Impaired Spatial Memory Performance Research Articles

BIN1 deficiency enhances ULK3-dependent autophagic flux and reduces dendritic size in mouse hippocampal neurons

ABSTRACT Genome-wide association studies identified variants around the BIN1 (bridging integrator 1) gene locus as prominent risk factors for late-onset Alzheimer disease. In the present study, we decreased the expression of BIN1 in mouse hippocampal neurons to investigate its neuronal function. Bin1 knockdown via RNAi reduced the dendritic arbor size in primary cultured hippocampal neurons as well as in mature Cornu Ammonis 1 excitatory neurons. The AAV-mediated Bin1 RNAi knockdown also generated a significant regional volume loss around the injection sites at the organ level, as revealed by 7-Tesla structural magnetic resonance imaging, and an impaired spatial reference memory performance in the Barnes maze test. Unexpectedly, Bin1 knockdown led to concurrent activation of both macroautophagy/autophagy and MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1). Autophagy inhibition with the lysosome inhibitor chloroquine effectively mitigated the Bin1 knockdown-induced dendritic regression. The subsequent molecular studydemonstrated that increased expression of ULK3 (unc-51 like kinase 3), which is MTOR-insensitive, supported autophagosome formation in BIN1 deficiency. Reducing ULK3 activity with SU6668, a receptor tyrosine kinase inhibitor, or decreasing neuronal ULK3 expression through AAV-mediated RNAi, significantly attenuated Bin1 knockdown-induced hippocampal volume loss and spatial memory decline. In Alzheimer disease patients, the major neuronal isoform of BIN1 is specifically reduced. Our work suggests this reduction is probably an important molecular event that increases the autophagy level, which might subsequently promote brain atrophy and cognitive impairment through reducing dendritic structures, and ULK3 is a potential interventional target for relieving these detrimental effects.Abbreviations: AV: adeno-associated virus; Aβ: amyloid-β; ACTB: actin, beta; AD: Alzheimer disease; Aduk: Another Drosophila Unc-51-like kinase; AKT1: thymoma viral proto-oncogene 1; AMPK: AMP-activated protein kinase; AP: autophagosome; BafA1: bafilomycin A1; BDNF: brain derived neurotrophic factor; BIN1: bridging integrator 1; BIN1-iso1: BIN1, isoform 1; CA1: cornu Ammonis 1; CA3: cornu Ammonis 3; CLAP: clathrin and adapter binding; CQ: chloroquine; DMEM: Dulbecco’s modified Eagle medium; EGFP: enhanced green fluorescent protein; GWAS: genome-wide association study; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MRI: magnetic resonance imaging; MTOR; mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; PET: positron emission tomography; qRT-PCR: real-time quantitative reverse transcription PCR; ROS: reactive oxygen species; RPS6KB1: ribosomal protein S6 kinase B1; TFEB: transcription factor EB; ULK1: unc-51 like kinase 1; ULK3: unc-51 like kinase 3.

Identification of Ndfip1 as a novel negative regulator for spatial memory formation associated with increased ubiquitination of Beclin 1 and PTEN.

Long-term memory formation requires de novo RNA and protein synthesis. By using the differential display-polymerase chain reaction strategy, we have presently identified the Nedd4 family interacting protein 1 (Ndfip1) cDNA fragment that is differentially expressed between the slow learners and the fast learners from the water maze learning task in rats. Further, the fast learners show decreased Ndfip1 mRNA and protein expression levels than the slow learners. Spatial training similarly decreases the Ndfip1 mRNA and protein expression levels. Conversely, the Ndfip1 conditional heterozygous (cHet) mice show enhanced spatial memory performance compared to the Ndfip1flox/WT control mice. Result from co-immunoprecipitation experiment indicates that spatial training decreases the association between Ndfip1 and the E3 ubiquitin ligase Nedd4 (Nedd4-1), and we have shown that both Beclin 1 and PTEN are endogenous ubiquitination targets of Nedd4 in the hippocampus. Further, spatial training decreases endogenous Beclin 1 and PTEN ubiquitination, and increases Beclin 1 and PTEN expression in the hippocampus. On the other hand, the Becn1 conditional knockout (cKO) mice and the Pten cKO mice both show impaired spatial learning and memory performance. Moreover, the expression level of Beclin 1 and PTEN is higher in the Ndfip1 cHet mice compared with the Ndfip1flox/WT control mice. Here, we have identified Ndfip1 as a candidate novel negative regulation for spatial memory formation and this is associated with increased ubiquitination of Beclin 1 and PTEN in the hippocampus.

Evaluation of the effects of phenylephrine and prazosin injection into basolateral amygdala on the post-stress experience of memory retrieval in rats

The present study explored the effect of α1-adrenergic receptors in the basolateral amygdala (BLA) on memory formation in the hippocampus under repeated stress. Male rats received injections of the α1-adrenergic receptor agonist (phenylephrine) or antagonist (prazosin) bilaterally into the BLA five min before foot-shock stress, and emotional and spatial memory and in-vivo long-term potentiation (LTP) in the Cornu Ammonis (CA1) region of the hippocampus were examined. Foot-shock stress impaired performance in emotional and spatial memory tests. However, it had no significant effect on any of the LTP parameters in the hippocampus. Intra-BLA phenylephrine injection significantly impaired emotional and spatial memory performance in stressed animals. On the other hand, administration of intra-BLA prazosin significantly reduced emotional and spatial memory in the control (intact) animals. Neither of the two drugs had any significant effects on LTP parameters. Prazosin effectively impaired memory in the control, but not in the stressed rats. Stress appears to have suppressed the effect of prazosin, and it seems to be a significantly stronger stimulus than prazosin. Taken together, these findings provide new insights into the effects of α1-adrenergic receptors in the BLA on memory storage, during the stress experience.

Chronic caffeine consumption improves the acute sleep deprivation-induced spatial memory impairment while altering N-methyl-D-aspartate receptor subunit expression in male rats.

Caffeine is a psychostimulant substance that is mostly used to prevent fatigue, increase alertness, and ameliorate sleep loss situations. In this study, we aimed to investigate the effect of chronic caffeine consumption on learning and memory functions and related genes in rapid eye movement (REM) sleep-deprived rats. During the neonatal period (postnatal day [PND] 28) Wistar albino male rats (n = 32) were randomly assigned into four groups: Control (C), caffeine application (Cf), acute REM sleep-deprivation (RD), and caffeine application + acute RD (Cf + RD). The 48 h of RD was executed when caffeine administration was completed. The learning and memory performance was evaluated by the Morris water maze test (MWMT). Following this, the rats were decapitated to isolate hippocampus tissues. In MWMT, time spent in the targeted quadrant decreased significantly in the RD group compared with the C and Cf + RD group. NR2A expression level increased in the RD group compared with C, Cf, and Cf + RD groups (p < 0.05). NR2B expression level increased in RD and Cf + RD groups compared with C and Cf groups (p < 0.05). BDNF and c-Fos expression levels did not differ significantly between the groups. RD impaired hippocampal spatial memory performance in the MWMT test. Our results indicated that chronic caffeine consumption has a therapeutic effect on spatial memory deterioration impairment caused by RD. Furthermore, it seems that the effect of caffeine RD on the hippocampus may be mediated by NR2A.

Disruption of the grid cell network in a mouse model of early Alzheimer\u2019s disease

Early-onset familial Alzheimer’s disease (AD) is marked by an aggressive buildup of amyloid beta (Aβ) proteins, yet the neural circuit operations impacted during the initial stages of Aβ pathogenesis remain elusive. Here, we report a coding impairment of the medial entorhinal cortex (MEC) grid cell network in the J20 transgenic mouse model of familial AD that over-expresses Aβ throughout the hippocampus and entorhinal cortex. Grid cells showed reduced spatial periodicity, spatial stability, and synchrony with interneurons and head-direction cells. In contrast, the spatial coding of non-grid cells within the MEC, and place cells within the hippocampus, remained intact. Grid cell deficits emerged at the earliest incidence of Aβ fibril deposition and coincided with impaired spatial memory performance in a path integration task. These results demonstrate that widespread Aβ-mediated damage to the entorhinal-hippocampal circuit results in an early impairment of the entorhinal grid cell network.

Assessment of long-term effects of smoke from wildfires on white rats

Introduction. The study of the effects of wildfire smoke on the reproductive function is the most important scientific problem at the present stage. The aim of study is to study the behavior and cognitive abilities of sexually mature offspring obtained from white male rats exposed to the smoke of wildfires. Materials and methods. Experiments were carried out on 30 white male rats and 60 adult male of their offspring. The duration of exposure was 4 weeks, 4 hours/day. To obtain progeny exposed males were mated with intact females immediately after the exposure and in long-term period after exposure. Examination of adult progeny was performed using the "open field", Morris water maze, and histological examination of brain tissue. Results. Behavioral and cognitive alterations in offspring of male rats exposed to wildfire smoke were obtained: significant decrease in motor activity and research on higher level of negative emotional state, impaired spatial memory performance. Individuals from offspring obtained in a long-term period after exposure to smoke showed a normalization of the studied parameters to background values. Conclusions. The long-term consequences of exposure to the smoke of wildfires were revealed, manifested in the offspring of the first generation in the form of impaired behavior and cognitive abilities. The recovery period after prolonged smoke intoxication, which is 60 days and is comparable in duration with the duration of spermatogenesis in rats, is important for reducing the risk of developing CNS disorders in offspring.

Blockage of ventrolateral periaqueductal gray matter cannabinoid 1 receptor increases dental pulp pain and pain-related subsequent learning and memory deficits in rats

Cannabinoid 1 receptor (CB1R) signaling has a pivotal role in the modulation of both pain and cognitive responses. This study aims at investigating the role of CB1R in the ventrolateral periaqueductal gray matter (vlPAG) on both pulpal pain and pain-related subsequent changes in learning and memory performances in rats. The adult male Wistar rats were cannulated in the vlPAG. The rats were pretreated by intra-vlPAG administration of selective CB1R antagonist AM-251 (2, 4 and 8 µg/rat) and vehicle dimethylsulfoxide. The drugs were microinjected 20 min before the induction of capsaicin-induced pulpalgia. The nociceptive behaviors were recorded for 40 min. Then, passive avoidance and spatial learning and memory were assessed using the shuttle box and Morris water maze tests, respectively. Following the administration of intradental capsaicin, there was a significant nociceptive response that increased after an induced blockage of CB1R by AM-251 at 4 and 8 µg. In addition, capsaicin impaired passive avoidance and spatial memory performance of rats. Microinjection of AM-251, prior to capsaicin, could dose-dependently exaggerate capsaicin-related learning and memory deficits in both tests. The present data indicated that the vlPAG endocannabinoid system is involved in the modulation of pain signals from dental pulp. It was also accompanied by learning and memory impairments.

Minocycline differentially modulates human spatial memory systems

Microglia play a critical role in many processes fundamental to learning and memory in health and are implicated in Alzheimer’s pathogenesis. Minocycline, a centrally-penetrant tetracycline antibiotic, inhibits microglial activation and enhances long-term potentiation, synaptic plasticity, neurogenesis and hippocampal-dependent spatial memory in rodents, leading to clinical trials in human neurodegenerative diseases. However, the effects of minocycline on human memory have not previously been investigated. Utilising a double-blind, randomised crossover study design, we recruited 20 healthy male participants (mean 24.6 ± 5.0 years) who were each tested in two experimental sessions: once after 3 days of Minocycline 150 mg (twice daily), and once 3 days of placebo (identical administration). During each session, all completed an fMRI task designed to tap boundary- and landmark-based navigation (thought to rely on hippocampal and striatal learning mechanisms respectively). Given the rodent literature, we hypothesised that minocycline would selectively modulate hippocampal learning. In line with this, minocycline biased use of boundary- compared to landmark-based information (t980 = 3.140, p = 0.002). However, though this marginally improved performance for boundary-based objects (t980 = 1.972, p = 0.049), it was outweighed by impaired landmark-based navigation (t980 = 6.374, p < 0.001) resulting in an overall performance decrease (t980 = 3.295, p = 0.001). Furthermore, against expectations, minocycline significantly reduced activity during memory encoding in the right caudate (t977 = 2.992, p = 0.003) and five other cortical regions, with no significant effect in the hippocampus. In summary, minocycline impaired human spatial memory performance, likely through disruption of striatal processing resulting in greater biasing towards reliance on boundary-based navigation.

Impairment of Sharp-Wave Ripples in a Murine Model of Dravet Syndrome.

Dravet syndrome (DS) is a severe early-onset epilepsy associated with heterozygous loss-of-function mutations in SCN1A Animal models of DS with global Scn1a haploinsufficiency recapitulate the DS phenotype, including seizures, premature death, and impaired spatial memory performance. Spatial memory requires hippocampal sharp-wave ripples (SPW-Rs), which consist of high-frequency field potential oscillations (ripples, 100-260 Hz) superimposed on a slower SPW. Published in vitro electrophysiologic recordings in DS mice demonstrate reduced firing of GABAergic inhibitory neurons, which are essential for the formation of SPW-R complexes. Here, in vivo electrophysiologic recordings of hippocampal local field potential in both male and female mice demonstrate that Scn1a haploinsufficiency slows intrinsic ripple frequency and reduces the rate of SPW-R occurrence. In DS mice, peak ripple-band power is shifted to lower frequencies, average intertrough intervals of individually detected ripples are slower, and the rate of SPW-R generation is reduced, while SPW amplitude remains unaffected. These alterations in SPW-R properties, in combination with published reductions in interneuron function in DS, suggest a direct link between reduced inhibitory neuron excitability and impaired SPW-R function. A simple interconnected, conductance-based in silico interneuron network model was used to determine whether reduced sodium conductance is sufficient to slow ripple frequency, and stimulation with a modeled SPW demonstrates that reduced sodium conductance alone is sufficient to slow oscillatory frequencies. These findings forge a potential mechanistic link between impaired SPW-R generation and Scn1a mutation in DS mice, expanding the set of disorders in which SPW-R dysfunction contributes to impaired memory.SIGNIFICANCE STATEMENT Disruption of sharp-wave ripples, a characteristic hippocampal rhythm coordinated by the precise timing of GABAergic interneurons, impairs spatial learning and memory. Prior in vitro patch-clamp recordings in brain slices from genetic mouse models of Dravet syndrome (DS) reveal reduced sodium current and excitability in GABAergic interneurons but not excitatory cells, suggesting a causal role for impaired interneuron activity in seizures and cognitive impairment. Here, heterozygous Scn1a mutation in DS mice reduces hippocampal sharp-wave ripple occurrence and slows internal ripple frequency in vivo and a simple in silico model demonstrates reduction in interneuron function alone is sufficient to slow model oscillations. Together, these findings provide a plausible pathophysiologic mechanism for Scn1a gene mutation to impair spatial memory.

Abolition of aberrant neurogenesis ameliorates cognitive impairment after stroke in mice

Poststroke cognitive impairment is considered one of the main complications during the chronic phase of ischemic stroke. In the adult brain, the hippocampus regulates both encoding and retrieval of new information through adult neurogenesis. Nevertheless, the lack of predictive models and studies based on the forgetting processes hinders the understanding of memory alterations after stroke. Our aim was to explore whether poststroke neurogenesis participates in the development of long-term memory impairment. Here, we show a hippocampal neurogenesis burst that persisted 1 month after stroke and that correlated with an impaired contextual and spatial memory performance. Furthermore, we demonstrate that the enhancement of hippocampal neurogenesis after stroke by physical activity or memantine treatment weakened existing memories. More importantly, stroke-induced newborn neurons promoted an aberrant hippocampal circuitry remodeling with differential features at ipsi- and contralesional levels. Strikingly, inhibition of stroke-induced hippocampal neurogenesis by temozolomide treatment or using a genetic approach (Nestin-CreERT2/NSE-DTA mice) impeded the forgetting of old memories. These results suggest that hippocampal neurogenesis modulation could be considered as a potential approach for treatment of poststroke cognitive impairment.

A meta-analytic approach to genes that are associated with impaired and elevated spatial memory performance

Spatial memory deficits are a common hallmark of psychiatric conditions, possibly due to a genetic predisposition. Thus, unravelling the relationship between genes and memory might suggest novel therapeutic targets and pathogenetic pathways. Genetic deletions are known to lead to memory deficits (post-deletion “forgetfulness” genes, PDF), or, in few instances to improve spatial memory (post-deletion “hypermnesic” genes, PDH). To assess this topic, we performed a meta-analytic approach on memory behavior in knock-out mice. We screened 300 studies from PubMed and retrieved 87 genes tested for possible effects on spatial memory. This database was crossed with the Allen Brain Atlas (brain distribution) and the Enrichr (gene function) databases. The results show that PDF genes have higher expression level in several ventral brain structures, particularly the encephalic trunk and in the hypothalamus. Moreover, part of these genes are implicated in synaptic functions. Conversely, the PDH genes are associated to G-protein coupled receptors downstream signalling. Some candidate drugs were also found to interfere with some of the PDH genes, further suggesting that this approach might help in identifying drugs to improve memory performance in psychiatric conditions.

Quantitative Proteomic Analysis of the Hippocampus of Rats with GCR-Induced Spatial Memory Impairment.

NASA is planning future missions to Mars, which will result in astronauts being exposed to ∼13 cGy/year of galactic cosmic radiation (GCR). Previous ground-based experiments have demonstrated that low (15 cGy) doses of 1 GeV/n 56Fe ions impair hippocampus-dependent spatial memory in rats. However, some irradiated rats maintain a spatial memory performance comparable to that seen in the sham-irradiated rats, suggesting that some of these animals are able to ameliorate the deleterious effects of the GCR, while others are not. This rat model provides a unique opportunity to increase our understanding of how GCR affects neurophysiology, what adaptive responses can be invoked to prevent the emergence of GCR-induced spatial memory impairment, as well as the pathways that are altered when spatial memory impairment occurs. A label-free, unbiased proteomic profiling approach involving quantitative protein/peptide profiling followed by Cytoscape analysis has established the composition of the hippocampal proteome in male Wistar rats after exposure to 15 cGy of 1 GeV/n 56Fe, and identified proteins whose expression is altered with respect to: 1. radiation exposure and 2. impaired spatial memory performance. We identified 30 proteins that were classified as "GCR exposure marker" (GEM) proteins (expressed solely or at higher levels in the irradiated rats but not related to spatial memory performance), most notably CD98, Cadps and GMFB. Conversely, there were 252 proteins that were detected only in the sham-irradiated samples, i.e., they were not detected in either of the irradiated cohorts; of these 10% have well-documented roles in neurotransmission. The second aspect of our data mining was to identify proteins whose expression was associated with either impaired or functional spatial memory. While there are multiple changes in the hippocampal proteome in the irradiated rats that have impaired spatial memory performance, with 203 proteins being detected (or upregulated) only in these rats, it would appear that spatial memory impairment may also arise from an inability of these rats to express "good spatial memory" (GSM) proteins, many of which play an important role in neuronal homeostasis and function, axonogenesis, presynaptic membrane organization and G-protein coupled receptor (GCPR) signaling. It may be possible to use this knowledge to develop two alternative countermeasure strategies, one that preserves critical pathways prophylactically and one that invokes restorative pathways after GCR exposure.

Melatonin restores hippocampal neural precursor cell proliferation and prevents cognitive deficits induced by jet lag simulation in adult mice.

Frequent flyers and shift workers undergo circadian dysrhythmia with adverse impact on body and mind. The circadian rhythm disorder "jet lag" disturbs hippocampal neurogenesis and spatial cognition, which represent morphological and functional adult brain plasticity. This raises the question if pro-neurogenic stimuli might prevent those consequences. However, suitable measures to mitigate jet lag-induced adverse effects on brain plasticity have been neglected so far. Here, we used adult C57Bl6 mice to investigate the pro-neurogenic stimuli melatonin (8mg/kg i.p.) as well as environmental enrichment as potential measures. We applied photoperiod alterations to simulate "jet lag" by shortening the dark period every third day by 6hours for 3weeks. We found that "jet lag" simulation reduced hippocampal neural precursor cell proliferation by 24% and impaired spatial memory performance in the water maze indicated by a prolonged swim path to the target (~23%). While melatonin prevented both the cellular (~1%) as well as the cognitive deficits (~5%), environmental enrichment only preserved precursor cell proliferation (~12%). Our results indicate that lifestyle interventions are insufficient to completely compensate jet lag-induced consequences. Instead, melatonin is required to prevent cognitive impairment caused by the same environmental factors to which frequent flyers and shift workers are typically exposed to.

Changes in the Hippocampal Proteome Associated with Spatial Memory Impairment after Exposure to Low (20 cGy) Doses of 1 GeV/n 56Fe Radiation.

Exposure to low (∼20 cGy) doses of high-energy charged (HZE) particles, such as 1 GeV/n 56Fe, results in impaired hippocampal-dependent learning and memory (e.g., novel object recognition and spatial memory) in rodents. While these findings raise the possibility that astronauts on deep-space missions may develop cognitive deficits, not all rats develop HZE-induced cognitive impairments, even after exposure to high (200 cGy) HZE doses. The reasons for this differential sensitivity in some animals that develop HZE-induced cognitive failure remain speculative. We employed a robust quantitative mass spectrometry-based workflow, which links early-stage discovery to next-stage quantitative verification, to identify differentially active proteins/pathways in rats that developed spatial memory impairment at three months after exposure to 20 cGy of 1 GeV/n 56Fe (20/impaired), and in those rats that managed to maintain normal cognitive performance (20/functional). Quantitative data were obtained on 665-828 hippocampal proteins in the various cohorts of rats studied, of which 580 were expressed in all groups. A total of 107 proteins were upregulated in the irradiated rats irrespective of their spatial memory performance status, which included proteins involved in oxidative damage response, calcium transport and signaling. Thirty percent (37/107) of these "radiation biomarkers" formed a functional interactome of the proteasome and the COP9 signalosome. These data suggest that there is persistent oxidative stress, ongoing autophagy and altered synaptic plasticity in the irradiated hippocampus, irrespective of the spatial memory performance status, suggesting that the ultimate phenotype may be determined by how well the hippocampal neurons compensate to the ongoing oxidative stress and associated side effects. There were 67 proteins with expression that correlated with impaired spatial memory performance. Several of the "impaired biomarkers" have been implicated in poor spatial memory performance, neurodegeneration, neuronal loss or neuronal susceptibility to apoptosis, or neuronal synaptic or structural plasticity. Therefore, in addition to the baseline oxidative stress and altered adenosine metabolism observed in all irradiated rats, the 20/impaired rats expressed proteins that led to poor spatial memory performance, enhanced neuronal loss and apoptosis, changes in synaptic plasticity and dendritic remodeling. A total of 46 proteins, which were differentially upregulated in the sham-irradiated and 20/functional rat cohorts, can thus be considered as markers of good spatial memory, while another 95 proteins are associated with the maintenance of good spatial memory in the 20/functional rats. The loss or downregulation of these "good spatial memory" proteins would most likely exacerbate the situation in the 20/impaired rats, having a major impact on their neurocognitive status, given that many of those proteins play an important role in neuronal homeostasis and function. Our large-scale comprehensive proteomic analysis has provided some insight into the processes that are altered after exposure, and the collective data suggests that there are multiple problems with the functionality of the neurons and astrocytes in the irradiated hippocampi, which appear to be further exacerbated in the rats that have impaired spatial memory performance or partially compensated for in the rats with good spatial memory.

The role of inflammatory cytokines and ERK1/2 signaling in chronic prostatitis/chronic pelvic pain syndrome with related mental health disorders

Mental health disorders(MHD) in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) have been widely studied. However, the underlying role of inflammatory cytokines and their associated signaling pathways have not been investigated. Here, we report the potential role of cytokines and associated signaling pathways in CP/CPPS patients with MHD and in a CP/CPPS animal model. CP/CPPS patients (n = 810) and control subjects (n = 992) were enrolled in this case-control multicenter study, and serum cytokine levels were measured. Male Sprague-Dawley rats received multiple intracutaneous injections of an immuno-agent along with a pertussis-diphtheria-tetanus triple vaccine for autoimmune CP/CPPS development. The results revealed that, in CP/CPPS patients with significant MHD, elevated IL-1α, IL-1β, IL-4, IL-13, and TNF-α serum levels were observed. The above five cytokines in CP/CPPS rats were significantly elevated in prostate tissue (p < 0.05), and IL-1β levels were elevated in serum and cerebrospinal fluid. In behavioral tests, CP/CPPS rats showed anxiety- and depression-like symptoms, and impaired spatial and associative memory performance (p < 0.05). In the CP/CPPS group, ERK1/2 phosphorylation levels were increased in the amygdala and nucleus accumbens, and decreased in the hippocampus, but not caudate nucleus. Thus, prostate-derived cytokines, especially IL-1β, cross the blood brain barrier and may lead to enhanced ERK1/2 signaling in several brain areas, possibly underlying induction of CP/CPPS-related MHD.

VISUO-SPATIAL MEMORY IMPAIRMENT IN OBSESSIVE COMPULSIVE DISORDER (OCD): FROM NEUROPSYCHOLOGICAL FINDINGS TO EYE-TRACKING

abstract There is a growing amount of evidence about the deficit of executive system in OCD, which is strongly related to the fronto-basal loop dysfunctions of the disorder (e.g. Chamberlain et al., 2005; Olley et al., 2007). In addition to the executive deficit, several studies found impaired visual and spatial memory performance in this disorder. In an early neuropsychological model, Savage (1998) suggested that the fronto-striatal dysfunctions along with impaired executive functioning leads to observed memory difficulties (encoding and retrieval of nonverbal information). Following this suggestion, here we aimed at investigating visuo-spatial memory functions in a pool of OCD patients in two studies. We combined neuropsychological tasks and computer based working memory paradigms with eye-tracking methodology. In Study 1 the Rey Complex Figure Task (RCFT) was used and it was found that OCD patients performed significantly poorer in the copy and recall phase of the task in comparison with matched healthy control group. Symptom severity and the level of anxiety were assessed by the Yale Brown Obsessive Compulsive Scale (Y-BOCS) and the State-Trait Anxiety Inventory (STAI), respectively. There was a significant negative correlation between symptom severity (Y-BOCS total scores) and the recall scores of the RCFT. In Study 2 we developed a computer-based Visual Pattern Task to investigate the eye movement correlates of cognitive processes involved in visuo-spatial working memory function. In addition subjects were also screened by a neuropsychological test battery including tasks on shifting (Wisconsin Card Sorting Test), response inhibition (Stop Signal Task, Stroop Task) and working memory capacity functions (n-back Task). According to our preliminary eye-tracking results, in comparison with healthy control subjects, OCD patients produced a significant decrease in target-related dwell time scores during the delay phase of the task. We will discuss the possible relationships between eye movement patterns, cognitive deficits and symptom severity.

PD20-09 THE ROLE OF INFLAMMATORY CYTOKINES AND MAPK SIGNALING IN CHRONIC PROSTATITIS/CHRONIC PELVIC PAIN SYNDROME WITH RELATED MENTAL HEALTH DISORDERS

You have accessJournal of UrologyInfections/Inflammation/Cystic Disease of the Genitourinary Tract: Prostate & Genitalia I1 Apr 2016PD20-09 THE ROLE OF INFLAMMATORY CYTOKINES AND MAPK SIGNALING IN CHRONIC PROSTATITIS/CHRONIC PELVIC PAIN SYNDROME WITH RELATED MENTAL HEALTH DISORDERS Chao Hu, Hualan Yang, Yanfang Zhao, Xiang Chen, Yinying Dong, Yehao Dong, Jiefeng Cui, Tongyu Zhu, Ping Zheng, Ching-Shwun Lin, and Jican Dai Chao HuChao Hu More articles by this author , Hualan YangHualan Yang More articles by this author , Yanfang ZhaoYanfang Zhao More articles by this author , Xiang ChenXiang Chen More articles by this author , Yinying DongYinying Dong More articles by this author , Yehao DongYehao Dong More articles by this author , Jiefeng CuiJiefeng Cui More articles by this author , Tongyu ZhuTongyu Zhu More articles by this author , Ping ZhengPing Zheng More articles by this author , Ching-Shwun LinChing-Shwun Lin More articles by this author , and Jican DaiJican Dai More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1422AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Mental health disorders (MHD) in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) have been widely studied. Among these MHD, depression has been identified in 78% of patients with CP/CPPS and even anxious symptoms have been observed in CP/CPPS patients. However, the underlying role of inflammatory cytokines and their associated signaling pathways has not been investigated. Recently, neuroscience research has identified the dysfunction of specific brain areas, such as the basolateral amygdala, nucleus accumbens, hippocampus, and caudate nucleus, are related to anxiety, depression, and spatial and associative memory. Here, we report the potential role of cytokines and associated signaling pathways in CP/CPPS patients with MHD and in a CP/CPPS animal model. METHODS Clinically, CP/CPPS patients (n=810) and control subjects (n=992) were enrolled in this case-control multicenter study with assessment of NIH-CPSI, anxiety and depression. The serum cytokine levels were measured by microarray. Male Sprague-Dawley rats received multiple intracutaneous injections of an immuno-agent along with a pertussis-diphtheria-tetanus triple vaccine for autoimmune CP/CPPS development. The evaluation of rodent animal behavior were performed by elevated plus maze test, open field test, Y maze test and shuttle box passive avoidance test. The levels of cytokines in serum and prostates were detected by ELISA and RT-PCR, and the levels of phospho-MAPK (Erk1/2) in specific brain areas were measured by western blot. All statistical analyses were performed on SAS for Windows 8.0. Statistical significance was considered at a p<0.05 level for all parameters. RESULTS The results revealed that, in CP/CPPS patients with significant MHD, elevated IL-1α, IL-1β, IL-4, IL-13, and TNF-α serum levels were observed. The above five cytokines in CP/CPPS rats were significantly elevated in prostate tissue (p<0.05), and IL-1β levels were elevated in serum and CSF. In behavioral tests, CP/CPPS rats showed anxiety- and depression-like symptoms, and impaired spatial and associative memory performance (p<0.05). In the CP/CPPS group ERK1/2 phosphorylation levels were increased in the amygdala and nucleus accumbens, and decreased in the hippocampus and caudate nucleus. CONCLUSIONS Thus, prostate-derived cytokines, especially IL-1β, cross the blood brain barrier and may lead to enhanced ERK1/2 signaling in several brain areas, possibly underlying induction of CP/CPPS-related MHD. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e454 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Chao Hu More articles by this author Hualan Yang More articles by this author Yanfang Zhao More articles by this author Xiang Chen More articles by this author Yinying Dong More articles by this author Yehao Dong More articles by this author Jiefeng Cui More articles by this author Tongyu Zhu More articles by this author Ping Zheng More articles by this author Ching-Shwun Lin More articles by this author Jican Dai More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Impaired Spatial Memory Performance in Adult Wistar Rats Exposed to Low (5-20 cGy) Doses of 1 GeV/n (56)Fe Particles.

Prolonged deep space missions to planets and asteroids will expose astronauts to galactic cosmic radiation, comprised of low-linear energy transfer (LET) ionizing radiations, high-energy protons and high-Z and energy (HZE) particles, such as (56)Fe nuclei. In prior studies with rodents exposed to HZE particle radiation at doses likely to be encountered during deep space missions (<20 cGy) investigators reported impaired hippocampal-dependent neurocognitive performance and further observed substantial variation among the irradiated animals in neurocognitive impairment, ranging from no observable effects to severe impairment. These findings point to the importance of incorporating quantitative measures of interindividual variations into next generation risk assessment models of radiation risks on neurocognition. In this study, 269 male proven breeder Wistar rats were exposed to 1 GeV/n (56)Fe at doses of 0, 5, 10, 15 and 20 cGy, and tested for spatial memory performance on the Barnes maze at three months after exposure. The radiation response data were compared using changes in mean cohort performance and by the proportion of poor responders using the performance benchmark of two standard deviations below the mean value among the sham-irradiated cohort. Acute exposures to mission-relevant doses of 1 GeV/n (56)Fe reduced the mean spatial memory performance at three months after exposure (P < 0.002) and increased the proportions of poor performers, 2- to 3-fold. However, a substantial fraction of animals in all exposure cohorts showed no detectable change in performance, compared to the distribution of sham-irradiated animals. Our findings suggest that individualized metrics of susceptibility or resistance to radiation-induce changes in neurocognitive performance will be advantageous to the development of probabilistic risk assessment models for HZE-induced neurocognitive impairment.

Reduced grid-cell-like representations in adults at genetic risk for Alzheimer's disease.

Alzheimer's disease (AD) manifests with memory loss and spatial disorientation. AD pathology starts in the entorhinal cortex, making it likely that local neural correlates of spatial navigation, particularly grid cells, are impaired. Grid-cell-like representations in humans can be measured using functional magnetic resonance imaging. We found that young adults at genetic risk for AD (APOE-ε4 carriers) exhibit reduced grid-cell-like representations and altered navigational behavior in a virtual arena. Both changes were associated with impaired spatial memory performance. Reduced grid-cell-like representations were also related to increased hippocampal activity, potentially reflecting compensatory mechanisms that prevent overt spatial memory impairment in APOE-ε4 carriers. Our results provide evidence of behaviorally relevant entorhinal dysfunction in humans at genetic risk for AD, decades before potential disease onset.

Optogenetic activation of intracellular adenosine A2A receptor signaling in the hippocampus is sufficient to trigger CREB phosphorylation and impair memory.

Human and animal studies have converged to suggest that caffeine consumption prevents memory deficits in aging and Alzheimer’s disease through the antagonism of adenosine A2A receptors (A2AR). To test if A2AR activation in hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A2AR, we have developed a chimeric rhodopsin-A2AR protein (optoA2AR), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine binding pockets) fused to the intracellular loop of A2AR to confer specific A2AR signaling. The specificity of the optoA2AR signaling was confirmed by light-induced selective enhancement of cAMP and phospho-MAPK (but not cGMP) levels in HEK293 cells, which was abolished by a point mutation at the C-terminal of A2AR. Supporting its physiological relevance, optoA2AR activation and the A2AR agonist CGS21680 produced similar activation of cAMP and phospho-MAPK signaling in HEK293 cells, of pMAPK in nucleus accumbens, of c-Fos/pCREB in hippocampus and similarly enhanced long-term potentiation in hippocampus. Remarkably, optoA2AR activation triggered a preferential phospho-CREB signaling in hippocampus and impaired spatial memory performance while optoA2AR activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A2AR signaling in hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A2AR signaling and functions depend on intracellular A2AR loops, prompts the possibility of targeting the intracellular A2AR interacting partners to selectively control different neuropsychiatric behaviors.