Long-COVID participants. Better MoCA scores of the Long-COVID group were strongly associated with shorter times to complete the immediate recall of the iVR-based OLM task. Besides, the months elapsed since the COVID-19 infection were slightly associated with fewer correct responses in the immediate and 24-hour recalls. These results corroborate previous findings of memory alterations in the Long-COVID syndrome using an iVR-based OLM task, adding new evidence on spatial memory and long-term memory in this population. Implementing spatial iVR tasks to clinical research may improve our understanding of neuropsychological disorders. • Long-COVID showed alteration of object-location memory in a virtual reality task. • Delayed memory was more altered than immediate memory in Long-COVID. • Long-COVID cognition was associated with completion-time of immediate recall. [ABSTRACT FROM AUTHOR]

It is to investigate the effects of β-asarone on learning and memory, hippocampal morphology, synaptophysin (SYP) and postsynaptic density 95(PSD95) protein expression, N-methyl-D-aspartic acid receptor 2B (NR2B)- Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) - Extracellular signal-regulated kinase (ERK) / Cyclic-AMP response element binding protein (CREB) signal in hippocampus of rats with exhaustive exercise-induced fatigue. Fifty Sprague-Dawley male rats were randomly divided into five groups: normal group, exercise group, exercise and β-asarone (2.5, 10, 40 mg/kg)–treated groups. The learning and memory in rats were tested by Morris water maze experiment. We measured the hippocampal morphology by Nissl staining. The levels of SYP, PSD95, NR2B, CaMKII, ERK1/2, CREB, p-NR2B, p-CaMKII, p-ERK1/2 and p-CREB expression were measured by western blot analysis. The results demonstrated that β-asarone (10, 40 mg/kg) treatment significantly decreased the latency to find the platform, increased the time spent in the target quadrant and the number of crossing the platform of rats with exhaustive exercise-induced fatigue. β-asarone (10, 40 mg/kg) treatment increased the cell density in the hippocampus CA1 region, significantly up-regulated NR2B-CaMKII-ERK/CREB signal and improved the protein expression levels of SYP and PSD95 in hippocampus of rats with exhaustive exercise-induced fatigue. It suggests that β-asarone could improve learning and memory of rats with exhaustive exercise-induced fatigue. The mechanism might be related to β-asarone protecting the morphology of hippocampus, increasing the protein expression levels of SYP and PSD95 and up-regulating NR2B-CaMKII-ERK/CREB signal in hippocampus of rats with exhaustive exercise-induced fatigue. [ABSTRACT FROM AUTHOR]

The effects of intra-hippocampal manipulation of glycine receptors on the reconsolidation of recent and late long-term spatial memory were evaluated and assessed in the Morris water maze. The results obtained from the intra-hippocampal infusion of glycine and taurine demonstrated that taurine at a 100 nmol/side dose impaired the reconsolidation of recent and late long-term spatial memory. In comparison, at a dose of 10 nmol/side, it only affected the reconsolidation of late long-term spatial memory, reinforcing that there are differences between molecular mechanisms underlying recent and late long-term memory reconsolidation. On the other hand, glycine impaired the reconsolidation of early and late spatial memory when infused at a dose of 10 nmol/side, but not at a dose of 100 nmol/side, unless it is co-infused with an allosteric site antagonist of the NMDA receptor. Altogether these results show that glycine acting in situ in the hippocampal CA1 region exerts a pharmacological effect on U-curve, which can be explained by its concomitant action on its ionotropic receptor GlyR and on its NMDA receptor co-agonist site. [ABSTRACT FROM AUTHOR]

This study explores the under-researched domain of long-term stimulant treatment in children and adolescents diagnosed with attention deficit hyperactivity disorder (ADHD). The necessity for extended treatment duration, often accompanied by safety concerns and side effects leading to treatment discontinuation, underscores the significance of this investigation. Concurrently, comparative studies have revealed adverse impacts on vulnerable regions within the hippocampal formation, accompanied by behavioral perturbations. We employed computerized tests and virtual reality to assess spatial memory, pattern separation, and object recognition memory in a cohort of children diagnosed with ADHD receiving stimulant treatment. We compared their performance to a group of neurotypical peers. Our findings indicate that the ADHD group exhibited a lower performance in spatial memory, pattern separation, and object recognition memory than ND group. Intriguingly, a positive relationship emerged between the duration of stimulant treatment and performance in these variables. Notably, this improvement was not immediate to MPH treatment but becomes significant after 24 months of treatment. In contrast to previous comparative investigations, our study did not reveal a detrimental impact on spatial navigation, object recognition memory, or pattern separation, despite the known interplay of these cognitive processes with the hippocampal formation. These results shed new light on the nuanced effects of stimulant treatment in ADHD, underscoring the need for a more comprehensive understanding of long-term treatment outcomes. [ABSTRACT FROM AUTHOR]

The present study aimed to assess the potential effect of vitamin B 12 (Vit B 12) on cognition impairment caused by nicotine (Nic) cessation in adolescent male rats. Adolescent male rats were categorized into two main groups as vehicle (normal saline, intraperitoneally), and Nic group in which received Nic (2 mg/kg) from 21 to 42 days of ages and then the Nic group were divided into three groups as withdrawal (the animals returned to regular diet without treatment), second and third groups received bupropion (20 mg/kg), and Vit B 12 at three different doses including 0.5,1, and 1.5 mg/kg by oral gavage as treatments to attenuate Nic withdrawal symptoms. The last group including normal animals received the highest doses of Vit B 12 just in the Nic abstinence period to compare the effect of that with vehicle. In MWM, Vit B 12 and bupropion increased the time spent in the target quadrant that is strongly associated with spatial memory as well as the more time spent with the NORT. Vit B 12 and bupropion modulated both oxidant/antioxidant and inflammatory/anti-inflammatory balance, alongside inhibitory effect on AChE, and GFAP. However, BDNF and amyloid-B showed insignificant difference as compared to Vit B 12 and bupropion. Considering the present results and similar related studies, Vit B 12 can be introduced as a strong anti-oxidant, and anti-inflammatory agent by which probably improved memory impairment caused by Nic addiction accompanied by withdrawal. Further, other mechanisms including activity reduction of AChE, and GFAP should be considered; however, it needs further investigation and larger-scale evidences. [Display omitted] [ABSTRACT FROM AUTHOR]

Chronic unpredictable mild stress (CUMS) method has been introduced as a rodent model of depression. On the other hand, olanzapine, as an antipsychotic, can induce antidepressant and antipsychotic effects. Also, olanzapine may improve cognitive functions. Both CUMS and olanzapine can also affect the expression level of brain-derived neurotrophic factor (BDNF) and synaptophysin, the molecular factors involved in synaptic function, and learning and memory. In this study, we investigated the effect of olanzapine on locomotor activity (using open field test), pain threshold (using hot plate), depressive-like behavior (using forced swim test), spatial learning and memory (using Morris water maze), and BDNF and synaptophysin hippocampal expression (using real-time PCR) in both male and female CUMS rats. CUMS was performed for three consecutive weeks. Olanzapine was also injected intraperitoneally at the dose of 5 mg/kg. Our data showed that olanzapine can reverse the effects of CUMS on behavioral functions and BDNF and synaptophysin expression levels in the hippocampus of both males and females. It was also shown that olanzapine effects on spatial memory, pain perception, and BDNF and synaptophysin level were stronger in females than males. In conclusion, we suggested that the therapeutic effects of olanzapine in CUMS rats may be closely related to the function of BDNF and synaptophysin. Also, the therapeutic effects of olanzapine may be stronger in females. Therefore, and for the first time, we showed that there may be a sex difference in the effects of olanzapine on behavioral and molecular changes following CUMS. [ABSTRACT FROM AUTHOR]

As the elderly population grows, the prevalence of dementia is also rapidly increasing worldwide. Metformin, an antidiabetic drug, has been shown to have ameliorative effects on impaired cognitive functions in experimental models. However, studies have generally used young animals. Additionally, although it has a major role in Alzheimer's disease (AD) and memory, literature information about the effects of metformin on the cholinergic system is limited. In this study, we investigated the effects of metformin on memory in a model of scopolamine-induced memory impairment in aged rats. We also examined the effects of metformin on the cholinergic system, which is very important in cognitive functions. Metformin was administered orally to male Wistar rats (20–22 months old) at 100 mg/kg/day for three weeks. Morris water maze (MWM) tests were performed to assess spatial memory. Before the probe test of the MWM test, scopolamine was injected intraperitoneally at a dose of 1 mg/kg. After testing, animals were sacrificed, whole brains were removed, and hippocampus samples were separated for biochemical analysis. Impaired memory associated with scopolamine administration was reversed by metformin. In addition, metformin administration ameliorated scopolamine-induced changes in acetylcholine (ACh) levels, acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and choline acetyltransferase (ChAT) activity. Our results show that metformin may have protective effects in a scopolamine-induced memory impairment model in aged animals by improving cholinergic function. Metformin shows promise in preventing dementia with its dual cholinesterase inhibition and ChAT activation effect. • Metformin may protect the memory in aged rats by regulating the cholinergic system. • Metformin shows dual cholinesterase inhibition and ChAT activation effects. • Metformin does not affect memory or cholinergic biomarkers in normal-aged rats. • Metformin may be effective in preventing the development of dementia. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a severe neurodegenerative disorder and the most common form of dementia in elderly individuals, characterized by memory deficits, cognitive decline, and neuropathology. The identification of preclinical markers for AD remains elusive. We employed an ultrasound-evoked spatial memory assay to investigate path integration (PI) in wild type C57BL/6 J and 5xFAD mice. We observed significant recruitment of the mammillary bodies (MB) and subiculum (Sub) – core regions of the Papez circuit during PI, as indicated by increased expression of the immediate early gene c-Fos in C57BL/6 J mice. In 5xFAD mice, amyloid-beta (Aβ) vulnerability in the MB and Sub was evident at 3-months of age, preceding widespread pathology at 5-months of age. In parallel, we detected significant behavioral deficits in PI in the 5XFAD mice at 5- but not 3-months of age. Sex based analysis revealed a more profound deficit in males compared to females at 5-months of age. Our data suggest PI may be as an early indicator of AD, potentially associated with dysfunction within the Papez circuit. • Recruitment of the Papez circuit is evident during path integration. • Transgenic 5xFAD mice display AD pathology in the Papez circuit at 3 months. • Path integration deficits are present in transgenic 5xFAD mice at 5 months. • Male 5xFAD mice display a more profound impairment in path integration. [ABSTRACT FROM AUTHOR]

In order to successfully navigate through space, animals must rely on multiple cognitive processes, including orientation in space, memory of object locations, and navigational decisions based on that information. Although highly-controlled behavioral tasks are valuable for isolating and targeting specific processes, they risk producing a narrow understanding of complex behavior in natural contexts. The Traveling Salesperson Problem (TSP) is an optimization problem that can be used to study naturalistic foraging behaviors, in which subjects select routes between multiple baited targets. Foraging is a spontaneous, yet complex, behavior, involving decision-making, attention, course planning, and memory. Previous research found that hippocampal lesions in rats impaired TSP task performance, particularly on measures of spatial memory. Although traditional laboratory tests have shown the medial entorhinal cortex (MEC) to play an important role in spatial memory, if and how the MEC is involved in finding efficient solutions to the TSP remains unknown. In the current study, rats were trained on the TSP, learning to retrieve bait from targets in a variety of spatial configurations. After recovering from either an MEC lesion or control sham surgery, the rats were tested on eight new configurations. Our results showed that, similar to rats with hippocampal lesions, MEC-lesioned rats were impaired on measures of spatial memory, but not spatial decision-making, with greatest impairments on configurations requiring a global navigational strategy for selecting the optimal route. These findings suggest that the MEC is important for effective spatial navigation, especially when global cue processing is required. • Lesions of the medial entorhinal cortex impaired performance on multiple TSP measures. • Spatial memory was more strongly affected by MEC lesions than route choice. • Impairment was greater on configurations requiring global rather than local strategy. • MEC lesions increased circling behavior, possibly as a compensatory response. [ABSTRACT FROM AUTHOR]

This study investigates the impact of orlistat on oxidative stress, spatial memory, recognition memory, and hippocampal tissue in obese rats. The study groups were divided into control, high fat diet-induced obese (HFDIO), HFDIO+orlistat (HFDIO+ORL) groups, each consisting of 8 animals. While control fed with standart diet, HFDIO and HFDIO+ORL fed with high-fat diets for 8 weeks to induce obesity. Then, ORL treated 10 mg/kg for 7 weeks, while control and HFDIO get water. At 16th week, novel object recognition (NOR) and Morris water maze (MWM) tests were performed. TNF-alpha, IL-1beta levels in hippocampal tissue, and total/native thiol/disulphide levels in serum were measured. TNF-alpha level of HFDIO was higher than control, while lower in HFDIO+ORL compared to HFDIO as like IL-1beta level. On the contrary, serum total thiol level was lower in HFDIO than control and higher in HFDIO+ORL compared to the HFDIO, while disulphide level was opposite of the total thiol levels. While recognition index was higher in HFDIO+ORL, in MWM, latency of finding platform in HFDIO was higher than control and latency of HFDIO+ORL was very similar to control in 2–4 days. The HFDIO group demonstrated decrease in time spent in platform zone compared to control, whereas time spent of the HFDIO+ORL was higher than HFDIO. Our study demonstrates that orlistat administration exerts beneficial effects on oxidative stress, spatial memory, recognition memory, and hippocampal tissue in obese rats. It shows that orlistat may have potential therapeutic implications for obesity-related cognitive impairments and hippocampal dysfunction. • Thiol/disulphide homeostasis was effected positively by ORL treatment. • ORL reduced the hippocampal inflammation. • ORL has improved the recognition memory and spatial memory in obese rats. • ORL treatment may have beneficial effects on recognition and spatial memory. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia nigra pars compacta (SNpc), which leads to motor and non-motor symptoms (NMS). NMS can appear many years before the classical motor symptoms and are associated with the neurodegeneration of several nuclei; in this work, we highlight the neurodegeneration of Locus coeruleus (LC) in PD. The aim was to investigate the effects of depleting SNpc and LC catecholaminergic neurons on behavioral and neurobiological endpoints. Here we used 6-hydroxydopamine (6-OHDA) in order to induced neurotoxic damage in three independent experimental groups: SNpc lesion group, which 6-OHDA was injected into CPu (CPu-6-OHDA), LC lesion group, which 6-OHDA was injected directly on LC to selectively caused a damage on this nucleus (LC-6-OHDA), and the combined SNpc and LC lesion group (CL-6-OHDA). Next, the behavioral studies were performed using the Morris water maze (MWM), open field (OF), and elevated plus maze (EPM). After stereotaxic surgeries, the animals showed a loss of 67% and 77% of Tyrosine hydroxylase (TH) reactive neurons in the SNpc and LC, respectively. The behavioral analysis showed the anxiety-like behavior in CL-6-OHDA group in the EPM test; in the MWM test, the combined lesions (CL-6-OHDA) showed an impairment in memory acquisition and spatial memory; and no changes were observed in locomotor activity in all the tests. Furthermore, our investigation demonstrating the effects of depleting SN and LC catecholaminergic neurons on behavioral and neurobiological parameters. All these data together lead us to believe that a bilateral PD model including a LC bilateral degeneration is potentially a more accurate model to evaluate the NMS in the pathological development of the disease in rodents. [Display omitted] • Bilateral 6-OHDA injections into the CPu (24 μg/μL; 0.5 μL) and/or LC (24 μg/μL; 0.5 μL) do not change locomotor activity. • The absence of LC with neurodegeneration of the SNpc leads to an anxiety-like behavior. • The absence of LC with neurodegeneration of the SNpc impaired memory acquisition and retention. [ABSTRACT FROM AUTHOR]

The storage of long-term memories is a dynamic process. Reminder cues can destabilize previously consolidated memories, rendering them labile and modifiable. However, memories that are strongly encoded or relatively remote at the time of reactivation can resist destabilization only being rendered labile under conditions that favour memory updating. Using the object location recognition task, here we show in male C57BL/6 mice that novelty-induced destabilization of strongly-encoded memories requires muscarinic acetylcholine receptor (mAChR) activation. Furthermore, we use the objects-in-updated locations task to show that updating of object location memories is mAChR-dependent. Thus, mAChR stimulation appears to be critical for spatial memory destabilization and related memory updating. Enhancing our understanding of the role of ACh in memory updating should inform future research into the underlying causes of behavioural disorders that are characterized by persistent maladaptive memories, such as age-related cognitive inflexibility and post-traumatic stress disorder. • Strongly encoded object location memories resist destabilization. • Destabilization of strongly encoded spatial memories requires acetylcholine. • Spatial memory updating is reliant on acetylcholine. • Preventing memory updating leaves the original memory intact. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is associated with traumatic stress experiences. This condition can be accompanied by learning and cognitive deficits. Studies have demonstrated that ketamine can rapidly and significantly alleviate symptoms in patients with chronic PTSD. Nonetheless, the effects of ketamine on neurocognitive impairment and its mechanism of action in PTSD remain unclear. In this study, different concentrations of ketamine (5, 10, 15, and 20 mg/kg, i.p.) were evaluated in rat models of single prolonged stress and electrophonic shock (SPS&S). Expression levels of brain-derived neurotrophic factor (BDNF) and post-synaptic density-95 (PSD-95) in the hippocampus (HIP) and amygdala (AMG) were determined by Western blot analysis and immunohistochemistry. The data showed that rats subjected to SPS&S exhibited significant PTSD-like cognitive impairment. The effect of ketamine on SPS&S-induced neurocognitive function showed a U-shaped dose effect in rats. A single administration of ketamine at a dosage of 10–15 mg/kg resulted in significant changes in behavioral outcomes. These manifestations of improvement in cognitive function and molecular changes were reversed at high doses (15–20 mg/kg). Overall, ketamine reversed SPS&S-induced fear and spatial memory impairment and the down-regulation of BDNF and BDNF-related PSD-95 signaling in the HIP and AMG. A dose equal to 15 mg/kg rapidly reversed the behavioral and molecular changes and promoted the amelioration of cognitive dysfunction. The enhanced association of BDNF signaling with PSD-95 effects could be involved in the therapeutic efficiency of ketamine for PTSD. • Post-traumatic stress disorder rats had learning and cognitive impairments. • Ketamine provides rapid and significant relief in patients with chronic PTSD. • Brain-derived neurotrophic factor and postsynaptic dense region protein 95 may be involved in the treatment of PTSD with ketamine. [ABSTRACT FROM AUTHOR]

Sex differences in declarative memory are described in humans, revealing a female or a male advantage depending on the task. Specifically, spatial memory (i.e., spatial navigation) is typically most efficient in men. This sexual dimorphism has been replicated in male rats but not clearly in mice. In this study, sex differences in spatial memory were assessed in thirty-six C57BL/6 J mice (Janvier Labs; i.e., C57BL/6JRj mice), a widely used mouse substrain. Both male and female mice (12 weeks-old) were subjected to standard behavioral paradigms: the elevated plus maze, the open field test, the novel object and place tests, the forced swimming test, and the water maze test for spatial navigation. Across assessment, no sex differences were found in measures of locomotor activity, emotional and behavioral responses, and object and place recognition memories. In the water maze, male mice were faster in learning the platform location in the reference memory training and used more spatial strategies during the first training days. However, both sexes reached a similar asymptotic performance and performed similarly in the probe trial for long-term memory consolidation. No sex differences were found in the cued training, platform inversion sessions, or spatial working memory sessions. Hippocampal expression of the brain-derived neurotrophic factor was similar in both sexes, either in basal conditions or after performing the behavioral training battery. Importantly, female mice were not more variable than males in any measure analyzed. This outcome encourages the investigation of sex differences in animal models and the usefulness of including female mice in behavioral research. • Declarative memory shows sex differences in humans, favoring men in spatial navigation. • This study assessed sex differences in spatial memory in C57BL/6 J mice with no locomotor differences found. • Male mice learned faster and used more strategies, but both sexes performed similarly in long-term memory. [ABSTRACT FROM AUTHOR]

Thyroid hormones are critical for healthy brain functions at every stage of life. Hypothyroidism can cause severe cognitive dysfunction in patients who do not receive adequate treatment. Although thyroid hormone replacement alleviates cognitive decline in hypothyroid patients, there are studies showing that there is no complete recovery. The aim of this study was to investigate the effects of high-intensity interval training (HIIT) in hypothyroid rats on spatial and recognition memory, neuroinflammation, amyloid-beta load and compare these effects with T3 replacement. Hypothyroidism was induced and maintained by administration of 6-n-propyl-2-thiouracil (PTU) with their drinking water to 6-weeks-old male Sprague–Dawley rats for 7 weeks. The animals exercised in the treadmill according to the HIIT protocol for four weeks. T3 was injected intraperitoneally daily during the last two weeks of the study. All animals performed in the elevated plus maze test, Morris water maze test, novel object recognition test, and rotarod motor performance test in the last week of the study and then the animals were sacrificed. Amyloid beta (1−42) and TNFα levels were measured in the prefrontal cortex and hippocampus by ELISA. Anxiety-like behaviors did not significantly differ between groups. T3 replacement with or without HIIT increased motor performance in PTU-treated rats. HIIT and/or T3 replacement increased the exercise performance. HIIT and/or T3 replacement alleviated spatial and recognition memory impairments and normalized TNFα and amyloid-beta levels in the hippocampus in hypothyroid rats. In summary, regular physical exercise may have potential benefits in preserving cognitive functions in hypothyroid patients. • High-intensity interval training improved learning and memory in PTU-treated rats. • Aβ(1-42) and TNFα levels decreased in the hippocampus with HIIT and/or T3 replacement. • Exercise performance increased with HIIT and/or T3 replacement in PTU-treated rats. • T3 replacement with or without HIIT increased motor performance in PTU-treated rats. • There was no significant difference between groups in terms of anxiety-like behaviors. [ABSTRACT FROM AUTHOR]

The Barnes maze is a task used to assess spatial learning and memory in rodents. It requires animals to learn the position of a hole that can be used as an escape from a bright and open arena. The often-used parameters of latency and path length to measure learning and memory do not reflect the different navigation strategies chosen by the animals. Here, we propose an 11-point scoring scheme to classify the search strategies developed by the animals during the initial training as well as after the change of the escape target to a new position. Strategy scores add an important dimension to time and path length to assess the behavior in this popular maze. [ABSTRACT FROM AUTHOR]

Impairment of learning and memory caused by sleep deprivation is a common symptom that significantly affects quality of life. Repetitive transcranial magnetic stimulation (rTMS) is a promising approach to exert a positive effect on cognitive impairment. However, there is less known about the mechanism of rTMS for learning and memory induced by chronic REM sleep deprivation (CRSD). This study was to detect the effects of rTMS on spatial learning and memory deficits by CRSD and explore possible mechanism. Sixty male Sprague-Dawley rats were randomly divided into four groups: wide platform (Control), sleep deprivation (SD), sleep deprivation + rTMS (TMS), and sleep deprivation + sham rTMS (Sham-TMS). Morris water maze (MWM) and open field test (OFT) assessed spatial learning and memory and anxiety of rats with pre/post-intervention. Golgi staining and transmission electron microscope (TEM) were used to observe structural variations of synapses in the hippocampus. The alteration in gene expression of different groups was analyzed by RNA-sequencing (RNA-Seq), and the key gene was screened and identified by quantitative polymerase chain reaction (qPCR) and subsequently verified with western blotting and immunofluorescence. The behavioral test showed spatial learning and memory decreased and anxiety increased in the SD group compared to the Control and TMS groups. Moreover, rTMS improved spine density, ultrastructural damage, and quantities of synapses. In accordance with RNA-Seq, 56 differentially expressed genes (DEGs) were identified by comparing alternations in four groups and concentrated on kynurenine 3-monooxygenase (KMO). The expression of KMO increased significantly in rats of the SD group compared to the Control and TMS groups identified by qPCR, western blotting, and immunofluorescence. 1 Hz rTMS alleviated spatial learning and memory deficits induced by CRSD probably via down-regulating the expression of KMO and improving the structure and quantity of synapses in the hippocampus of rats. [Display omitted] • Behavioral tests, pathological methods, RNA-sequencing analysis (RNA-Seq), and some molecular biology methods such as quantitative polymerase chain reaction (qPCR), western blotting and immunofluorescence were employed to explore the underlying mechanisms in spatial learning and memory of rats subjected to chronic REM sleep deprivation (CRSD) and treated with repetitive transcranial magnetic stimulation (rTMS). • Based on RNA-Seq, the potential gene involved in the modulation of spatial learning and memory with CRSD intervened by low-frequency rTMS was investigated. • 1 Hz rTMS alleviated spatial learning and memory deficits induced by CRSD probably via down-regulating the expression of kynurenine 3-monooxygenase (KMO). [ABSTRACT FROM AUTHOR]

General anesthesia is considered a risk factor for postoperative cognitive dysfunction. However, it is unclear what the neuronal and cognitive consequences of general anesthesia are and whether they can be treated. One possible pathomechanism is hippocampal neurogenesis. We investigated how the anesthetic isoflurane affects adult hippocampal neurogenesis and associated cognitive functions and whether the neurogenic stimulus of physical activity reverses isoflurane-induced changes. We exposed young adult mice to isoflurane (ISO) - half had access to a running wheel (ISO-RW). Both groups were compared with a control condition (CTR; CTR-RW). Cell proliferation and survival in the dentate gyrus of the hippocampus were quantified histologically 48 h and 3 weeks after anesthesia by bromodeoxyuridine incorporation. Cell phenotype was determined by expression of neuronal markers, and the extent of continuous endogenous neuronal proliferation was estimated from the number of doublecortin-positive cells. The Morris water maze was used to test hippocampus-dependent functions. We found that isoflurane decreased proliferation of neuronal progenitor cells, whereas survival of mature neurons remained intact. Consistent with intact neuronal survival, spatial memory associated with neurogenesis also proved intact in the Morris water maze despite isoflurane exposure. Physical activity attenuated the observed neuronal changes by preventing the decrease in newborn neuronal progenitor cells and the decline in continuous endogenous neuronal proliferation in isoflurane-treated animals. In conclusion, isoflurane selectively impairs neuronal proliferation but not survival or neurogenesis-linked cognition in adult mice. The observed adverse effects can be attenuated by physical activity, a cost-effective means of preventing the neurogenic consequences of general anesthesia. [Display omitted] • Isoflurane differentially affects the stages of newborn hippocampal neurons. • Isoflurane exposure spares spatial memory associated with hippocampal neurogenesis. • Physical activity prevents isoflurane-induced neurostructural changes. [ABSTRACT FROM AUTHOR]

In dementia, synaptic dysfunction appears before neuronal loss. Stem cell therapy could potentially provide a promising strategy for the treatment of dementia models. The carbamylated erythropoietin fusion protein (CEPO-Fc) has shown synaptotrophic effects. This study aimed to determine the efficiency of the combined use of hair follicle stem cells (HFSC) and CEPO-Fc in the basal synaptic transmission (BST) and long-term plasticity (LTP) of chronic cerebral hypoperfusion (CCH) rats. We divided 64 adult rats into control, sham, CCH+vehicle, CCH+CEPO, CCH+HFSC, and CCH+HFSC+CEPO groups. The CEPO-Fc was injected three times/week for 30 days. HFSC transplantation was done on days 4, 14, and 21 after surgery. The Morris water maze test and passive avoidance were used to assess memory. BST and LTP were assessed by a field-potential recording of the CA1 region. The hippocampal mRNA expression of IGF-1, TGF-β1, β1-Catenine, NR2B, PSD-95, and GSk-3β was evaluated by quantitative RT-PCR. Following combination therapy, spatial memory retention, and BST showed significant improvement relative to HFSC and CEPO-Fc groups. These effects were also confirmed by recovered mRNA expression of β1-catenin, TGF-β1, and NR2B. GSK-3β expression was downregulated in all treatment groups. The upregulated PSD-95 was identified in HFSC and combination groups compared to the vehicle group. These findings indicate that the combined use of HFSC and CEPO-Fc may be more advantageous for treating memory disruption in the CCH model than CEPO-Fc or HFSC alone. This type of combination therapy may hopefully lead to a new approach to treatment for dementia. • Combination therapy of CEPO-Fc and HFSC improves spatial memory retention and synaptic transmission in CCH rats. • Memory deterioration is related to disruption in hippocampal β1-catenin, TGF-β1, NR2B, GSK-3β, and PSD-95 expression. • Combination therapy of CEPO-Fc and HFSC recovered hippocampal β1-catenin, TGF-β1, NR2B, GSK-3β, and PSD-95 expression. • Combination therapy of CEPO-Fc and HFSC may have more benefits than CEPO-Fc or HFSC alone in the CCH model. [ABSTRACT FROM AUTHOR]

Highlights • Chronic Hypobaric Hypoxia for 7 days causes deficits in spatial working memory. • HH resulted in the synaptic dysregulation of Kalirin 7 in the dorsal hippocampus of rat. • HH induces significant decrease in the Kalirin 7 expression in the CA1, CA3 & DG region of the hippocampus. Abstract Hypobaric hypoxia (HH) is an environmental stress encountered at high altitude. It has been shown that HH resulted in spine atrophy and working memory deficits. Kalirin-7, a postsynaptic density protein, plays an important and key role in regulating spine dynamics and its plasticity. Spine atrophy is implicated in HH induced memory deficits but role of Kalirin-7 in this phenomenon is not studied. Present study is therefore designed to investigate the effect of chronic HH exposure on Kalirin-7 expression in hippocampus and its role in spatial working memory deficits. Adult rats (n = 12, 3 months old) were exposed to a simulated altitude of 25,000 feet for 7 days. Following HH exposure, spatial working memory was assessed with Radial arm maze and T maze. Hippocampal expression of Kalrin-7 was estimated at mRNA and protein levels. Results of behavioural experiments showed that HH causes significant decrease in the spatial working memory. There was a significant reduction in the protein expression of Kalirin-7 in the hippocampus of hypoxia exposed rats (43.89 ± 7.43) as compared to the control (69.54 ± 10.99). The mRNA expression of Kalrin-7 also exhibits significant reduction (0.59 ± 0.05) in the exposed group as compared to the control (0.98 ± 0.07). Immunohistochemistry showed that Kalirin-7 is decreased significantly in CA1, CA3 and DG regions of the hippocampus. Moreover, memory deficits are significantly correlated with decreased immunoreactivity of the hippocampal Kalirin-7. In conclusion, it can be said therefore, that change in Kalirin-7 expression in the hippocampus is associated with HH induced working memory deficit. [ABSTRACT FROM AUTHOR]

Highlights • Adult rat social isolation leads to anxiety-like behaviour. • Adult rat social isolation impairs Working Memory processes. • Less c-Fos learning-related activity is observed in adult socially isolated rats. • Metabolic brain activity is disrupted in adult socially isolated rats. Abstract Social isolation during adulthood is a frequent problem that leads to a large variety of adverse emotional and cognitive effects. However, most of the social isolation rodent procedures begin the separation early post-weaning. This work explores locomotor activity, anxiety-like behaviour, and spatial working memory after twelve weeks of adult social isolation. In order to study the functional contribution of selected brain areas following a working memory task, we assessed neuronal metabolic activity through quantitative cytochrome oxidase histochemistry and c-Fos immunohistochemistry. Behaviourally, we found that isolated animals (IS) showed anxiety-like behaviour and worse working memory than controls, whereas motor functions were preserved. Moreover, IS rats showed lower levels of learning-related c-Fos immunoreactivity, compared to controls, in the medial prefrontal cortex (mPFC), ventral tegmental area (VTA), and nucleus accumbens shell. In addition, the IS group showed lower neuronal metabolic activity in the mPFC, VTA, and CA1 subfield of the hippocampus. These results indicate that twelve weeks of social isolation in adult rats leads to different behavioural and brain alterations, and they highlight the importance of social support, not only in development, but also in adulthood. [ABSTRACT FROM AUTHOR]

Highlights • Healthy older adults learn environmental layout less well than younger adults. • Older adults have difficulty in learning a large-scale space from multiple views. • This change very likely stems from functional decline of the medial temporal lobe. Abstract It has been suggested that older adults suffer a greater degree of decline in environmental learning when navigating in an environment than when reading a map of the environment. However, the two types of spatial learning differ not only in perspectives (i.e., navigation is done with a ground-level perspective; a map is read from an aerial perspective) but also in orientations (i.e., orientations vary during navigation; spatial information is drawn from a single orientation in a map), making it unclear which factor critically affects older adults' spatial learning. The present study addressed this issue by having younger and older participants learn the layout of a large-scale environment through an aerial movie that contained changes in orientations from which the environment was depicted. Results showed that older participants' memories for the environmental layout were as distorted as those created through a ground-level movie (which involved the same orientation changes), whereas they formed more accurate memories through another aerial movie in which an orientation was fixed. By contrast, younger participants learned the environment equally well from the three movies. Taken together, these findings suggest that there is age-related alteration specifically in the ability to process multiple orientations of an environment while encoding its layout in memory. It is inferred that this alteration stems from functional deterioration of the medial temporal lobe, and possibly that of posterior cingulate areas as well (e.g., the retrosplenial cortex), in late adulthood. [ABSTRACT FROM AUTHOR]

Highlights • A mouse model for weak, single mild traumatic brain injury (minimal TBI) is used. • Minimal TBI results in transient deficits in long-term memory reconsolidation. • Minimal TBI causes relapse to less effective search strategies in the water maze. • Minimal TBI leads to a transient increase in freezing during fear conditioning. • A transient rise in hippocampal GFAP after minimal TBI indicates astrogliosis. Abstract Mild traumatic brain injury (mTBI) can lead to diffuse neurophysical damage as well as cognitive and affective alterations. The nature and extent of behavioral changes after mTBI are still poorly understood and how strong an impact force has to be to cause long-term behavioral changes is not yet known. Here, we examined spatial learning acquisition, retention and reversal in a Morris water maze, and assessed search strategies during task performance after a single, mild, closed-skull traumatic impact referred to as "minimal" TBI. Additionally, we investigated changes in conditioned learning in a contextual fear-conditioning paradigm. Results show transient deficits in spatial memory retention, which, although limited, are indicative of deficits in long-term memory reconsolidation. Interestingly, minimal TBI causes animals to relapse to less effective search strategies, affecting performance after a retention pause. Apart from cognitive deficits, results yielded a sub-acute, transient increase in freezing response after fear conditioning, with no increase in baseline behavior, an indication of a stronger affective reaction to aversive stimuli after minimal TBI or greater susceptibility to stress. Furthermore, western blot analysis showed a short-term increase in hippocampal GFAP expression, most likely indicating astrogliosis, which is typically related to injuries of the central nervous system. Our findings provide evidence that even a very mild impact to the skull can have detectable consequences on the molecular, cognitive and affective-like level. However, these effects seemed to be very transient and reversible. [ABSTRACT FROM AUTHOR]

Abstract Age is a consistent predictor of outcome following traumatic brain injury (TBI). Although children and adolescents have the highest rate of hospitalizations and long-term disabilities, few preclinical studies have attempted to model and treat TBI in this population. Studies using nicotinamide (NAM), a soluble B-group vitamin, in older animals (3–6 months) have shown improved functional recovery in experimental models of TBI. The purpose of this study was two-fold: to examine the preclinical efficacy of NAM at different doses on behavioral outcomes in juvenile rats and examine the microglial response over time. Groups of juvenile rats (PND 28–60) were assigned to sham, NAM (125 mg/kg, 500 mg/kg, or 1000 mg/kg) or saline (1 mL/kg) and received unilateral cortical contusion injuries (CCI) and received injections at 15 min, 24 h, and 72 h after injury. Animals treated with NAM demonstrated no significant behavioral improvements over saline treatments. NAM treatments did however show slowed cortical loss and reduced microglia compared to saline treated animals. In summary, the preclinical efficacy of NAM as a treatment following CCI in juvenile animals differs from that previously documented in older rat models. While NAM treatments did reduce microglial activity and slowed progression of cortical loss, it did not reduce the total cortical volume lost nor did it improve behavioral outcomes. The findings of this study emphasize the need to examine potential treatments for TBI utilizing juvenile populations and may explain why so many treatments have failed in clinical trials. [ABSTRACT FROM AUTHOR]

Highlights • Hippocampal Rictor was regulated by ovariectomy and E2 replacement. • siRictor inhibited E2 induced changes of spine density and synapse density. • siRictor inhibited E2 induced changes of actin remodeling and synaptic proteins. • siRictor inhibited E2 induced changes of spatial memory disorder caused by OVX. • Rictor might be the target against estrogen-related cognitive disorder.. Abstract Estrogens have been shown to play profound roles in the regulation of the structure and function of the hippocampus; however, the underlying mechanism is not clear. Previous studies have shown that when Rictor, the core component of the mammalian target of the rapamycin complex 2 (mTORC2), was deleted, hippocampal actin polymerization was reduced and long-term memory was seriously impaired. Although hippocampal Rictor could be regulated by estrogen receptor agonists/antagonists, whether Rictor could directly mediate estrogenic regulation of neuronal plasticity, spatial learning and memory remains unclear. In this study, we first examined the regulation of hippocampal Rictor and P-AKTser473 (P-AKT) by E2, then we used Rictor-specific dsRNA (shRictor) injected into the hippocampi of E2-treated ovariectomized (OVX) mice or into cultured cells. The results showed that both Rictor and P-AKT could be regulated by E2. OVX induced actin depolymerization, decreases in CA1 spine density and synapse density as well as changes in synaptic proteins were reversed by E2 replacement. However, these E2-mediated effects were significantly blocked by shRictor treatment. Similar results were also demonstrated by in vitro cell culture studies using E2 and/or shRictor. Importantly, we found that E2 replacement induced improvements in learning and memory impairment seen in OVX mice were significantly blocked by shRictor. Taken together, the current studies provided the first direct evidence for the important role of Rictor in estrogenic action on the hippocampus, indicating that it may be a therapeutic target for the treatment of E2-related, hippocampus-dependent cognitive dysfunction. [ABSTRACT FROM AUTHOR]

Highlights • I.c.v. administration of NST increased the cAMP levels, GPR107 protein expression and phosphorylation of PKA in brain. • NST promoted Aβ42 oligomers -induced cognitive impairments in mice through GPR107/PKA/Akt signaling pathway. • NST promoted Aβ42 oligomers hyperactivation of GFAP and neuroinflammation cytokines in brain. • I.c.v. co-administration of NST and Aβ42 oligomers led to reduction in ATP and hexokinase in the cortex of mice. Abstract Neuronostatin (NST) is composed of a 13-amino acid and amidated peptide hormone encoded in the somatostatin (SST) gene, and plays an important physiological function in diverse tissues. Previous studies have shown that intracerebroventricular (i.c.v.) and intra-hippocampally administration of NST can significantly decrease the percentage of novel object exploration time in the step-down test. In this study, to define the contribution of NST to cognitive impairments induced by soluble Aβ42 oligomers (oAβ), along with the underlying mechanisms. This study used behavioral, biochemical and immunohistological methods to find that i.c.v. administration of NST (3 nmol/mouse) disrupted the ability of spatial learning and memory in mice, led to increase the levels of cAMP, GPR107 protein expression and phosphorylation of PKA at Thr197 in the cortex and hippocampus. NST promoted oAβ (1 nmol/mouse) -induced cognitive impairments, subsequently co-injection of NST and oAβ increased the levels of GPR107 expression and PKA phosphorylation, which also led to hyperactivation of GFAP in the cortex and neuroinflammation cytokines (IL-1β, IL-6 and TNFα) both in the cortex and hippocampus. Moreover, it was demonstrated that co-administration of NST and oAβ had increased the phosphorylation of Akt and GSK3β and reduced the levels of ATP and hexokinase (HK) activity in the cortex. Therefore, taken together, this study provided powerful insight into the mechanism of NST for memory impairments induced by oAβ, and may potentially serve as a promising target for future Alzheimer's disease interventions. [ABSTRACT FROM AUTHOR]

Abstract Despite substantial increases in the use of antipsychotics to treat various psychiatric conditions in children, there is a lack of literature regarding long-term effects of early treatment. Some studies have indicated that early administration results in differential alterations to neurotransmission systems, but few studies have investigated whether there are long-term behavioral modifications. Therefore, the aim of the current study was to investigate the neurobehavioral effects of low dose risperidone (a commonly prescribed antipsychotic) treatment using juvenile rats. Twenty-four male Sprague-Dawley rats were either subcutaneously implanted with a continuous release risperidone pellet (.04 mg/day) or a placebo pellet. To encompass the peri-adolescent to adolescent timeframe (postnatal day 40–70) thought to be important for brain development, male rats began risperidone treatment at post-natal day 35. Six weeks following commencement of risperidone treatment, all rats were tested on a battery of behavioral assessments including open field, object recognition, Morris Water Maze, and Y-Maze tasks. Risperidone treatment did not affect performance on the open field, object recognition, or Morris Water maze. A significant effect was found on the Y-maze. Although all rats exhibited normal spontaneous alternation, risperidone treated rats demonstrated significantly higher same arm returns, indicative of a working memory deficit. Continued research is needed to determine whether early exposure to risperidone may lead to differences in working memory at longer time-points. These results seem to indicate that early low dose risperidone treatment during the peri-adolescent and adolescent period does not severely impair behavior. [ABSTRACT FROM AUTHOR]

Highlights • The early introduction of impoverished condition at the period from postnatal day (PD) 41 to PD 60 significantly decreased the beneficial effect of environmental enrichment on Morris Water Maze performance in adulthood, compared with late impoverished condition exposure at the period from postnatal day 51 to PD 70. • Different rearing conditions also altered c-Fos expression and N-methyl D-aspartate receptor subtype 2B (NMDAR2B) receptor activity in a regionally specific pattern. • Earlier exposure of dizocilpine (MK-801) significantly decreased protective effects of environmental enrichment against Morris Water Maze performance, methamphetamine self-administration and cue-induced reinstatement. • The different rearing conditions have a profound impact on the reinforcing, rather than the motivational, effects of methamphetamine. Abstract Objective Accumulating evidence indicates an association between improved cognition and the early introduction of environmental enrichment (EE). The beneficial effect of EE has also been examined in the field of methamphetamine (METH) dependence. The present study was designed to examine whether early cognitive alterations by dizocilpine (MK-801) in adolescence can impact the effect of EE on spatial memory, METH self-administration (SA), and cue-induced renewal in adulthood. Methods In Experiments 1 and 2, Morris Water Maze (MWM) performance, c-Fos expression and N -methyl d -aspartate receptor subtype 2B (NMDAR2B) levels were determined in various brain regions following a change in rearing condition from EE to an isolation environment (IE) at different points (PD 41–60 or PD 51–70). In Experiments 3 and 4, MWM performance and METH SA behaviors in adulthood were tested following adolescent administration of MK-801 during different periods of adolescence (PD 41–60 or PD 51–70) under EE rearing conditions. Results The early introduction of the IE at PD 41–60 significantly decreased the beneficial effect of EE on MWM performance in adulthood as compared to IE exposure at PD 51–70. Different rearing conditions also altered c-Fos expression and NMDA2B receptor activity in a regionally specific pattern. EE induced structural and systemic changes in the hippocampus that were associated with improvements in spatial memory. Early administration of MK-801 at PD 41–60 and PD 51–70 produced distinctive effects on the behavioral outcomes of METH SA and cue-induced renewal. Conclusion Early cognitive alterations have a profound impact on spatial memory and METH dependence. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The cell adhesion molecule neuroligin2 (NLGN2) regulates GABAergic synapse development, but its role in neural circuit function in the adult hippocampus is unclear. We investigated GABAergic synapses and hippocampus-dependent behaviors following viral-vector-mediated overexpression of NLGN2. Transducing hippocampal neurons with AAV-NLGN2 increased neuronal expression of NLGN2 and membrane localization of GABAergic postsynaptic proteins gephyrin and GABA A Rγ2, and presynaptic vesicular GABA transporter protein (VGAT) suggesting trans-synaptic enhancement of GABAergic synapses. In contrast, glutamatergic postsynaptic density protein-95 (PSD-95) and presynaptic vesicular glutamate transporter (VGLUT) protein were unaltered. Moreover, AAV-NLGN2 significantly increased parvalbumin immunoreactive (PV+) synaptic boutons co-localized with postsynaptic gephyrin+ puncta. Furthermore, these changes were demonstrated to lead to cognitive impairments as shown in a battery of hippocampal-dependent mnemonic tasks and social behaviors. [ABSTRACT FROM AUTHOR]

Abstract Anodal Direct Current Stimulation (DC) over prefrontal cortex improves working memory. This study investigated the influence of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) on prefrontal anodal DC-induced effects on spatial working memory and GAP-43 expression. Male Wistar rats well-trained in radial maze procedures received five sessions of anodal epidural DC stimulation (eDCS: 400 μA, 13 min, one daily session) over the left mPFC, or a respective sham procedure, and afterwards they received a single dose (1 mg/kg) of perampanel (PRP), an AMPARs antagonist, or vehicle 30 min before the performance of 4-h delayed task. The prefrontal cortex (PFC) and hippocampus (HPC) were removed 24-h later and GAP-43 (growth-associated protein) expression was measured by Western blot analysis. Repetitive eDCS decreased the number of errors in the 4-h post-delay performance (p < 0.05) and increased the expression of GAP-43 (p < 0.01) in the PFC when compared to sham stimulation. These behavioral and prefrontal molecular changes induced by the repetitive eDCS seem to involve AMPAR activity, because they were abolished when AMPARs were blocked by PRP (p < 0.01 and 0.05, respectively). Besides, in the HPC, changes of GAP-43 expression induced by eDCS was only seen when AMPARs were blocked by PRP. Therefore, the neuronal plasticity involving AMPARs may underlie, at least in part, the improving of spatial working memory and GAP-43 expression induced by the repetitive anodal prefrontal DC stimulation. [ABSTRACT FROM AUTHOR]

Highlights • Periconceptional alcohol exposure programmed an anxiety phenotype in female but not male offspring at 6 months of age. • Periconceptional alcohol exposure resulted in spatial memory deficits only in female offspring at 18 months of age. • Alchohol exposure resulted in increased hippocampal mRNA expression of bdnf, grin2a and grin2b in offspring at 18 months. • Hippocampal mRNA expression of dnmt1 , dnmt3a and hdac2 was increased in alcohol exposed offspring in a sex specific manner. • Alcohol around conception can cause behavioural deficits associated with altered hippocampal gene expression. Abstract Maternal alcohol consumption throughout pregnancy can result in long term behavioural deficits in offspring. However, less is known about the impact of alcohol during the periconceptional period (PC). The aim of this study was to examine the effect of PC ethanol (PC:EtOH) exposure on long term cognitive function; including memory and anxiety. Rats were exposed to a liquid diet containing ethanol (EtOH) (12.5% vol;vol) or a control diet from 4 days prior to mating until day 4 of pregnancy. Separate cohorts of animals were tested at 6 months (adult) or 15–18 months of age (aged). Offspring underwent a series of behavioural tests to assess anxiety, spatial and recognition memory. The hippocampus was collected, and mRNA expression of epigenetic modifiers and genes implicated in learning and memory were examined. PC:EtOH exposure resulted in a subtle anxiety like behaviour in adult female offspring with a significant reduction in directed exploring/head dipping behaviour during holeboard testing. In aged male offspring, PC:EtOH exposure resulted in a tendency for increased directed exploring/head dipping behaviour during holeboard testing. No differences between treatments were observed in the elevated plus maze. Aged female offspring exposed to PC:EtOH demonstrated short term spatial memory impairment (P < 0.05). PC:EtOH resulted in an upregulation of hippocampal mRNA expression of bdnf, grin2a and grin2b at 18 months of age along with increased expression of epigenetic modifiers (dnmt1 , dnmt3a and hdac2). In conclusion, PC:EtOH can lead to sex specific anxiety-like behaviour and impairments in spatial memory and altered hippocampal gene expression. [ABSTRACT FROM AUTHOR]

Highlights • P38 but not P38-alg systemic administration produced an enhancement of memory in a spatial learning task. • Training modulated hippocampal BDNF, and stress oxidative biomarkers. • P38 and P38-alg yielded different effects on BDNF and stress oxidative biomarkers. • P38-alg functional impact is different from P38. Abstract We compared the effects of single intraveinous injection of pituitary adenylate cyclase-activating polypeptide-38 (P38) to those of its analog, acetyl-[Ala15, Ala20]PACAP-38-propylamide (P38-alg) on spatial memory in the Morris water maze (MWM) using a weak massed-learning procedure, post-training brain derived neurotrophic factor (BDNF) and post-training oxidative stress biomarker assays in male Wistar rats. Acquisition of the MWM task following P38 (30 μg/kg) and P38-alg (30 μg/kg) treatments was similar to control group (Saline: 0.9% NaCl) and there was no interaction between treatments and performance. However, in the probe test, P38-treated group showed a specific interest for the target quadrant whereas the two other groups exhibited less focused place searching behavior. Moreover, P38 had an anxiogenic effect as measured by the distribution of swimming at the periphery of the pool. The swimming test resulted in a decrease in BDNF contents in the hippocampus. P38 but not P38-alg treatment restored BDNF expression. In terms of oxidative stress, both P38 and P38-alg treatments had antioxidative effects. The activity of antioxidative enzymes in the neocortex was increased. However only P38 reduced the levels of carbonylated proteins (CP). These data show that P38 and P38-alg have different behavioral and neurobiological effects. Thus, P38-alg and other analogs with specific functional profiles, inducing beneficial central effects (e.g. neuroprotection) while minimizing undesired peripheral effects may be useful for potential therapeutical use. [ABSTRACT FROM AUTHOR]

Highlights • Morphine-induced spatial memory impairment improved by morphine sensitization. • CamKII inhibition in the hippocampus facilitated memory retention induced by morphine sensitization. • Glutamate NMDA receptor plays a major role in morphine-sensitization memory retrieval. Abstract It has been shown that drug addiction and memory system are related but the signaling cascades underlying this interaction is not completely revealed yet. It has been demonstrated that binding of Calcium-calmodulin-dependent protein kinase II (CaMKII) to NMDA receptor is important in the memory process. The main objective of the study was to evaluate the role of CaMKII on the spatial memory of rats which previously were sensitized by morphine. The effect of CaMKII inhibitor (KN-93) on memory changes was investigated by hippocampal microinjection of KN-93 on the morphine-sensitized rats. Also, the role of the NMDA receptor in memory retention by KN-93 on the morphine sensitized rat was investigated with NMDA agonist and antagonist. Sensitization was induced by morphine injection (once daily for 3 days) followed by 5 days free of the drug before the trial phase. For the evaluation of spatial memory, the Morris Water Maze test (MWM) was used. Results showed that pre-trial administration of morphine, induced amnesia in MWM (p < 0.05). Also, three days pretreatment with morphine (20 mg/kg) followed by five days washout period, caused to enhance memory retrieval in confront with a pre-trial challenging dose of morphine (5 mg/kg). In addition, KN-93 administration during induction phase in morphine sensitization phenomena facilitated morphine-induced memory retention. In addition, inhibition of the NMDA receptor and KN-93 during the induction phase did not improve memory. However; intra-CA1 co-administration of KN-93 and NMDA during the induction phase of morphine sensitization resulted in improving spatial memory. It can be concluded that the effect of CaMKII on memory retention in morphine-sensitized rats depends on NMDA receptor. [ABSTRACT FROM AUTHOR]

Highlights • Egocentric and allocentric memory were assessed with a card placing test. • Gender differences were observed in Egocentric and Allocentric spatial memory. • Spatial memory was associated with visuospatial span and working memory. • Women achieved better scores on the Allocentric test than on the Egocentric test. Abstract Spatial memory allows us to locate objects and organisms in space and move through the environment. We frequently use two strategies for this purpose: egocentric, related to the viewer's perspective, and allocentric, associated with environmental cues. This ability is usually assessed by 2D or virtual reality-based tasks. Gender differences have been reported on these tasks. We designed two card-placing tasks with the aim of assessing egocentric and allocentric spatial memory in a real environment. This task makes it possible to separately compare egocentric and allocentric strategies, providing participants with 3D information naturally present in daily orientation activities. We will assess the performance of male and female young adults on the two strategies. Ninety-four subjects were recruited and performed egocentric and allocentric spatial memory card placing tasks. Spatial Span, forward and backward, was also assessed using the Cambridge Neuropsychological Assessment Battery (CANTAB), and the brief version of Benton's Judge of Line Orientation Test (JoLO) was used to evaluate the ability to judge spatial relations. Our results show that men outperformed women on both spatial memory tasks. Women performed better on Allocentric tasks than on Egocentric tasks, whereas men's scores did not show differences between strategies. Spatial memory performance on the card placing tasks was significantly correlated with performance on the backward visuospatial span from the CANTAB. This study supports the existence of gender differences in spatial memory functioning, and it provides novel tools for the neuropsychological assessment of spatial memory. [ABSTRACT FROM AUTHOR]

Highlights • Infusion of 5-HT 1B receptor antagonist GR55562 into hippocampal CA1 did not affect spatial memory acquisition. • Infusion of GR55562 into hippocampal CA1 enhanced spatial memory consolidation. • Infusion of GR55562 into hippocampal CA1 increased, but the 5-HT 1B receptor agonist CP93129 reduced, the spine density on the distal apical dendrites of CA1 pyramidal neurons and Kalirin-7 expression. • Infusion of GR55562 into hippocampal CA1 increased, but CP93129 reduced, the expression of GluA2/3 subunits of AMPA receptors. Abstract Serotonin 5-HT1B receptors (5-HT1BRs) are distributed in hippocampal CA1 and play a pivotal role in cognitive function. Activation of 5-HT1BRs regulates synaptic plasticity at the excitatory synapses in the hippocampus. However, the role and its underlying mechanism of 5-HT1BR activation-mediated glutamatergic synaptic plasticity in spatial memory are not fully understood. In this study, spatial memory of Sprague-Dawley (SD) rats was assessed in a Morris water maze after bilateral dorsal hippocampal CA1 infusion of the 5-HT1BR antagonist GR55562 (25 μg/μL) or agonist CP93129 (25 μg/μL). GR55562 did not affect the spatial memory acquisition but significantly increased the target quadrant preference during the memory consolidation probe performed 14 d after the training session, while CP93129 impaired the memory consolidation process. Moreover, GR55562 significantly increased, while CP93129 significantly decreased, the density of dendritic spines on the distal apical dendrites of CA1 pyramidal neurons. Furthermore, western blot experiments indicated that GR55562 significantly increased, but CP93129 significantly reduced, the expression of Kalirin-7 (Kal-7), PSD95, and GluA2/3 subunits of AMPA receptors. Our results suggest that Kal-7 and Kal-7-mediatedalteration of AMPA receptor subtype expression may play crucial roles in the impact of hippocampal CA1 5-HT1BR activation on spatial memory consolidation. [ABSTRACT FROM AUTHOR]

It has been suggested that the orexin system modulates learning and memory-related processes. However, the possible influence that training could have on the effect of the blockade of orexin-A selective receptor (OX1R) on a spatial memory task has not been explored. Therefore, the present study attempts to compare the effects of OX1R antagonist SB-334867 infusion on spatial memory in two different conditions in the Morris Water Maze (MWM). This experiment evaluated the animals’ performance in weak training (2 trials per session) vs strong training (6 trials per session) protocols in a spatial version of the MWM. We found that in the 2-trial condition the post-training SB-334867 infusion had a negative effect on consolidation as well as on the retention and reversal learning of the task 72 h later. This effect was not apparent in the 6-trial condition. In addition, while the strong training groups showed a general increase in c-Fos expression in several brain areas of the hippocampal-thalamic-cortical circuit, SB-334867 administration had the opposite effect in areas that have been previously reported to have a high density of OX1R. Specifically, the SB-infused group in the 2-trial condition showed a decrease in c-Fos immunoreactivity in the dentate gyrus, granular retrosplenial and prelimbic cortices, and centrolateral thalamic nucleus. This was not observed for subjects in the 6-trial condition. The activation of these areas could constitute a neuroanatomical substrate involved in the compensatory mechanisms of training upon SB-334867 impairing effects on a MWM spatial task. [ABSTRACT FROM AUTHOR]

To evaluate permanent effects of hippocampal and prefrontal cortex lesion on spatial tasks, lesioned and sham-operated female C57BL/6 mice were exposed to a series of conditioning schemes in IntelliCages housing 8–10 transponder-tagged mice from each treatment group. Sequential testing started at 51–172 days after bilateral lesions and lasted for 154 and 218 days in two batches of mice, respectively. Spontaneous undisturbed behavioral patterns clearly separated the three groups, hippocampals being characterized by more erratic hyperactivity, and strongly impaired circadian synchronization ability. Hippocampal lesions led to deficits in spatial passive avoidance, as well as in spatial reference and working memory tasks. Impairment was minimal in rewarded preference/reversal schemes, but prominent if behavioral responses required precise circadian timing or included punishment of wrong spatial choices. No differences between sham-operated and prefrontally lesioned subjects in conditioning success were discernible. These results corroborate the view that hippocampal dysfunction spares simple spatial learning tasks but impairs the ability to cope with conflicting task-inherent spatial, temporal or emotional cues. Methodologically, the results show that automated testing and data analysis of socially kept mice is a powerful, efficient and animal-friendly tool for dissecting complex features and behavioral profiles of hippocampal dysfunction characterizing many transgenic or pharmacological mouse models. [ABSTRACT FROM AUTHOR]

In a previous study, we demonstrated that intermittent ethanol administration in male adolescent animals impaired hippocampus-dependent spatial memory, particularly under conditions of excessive ethanol administration. In this current study, we subjected adolescent male and female Wistar rats an alcohol schedule-induced drinking (SID) procedure to obtain an elevated rate of alcohol self-administration and assessed their hippocampus-dependent spatial memory. We also studied hippocampal synaptic transmission and plasticity, as well as the expression levels of several genes involved in these mechanisms. Both male and female rats exhibited similar drinking patterns throughout the sessions of the SID protocol reaching similar blood alcohol levels in all the groups. However, only male rats that consumed alcohol showed spatial memory deficits which correlated with inhibition of hippocampal synaptic plasticity as long-term potentiation. In contrast, alcohol did not modify hippocampal gene expression of AMPA and NMDA glutamate receptor subunits, although there are differences in the expression levels of several genes relevant to synaptic plasticity mechanisms underlying learning and memory processes, related to alcohol consumption as Ephb2 , sex differences as Pi3k or the interaction of both factors such as Pten. In conclusion, elevated alcohol intake during adolescence seems to have a negative impact on spatial memory and hippocampal synaptic plasticity in a sex dependent manner, even both sexes exhibit similar blood alcohol concentrations and drinking patterns. [ABSTRACT FROM AUTHOR]

The rostral anterior cingulate cortex (rACC) of rat brain is associated with pain-related emotions. However, the underlying molecular mechanism remains unclear. Here, we investigated the effects of the N-methyl- D -aspartate (NMDA) receptor and Ca 2+ /Calmodulin-dependent protein kinase type II (CaMKII)α signal on pain-related aversion in the rACC of a rat model of neuropathic pain (NP). Mechanical and thermal hyperalgesia were examined using von Frey and hot plate tests in a rat model of NP induced by spared nerve injury (SNI) of the unilateral sciatic nerve. Bilateral rACC pretreatment with the CaMKII inhibitor tat-CN21 (derived from the cell-penetrating tat sequence and CaM-KIIN amino acids 43–63) or tat-Ctrl (the tat sequence and the scrambled sequence of CN21) was performed on postoperative days 29–35 in Sham rats or rats with SNI. Spatial memory performance was tested using an eight-arm radial maze on postoperative days 34–35. Pain-related negative emotions (aversions) were evaluated using the place escape/avoidance paradigm on postoperative day 35 following the spatial memory performance test. The percentage of time spent in the light area was used to assess pain-related negative emotions (i.e., aversion). The expression levels of the NMDA receptor GluN2B subunit, CaMKIIα, and CaMKII-Threonine at position 286 (Thr286) phosphorylation in contralateral rACC specimens were detected by Western blot or real time PCR following the aversion test. Our data showed that pretreatment of the rACC with tat-CN21 increased determinate behavior but did not alter hyperalgesia or spatial memory performance in rats with SNI. In addition, tat-CN21 reversed the enhanced CaMKII-Thr286 phosphorylation and had no effect on the upregulated expression of GluN2B, CaMKIIα protein, and mRNA. Our data suggested that activation of the NMDA receptor-CaMKIIα signal in rACC is associated with pain-related aversion in rats with NP. These data may provide a new approach for the development of drugs that modulate cognitive and emotional pain aspects. ● The rACC is involved in cognitive and emotional pain. ● The NMDA receptor and CaMKIIα signal in the rACC adjust cognitive and emotional pain aspects. ● tat-CN21 pretreatment in the rACC increases determinate behavior. ● The NMDA receptor and CaMKIIα signal in the rACC did not affect somatic irritant hyperalgesia. ● The NMDA receptor and CaMKIIα signal in the rACC did not affect spatial memory performance in rats with SNI. [ABSTRACT FROM AUTHOR]

The prevalence of mental disorders such as depression and anxiety is high and often comorbid with other diseases. Chronic stress is a common risk factor for these disorders, but the mechanisms behind their development are not yet fully understood. Metabolomics has revealed a close association between purine and pyrimidine metabolism and depression and anxiety, with increased levels of serum xanthine observed in both humans and mice. Xanthine is known as purine metabolism, and this compound shows several biological activities, but the impact of xanthine on our brain function is still unclear. The hippocampus, which plays a crucial role in memory and learning, is also implicated in the pathophysiology of depression and anxiety. Here, we investigated the effects of xanthine intraperitoneal administration on spatial memory and anxiety-like behavior in mice. The findings indicated that xanthine administration induced a deficit of hippocampus-dependent spatial memory and a tendency to anxiety-like behavior in mice. RNA-seq analysis showed that xanthine administration upregulated hemoglobin (Hb) genes involved in oxygen transport in the hippocampus. The upregulated Hb genes occurred in the neuronal cells, and in vitro experiments revealed that both Hba-a1 derived from mice and HBA2 derived from humans were upregulated by xanthine treatment. These observations suggest that the xanthine-induced Hb in the hippocampus could be related to spatial memory deficit and anxiety. This study sheds light on the direct effects of xanthine on the brain and its potential role in the development of depression and anxiety symptoms caused by chronic stress. [ABSTRACT FROM AUTHOR]

Spatial memory enables us to locate places and objects in space, to determine our position and manage spatial relationships in our environment. Our operations are displayed in a space that sometimes is inaccessible. In this case, the impossibility of movement within the context forces individuals to rely on the information gathered from limited viewpoints. This study investigates the use of walking and non-walking spaces using two equivalent virtual reality tasks in which displacement is only permitted in one of them. One hundred and fifty participants were divided into three age groups: 50–59, 60–69 and 70–79 year-old subjects. The starting position changed pseudo-randomly and two difficulty levels were set, with one and three positions to be found. Results provided evidence for 70–79 year-old people impairment of their spatial abilities compared with 50–59 and 60–69 year-old groups. In both difficulty conditions, participants made more errors in the non-walking space than in the walking space. All participants showed an improvement in the last trials of the task. Moreover, sexual dimorphism was registered in the high level of difficulty, in which men outperformed women. This study supports the idea that aging impairs the organization of spatial representations of the environment, and that this aspect is more noticeable in conditions where displacement is limited. [ABSTRACT FROM AUTHOR]

For fourteen days, male and female PVG/c hooded rats were provided continuously with either pure drinking water, or water containing caffeine in a quantity approximating a daily dose of 31.1 mg/kg. Then at intervals of 3 days, they were administered 1, 2 mg/kg methamphetamine (MA) or saline before being tested for anxiety-related behavior in a zero maze or a light/dark box, or their short-term spatial memory was assessed in a Y maze following introduction of a novel brightness change in one of the arms. Each rat experienced each type of apparatus with the same acute MA or saline treatment while still exposed to chronic caffeine or pure drinking water. While chronic caffeine on its own did not affect any behavioral measure, acute MA was anxiolytic for male rats suggested by increased entries and occupancy of zero-maze enclosed areas, and decreased emergence latencies and increased entries into the light/dark-box light compartment. Females were less affected than males by MA in both types of apparatus unless they also consumed caffeine. For male rats, choices of the Y-maze novel arm were affected by neither caffeine nor MA, but for females provided with unadulterated water, such choices were reduced by 1 mg/kg MA but increased for those exposed to caffeine, thereby suggesting either impaired or improved memory respectively. However, changes in anxiety could also explain these results. Overall, results generated in the three types of apparatus supported potentiation by caffeine of any effects of MA on anxiety for females only. [ABSTRACT FROM AUTHOR]

Strategic neuronal encoding in the medial prefrontal cortex (mPFC) of the rat was correlated with spatial working memory (sWM) assessed by behavior in the T-maze. Neurons increased their firing rate around choice, with the increase largely occurring before choice as a prospective encode of behavior. This could be classified as sensitive-to-spatial information or sensitive-to-choice outcome. The sensitivity-to-spatial choice was defined by distinct firing rate changes before left- or right-choice. The percentage of left-choice sensitive neurons was not different from the percentage of right-choice sensitive neurons. There was also location-related neuronal activity in which neurons fired at distinct rates when rats were in a left- or right-location. More neurons were sensitive to left-location, as most of them were recorded from rats preferring to enter the right-location. The sensitivity to outcome was defined by a distinct firing rate around correct or error choice. Significantly more neurons were sensitive to error outcome, and, among these, more preferred to encode prospectively, increasing firing in advance of an error outcome. Similar to single neuron activity, the mPFC enhanced its neuronal network as measured by the oscillation of local field potential. The maximum power of oscillation was around choice, and occurred slightly earlier before error versus before correct outcome. Thus, sWM modulation in the mPFC includes not only spatial, but also outcome-related inputs, and neuronal ensembles monitor behavioral outcome to make strategic adjustments ensuring successful task performance. [ABSTRACT FROM AUTHOR]

Previous evidence suggests that a significant decline in cognitive ability begins during middle-age and continues to deteriorate with increase in age. Recent work has demonstrated the potential rejuvenation impact of growth differentiation factor-11 (GDF-11) in aged mice. We carried out experiments to evaluate the impact of a single dose of recombinant (rGDF-11) on short-term visual and spatial memory in middle-aged male mice. On the novel object recognition task, we observed middle-aged mice treated rGDF-11 showed improved performance on the novel object recognition task. However, middle-aged mice did not show increased expression of phosphorylated-Smad2/3, a downstream effector of GDF-11. We noted however that the expression of the transcription factor, Sox2 was increased within the dentate gyrus. Our data suggest that a single injection of rGDF-11 contributes to improvements in cognitive function of middle-aged animals, which may be critical in the preservation of short-term memory capacity in old age. [ABSTRACT FROM AUTHOR]

The lateral mammillary nuclei are a central structure within the head direction system yet there is still relatively little known about how these nuclei contribute to spatial performance. In the present study, rats with selective neurotoxic lesions of the lateral mammillary nuclei were tested on a working memory task in a radial-arm maze. This task requires animals to distinguish between eight radially-oriented arms and remember which arms they have entered within a session. Even though it might have been predicted that this task would heavily tax the head direction system, the lesion rats performed equivalently to their surgical controls on this task; no deficit emerged even when the task was made more difficult by rotating the maze mid-way through testing in order to reduce reliance on intramaze cues. Rats were subsequently tested in the dark to increase the use of internally generated direction cues but the lesion rats remained unimpaired. In contrast, the lateral mammillary nuclei lesions were found to decrease retrosplenial c-Fos levels. These results would suggest that the head direction system is not required for the acquisition of the standard radial-arm maze task. It would also suggest that small decreases in retrosplenial c-Fos are not sufficient to produce behavioural impairments. [ABSTRACT FROM AUTHOR]

Left-right asymmetry is known to exist at several anatomical levels in the brain and recent studies have provided further evidence to show that it also exists at a molecular level in the hippocampal CA3-CA1 circuit. The distribution of N-methyl- d -aspartate (NMDA) receptor NR2B subunits in the apical and basal synapses of CA1 pyramidal neurons is asymmetrical if the input arrives from the left or right CA3 pyramidal neurons. In the present study, we examined the role of hippocampal asymmetry in cognitive function using β2-microglobulin knock-out (β2m KO) mice, which lack hippocampal asymmetry. We tested β2m KO mice in a series of spatial and non-spatial learning tasks and compared the performances of β2m KO and C57BL6/J wild-type (WT) mice. The β2m KO mice appeared normal in both spatial reference memory and spatial working memory tasks but they took more time than WT mice in learning the two non-spatial learning tasks (i.e., a differential reinforcement of lower rates of behavior (DRL) task and a straight runway task). The β2m KO mice also showed less precision in their response timing in the DRL task and showed weaker spontaneous recovery during extinction in the straight runway task. These results indicate that hippocampal asymmetry is important for certain characteristics of non-spatial learning. [ABSTRACT FROM AUTHOR]

Objectives Sex differences have been found in spatial learning and spatial memory, with several studies indicating that males outperform females. We tested in the virtual Morris Water Maze (vMWM) task, whether sex differences in spatial cognitive processes are attributable to differences in spatial learning or spatial memory retrieval in a large student sample. Methods We tested 90 healthy students (45 women and 45 men) with a mean age of 23.5 years ( SD = 3.5). Spatial learning and spatial memory retrieval were measured by using the vMWM task, during which participants had to search a virtual pool for a hidden platform, facilitated by visual cues surrounding the pool. Several learning trials assessed spatial learning, while a separate probe trial assessed spatial memory retrieval. Results We found a significant sex effect during spatial learning, with males showing shorter latency and shorter path length, as compared to females (all p < 0.001). Yet, there was no significant sex effect in spatial memory retrieval ( p = 0.615). Furthermore, post-hoc analyses revealed significant sex differences in spatial search strategies ( p < 0.05), but no difference in the number of platform crossings ( p = 0.375). Conclusion Our results indicate that in healthy young adults, males show faster spatial learning in a virtual environment, as compared to females. Interestingly, we found no significant sex differences during spatial memory retrieval. Our study raises the question, whether men and women use different learning strategies, which nevertheless result in equal performances of spatial memory retrieval. [ABSTRACT FROM AUTHOR]

Cognitive impairment and memory deficit are common features in multiple Sclerosis patients. The mechanism of memory impairment in MS is unknown, but neuroimaging studies suggest that hippocampal demyelination is involved. Here, we investigate the role of GABA A receptor on spatial memory in the local model of hippocampal demyelination. Demyelination was induced in male Wistar rats by bilaterally injection of lysophosphatidylcholine (LPC) 1% into the CA1 region of the hippocampus. The treatment groups were received daily intraventricular injection of bicuculline (0.025, 0.05 μg/2 μl/animal) or muscimol (0.1, 0.2 μg/2 μl/animal) 5 days after LPC injection. Morris Water Maze was used to evaluate learning and memory in rats. We used Luxol fast blue staining and qPCR to assess demyelination extention and MBP expression level respectively. Immunohistochemistry (IHC) for CD45 and H&E staining were performed to assess inflammatory cells infiltration. Behavioral study revealed that LPC injection in the hippocampus impaired learning and memory function. Animals treated with both doses of bicuculline improved spatial learning and memory function; however, muscimol treatment had no effect. Histological and MBP expression studies confirmed that demylination in LPC group was maximal. Bicuculline treatment significantly reduced demyelination extension and increased the level of MBP expression. H&E and IHC results showed that bicuculline reduced inflammatory cell infiltration in the lesion site. Bicuculline improved learning and memory and decreased demyelination extention in the LPC-induced hippocampal demyelination model. We conclude that disruption of GABAergic homeostasis in hippocampal demyelination context may be involved in memory impairment with the implications for both pathophysiology and therapy. [ABSTRACT FROM AUTHOR]

Cholinergic dysfunction in the hippocampus causes memory impairment, and degradation of the forebrain cholinergic system has been implicated in several neurological disorders. One such disorder, Alzheimer's Disease (AD) is associated with the abnormal expression of various proteins including matrix metalloproteinase-9 (MMP-9), an enzyme known to regulate hippocampus-dependent memory. Memory involves several stages including acquisition, consolidation, and retrieval, but the neurobiological correlates of retrieval have been studied much less than other stages of memory. We sought to investigate the potential relationship between cholinergic signaling and hippocampal MMP-9 expression and the involvement of each in spatial memory retrieval. We trained rats in the water maze until the task was well-learned, then, seven days later, we allowed some to retrieve the memory after an intracerebroventricular injection of scopolamine or vehicle. Western blot analysis of hippocampal tissue shows elevated levels of a truncated form of MMP-9 associated with spatial memory retrieval. Additionally, our results indicate that centrally administered scopolamine both impairs spatial memory retrieval and prevents retrieval-induced elevations in MMP-9. These findings provide evidence for a potential link between cholinergic dysregulation and abnormal MMP-9 levels seen in the brains of AD patients. An important, yet unresolved question is whether MMP-9 serves to support memory retrieval itself or if it is involved in maintaining the ongoing stability of a retrieved memory. • Scopolamine impairs retrieval of a previously consolidated spatial memory. • Spatial memory retrieval is associated with elevations in hippocampal MMP-9. • Scopolamine prevents retrieval-induced elevations in MMP-9 in the hippocampus. [ABSTRACT FROM AUTHOR]

Progestogens are a key component of menopausal hormone therapies. While some progestogens can be detrimental to cognition, there is preclinical evidence that progestogens with a strong progesterone-receptor affinity benefit some molecular mechanisms believed to underlie cognitive function. Thus, a progestin that maximizes progesterone-receptor affinity and minimizes affinities to other receptors may be cognitively beneficial. We evaluated segesterone-acetate (SGA), a 19-norprogesterone derivative with a strong progesterone-receptor affinity and no androgenic or estrogenic-receptor activity, hypothesizing that it would enhance cognition. Middle-aged rats underwent Sham or Ovariectomy (Ovx) surgery followed by administration of medroxyprogesterone-acetate (MPA; used as a positive control as we have previously shown MPA-induced cognitive deficits), SGA (low or high dose), or vehicle (one Sham and one Ovx group). Spatial working and reference memory, delayed retention, and anxiety-like behavior were assessed, as were memory- and hormone- related protein assays within the frontal cortex, dorsal hippocampus, and entorhinal cortex. Low-dose SGA impaired spatial working memory, while high-dose SGA had a more extensive detrimental impact, negatively affecting spatial reference memory and delayed retention. Replicating previous findings, MPA impaired spatial reference memory and delayed retention. SGA, but not MPA, alleviated Ovx-induced anxiety-like behaviors. On two working memory measures, IGF-1R expression correlated with better working memory only in rats without hormone manipulation; any hormone manipulation or combination of hormone manipulations used herein altered this relationship. These findings suggest that SGA impairs spatial cognition after surgical menopause, and that surgical menopause with or without progestin administration disrupts relationships between a growth factor critical to neuroplasticity. ● Progestins, used in menopausal hormone therapies, can impact the brain, cognition, and anxiety. ● Progestins with a strong progesterone receptor (PR) affinity have benefitted molecular mechanisms related to cognition. ● Segesterone acetate, a progestin with a strong PR affinity, impaired memory and improved anxiety profiles in a rat menopause model. ● Brain tissue assays revealed higher IGF-1R expression correlated with better working memory only in rats without hormone manipulation. [ABSTRACT FROM AUTHOR]