Applicability of an immersive virtual reality system for assessing route learning in older adults / Aplicabilidade de um sistema de realidade virtual imersivo para avaliação da aprendizagem de rotas em idosos

ABSTRACT. Spatial orientation is defined as the ability to find one's way around an environment, follow familiar routes, recognize places, and learn new routes. Spatial disorientation is one of the early symptoms of Alzheimer's disease (AD), and traditional cognitive evaluation lacks ecological validity. Therefore, new assessment methods are needed for the early identification of this cognitive impairment. Objective: This study aimed to compare the applicability and stability of an immersive virtual reality (VR) system developed to assess route learning between older adults with and without mild cognitive impairment (MCI). Methods: The study sample included 43 older adults: 22 without MCI and 23 with MCI. Applicability was assessed based on the recording of adverse events and the sense of presence reported through questionnaires. The Mann-Whitney U test was applied to compare the applicability of the Spatial Orientation in Immersive Virtual Environment Test (SOIVET)-Route task between older adults with and without MCI. Both short- and long-term stabilities of the task were evaluated using the intraclass correlation coefficient (ICC). Results: The mean age of participants was 71.4 years (SD=5.5). A minimum number of adverse events (mean=1.46; SD=2.11) and high levels of presence (mean=138.04; SD=14.80) were reported, and there was no difference between groups with and without MCI. A good to excellent correlation was found for short-term stability (CCI 0.78) and a reasonable correlation was found for long-term stability (CCI 0.58). Conclusions: The VR system was applicable for older adults and showed a good to excellent correlation for short-term stability.

RESUMO. Orientação espacial é a capacidade de encontrar um caminho em um ambiente, seguir rotas familiares, reconhecer lugares e aprender novas rotas. A desorientação espacial é um dos primeiros sintomas da doença de Alzheimer, e a avaliação cognitiva tradicional carece de validade ecológica. Diante disso, novos métodos de avaliação são necessários para a identificação precoce desse comprometimento cognitivo. Objetivo: Este estudo teve como objetivo comparar a aplicabilidade e a estabilidade de um sistema de realidade virtual imersivo desenvolvido para avaliar a aprendizagem de rotas entre idosos com e sem comprometimento cognitivo leve (CCL). Métodos: Participaram do estudo 43 idosos: 22 sem CCL e 23 com CCL. A aplicabilidade foi avaliada por meio do registro de eventos adversos e pela sensação de presença relatados. O teste de Mann-Whitney foi aplicado para comparar a aplicabilidade da tarefa SOIVET-Route entre idosos com e sem CCL. A estabilidade da tarefa em curto e longo prazo foi avaliada pelo coeficiente de correlação intraclasse (ICC). Resultados: A idade média dos participantes foi de 71,4 anos (desvio padrão — DP=5,5). Em relação à aplicabilidade, encontramos mínimo relato de sintomas adversos (média=1,46; DP=2,11) e altos níveis de sensação de presença (média 138,04; DP=14,80), e não houve diferença entre os grupos com e sem CCL. Ao analisarmos a estabilidade, encontramos de boa a excelente correlação em curto prazo (CCI=0,78) e uma correlação razoável em longo prazo (CCI=0,58). Conclusões: O sistema de realidade virtual foi aplicável em idosos e mostrou boa correlação na estabilidade de curto prazo.

Análise do primeiro evento-teste de Santa Catarina no contexto da pandemia da COVID-19, em julho de 2021: um relato de experiência / Análisis del primer evento-prueba de Santa Catarina, Brasil, en el contexto de la pandemia COVID-19 en julio de 2021: relato de experiencia / Analysis of the first test event in Santa Catarina, Brazil, in the context of the COVID-19 pandemic in July 2021: an experience report

Este estudo visou descrever a gestão e os resultados do evento-teste para flexibilização das medidas de distanciamento em Santa Catarina, Brasil. Trata-se de relato de experiência que descreveu os resultados do evento-teste, realizado em julho de 2021, quando os participantes foram submetidos ao teste diagnóstico de reação em cadeia da polimerase em tempo real 72-48 horas antes, sendo monitorados por 15 dias. Os desfechos analisados foram a infecção pelo SARS-CoV-2 até 14 dias após o evento e a presença de sintomas. Entre 313 participantes, a média de idade foi de 45,1 anos e 54,3% eram do sexo feminino. No monitoramento, 7,7% (24) dos participantes contactados relataram sintomas compatíveis com infecção, embora, dos 240 que compareceram para testagem pós-evento, nenhum resultado tenha acusado presença do vírus. Não houve registro de casos de COVID-19 pós-evento. Sugere-se realização de outros eventos-teste para avaliar as recomendações indicadas.

Este estudio tuvo como objetivo describir la gestión y los resultados del evento test para flexibilizar las medidas de distanciamiento en Santa Catarina, Brasil. Este es un relato de experiencia que describe los resultados del evento, realizado en julio de 2021 y para el cual, los participantes se sometieron a la prueba diagnóstica de reacción en cadena de la polimerasa en tiempo real, 72-48 horas antes, monitoreados durante 15 días. Los desenlaces analizados fueron la infección por SARS-CoV-2 hasta 14 días después del evento y presencia de síntomas. Entre 313 participantes, la edad promedio fue de 45,1 años y 54,3% fueran del sexo femenino. En el seguimiento, 7,7% (24) reportaron síntomas compatibles con infección, pero de los 240 que acudieron a los exámenes posteriores al evento, ninguno de los resultados detectó virus. No se informaron casos de COVID-19 posteriores al evento. Se sugiere realizar otros eventos de prueba para evaluar las recomendaciones indicadas.

This study aimed to describe the management and results of the test event for evaluating relaxation of social distancing measures in Santa Catarina, Brazil. This is an experience report that described results of the test event carried out in July 2021 and for which the participants underwent real-time polymerase chain reaction diagnostic testing 72-48 hours before the event and had follow-up for 15 days afterwards. The outcomes analyzed were SARS-CoV-2 infection up to 14 days after the event and presence of symptoms. Among 313 participants, the mean age was 45.1 years and 54.3% were female. During follow-up, 7.7% (24) of the contacted participants reported symptoms compatible with infection, but of the 240 who attended post-event testing, none of the results detected the presence of the virus. No post-event COVID-19 cases were reported. We suggest that other test events be carried out to evaluate the recommendations indicated.

Ultrasonic control of neurite outgrowth direction.

This study investigated a method to control neurite outgrowth direction using ultrasound vibration. An ultrasound cell culture dish comprising a glass-bottom culture surface and a glass disc with an ultrasound transducer was fabricated, and undifferentiated neuron-like PC12 cells were grown on the dish as an adherent culture. The 78 kHz resonant concentric flexural vibration mode of the dish was used to quantitatively evaluate the neurite outgrowth direction and length. Time-lapse imaging of cells was performed for 72 h under ultrasound excitation. Unsonicated neurites grew in random directions, whereas neurite outgrowth was circumferentially oriented during ultrasonication in a power-dependent manner. The neurite orientation correlated with the spatial gradient of the ultrasound vibration, implying that neurites tend to grow in directions along which the vibrational amplitude does not change. Ultrasonication with 30 Vpp for 72 h increased the neurite length by 99.7% compared with that observed in unsonicated cells.

Integrating pheromonal and spatial information in the amygdalo-hippocampal network.

Vomeronasal information is critical in mice for territorial behavior. Consequently, learning the territorial spatial structure should incorporate the vomeronasal signals indicating individual identity into the hippocampal cognitive map. In this work we show in mice that navigating a virtual environment induces synchronic activity, with causality in both directionalities, between the vomeronasal amygdala and the dorsal CA1 of the hippocampus in the theta frequency range. The detection of urine stimuli induces synaptic plasticity in the vomeronasal pathway and the dorsal hippocampus, even in animals with experimentally induced anosmia. In the dorsal hippocampus, this plasticity is associated with the overexpression of pAKT and pGSK3ß. An amygdalo-entorhino-hippocampal circuit likely underlies this effect of pheromonal information on hippocampal learning. This circuit likely constitutes the neural substrate of territorial behavior in mice, and it allows the integration of social and spatial information.

Deep learning-based cross-classifications reveal conserved spatial behaviors within tumor histological images.

Histopathological images are a rich but incompletely explored data type for studying cancer. Manual inspection is time consuming, making it challenging to use for image data mining. Here we show that convolutional neural networks (CNNs) can be systematically applied across cancer types, enabling comparisons to reveal shared spatial behaviors. We develop CNN architectures to analyze 27,815 hematoxylin and eosin scanned images from The Cancer Genome Atlas for tumor/normal, cancer subtype, and mutation classification. Our CNNs are able to classify TCGA pathologist-annotated tumor/normal status of whole slide images (WSIs) in 19 cancer types with consistently high AUCs (0.995 ± 0.008), as well as subtypes with lower but significant accuracy (AUC 0.87 ± 0.1). Remarkably, tumor/normal CNNs trained on one tissue are effective in others (AUC 0.88 ± 0.11), with classifier relationships also recapitulating known adenocarcinoma, carcinoma, and developmental biology. Moreover, classifier comparisons reveal intra-slide spatial similarities, with an average tile-level correlation of 0.45 ± 0.16 between classifier pairs. Breast cancers, bladder cancers, and uterine cancers have spatial patterns that are particularly easy to detect, suggesting these cancers can be canonical types for image analysis. Patterns for TP53 mutations can also be detected, with WSI self- and cross-tissue AUCs ranging from 0.65-0.80. Finally, we comparatively evaluate CNNs on 170 breast and colon cancer images with pathologist-annotated nuclei, finding that both cellular and intercellular regions contribute to CNN accuracy. These results demonstrate the power of CNNs not only for histopathological classification, but also for cross-comparisons to reveal conserved spatial behaviors across tumors.

Isoform-specific roles for AKT in affective behavior, spatial memory, and extinction related to psychiatric disorders.

AKT is implicated in neurological disorders. AKT has three isoforms, AKT1/AKT2/AKT3, with brain cell type-specific expression that may differentially influence behavior. Therefore, we examined single Akt isoform, conditional brain-specific Akt1, and double Akt1/3 mutant mice in behaviors relevant to neuropsychiatric disorders. Because sex is a determinant of these disorders but poorly understood, sex was an experimental variable in our design. Our studies revealed AKT isoform- and sex-specific effects on anxiety, spatial and contextual memory, and fear extinction. In Akt1 mutant males, viral-mediated AKT1 restoration in the prefrontal cortex rescued extinction phenotypes. We identified a novel role for AKT2 and overlapping roles for AKT1 and AKT3 in long-term memory. Finally, we found that sex-specific behavior effects were not mediated by AKT expression or activation differences between sexes. These results highlight sex as a biological variable and isoform- or cell type-specific AKT signaling as potential targets for improving treatment of neuropsychiatric disorders.

HippoBellum: Acute Cerebellar Modulation Alters Hippocampal Dynamics and Function.

Here we examine what effects acute manipulation of the cerebellum, a canonically motor structure, can have on the hippocampus, a canonically cognitive structure. In male and female mice, acute perturbation of the cerebellar vermis (lobule 4/5) or simplex produced reliable and specific effects in hippocampal function at cellular, population, and behavioral levels, including evoked local field potentials, increased hippocampal cFos expression, and altered CA1 calcium event rate, amplitudes, and correlated activity. We additionally noted a selective deficit on an object location memory task, which requires objection-location pairing. We therefore combined cerebellar optogenetic stimulation and CA1 calcium imaging with an object-exploration task, and found that cerebellar stimulation reduced the representation of place fields near objects, and prevented a shift in representation to the novel location when an object was moved. Together, these results clearly demonstrate that acute modulation of the cerebellum alters hippocampal function, and further illustrates that the cerebellum can influence cognitive domains.SIGNIFICANCE STATEMENT The cerebellum, a canonically motor-related structure, is being increasingly recognized for its influence on nonmotor functions and structures. The hippocampus is a brain region critical for cognitive functions, such as episodic memory and spatial navigation. To investigate how modulation of the cerebellum may impact the hippocampus, we stimulated two sites of the cerebellar cortex and examined hippocampal function at multiple levels. We found that cerebellar stimulation strongly modulates hippocampal activity, disrupts spatial memory, and alters object-location processing. Therefore, a canonically cognitive brain area, the hippocampus, is sensitive to cerebellar modulation.

Comportamiento epidemiológico de la leptospirosis en México durante el periodo 2013-2019 / Epidemiologic behavior of leptospirosis in México during the period 2013-2019

RESUMEN Objetivo Determinar el comportamiento temporal y espacial de la leptospirosis en México durante el periodo 2013-2019. Materiales y Métodos Se utilizó la información depositada en los boletines epidemiológicos del Sistema Nacional de Vigilancia Epidemiológica de México. Para determinar el comportamiento espacial se construyeron canales endémicos y análisis de series de tiempo. Para determinar el comportamiento espacial, se utilizó el modelo estadístico espacial Scan. Resultados Se determinó que los casos de leptospirosis en México se presentan todo el año; sin embargo, los picos endémicos se observaron en los meses de agosto, septiembre y octubre. Con respecto al comportamiento espacial, no se determinó ninguna agrupación estadísticamente; no obstante, los estados con la mayor prevalencia fueron: Sinaloa, con 146.7 casos por cada millón de habitantes, y Tabasco, con 142 casos por cada millón de habitantes. Discusión La leptospirosis es una enfermedad influenciada por los hábitos y las costumbres de la población, al igual que por variables climatológicas que favorecen el contacto con el agente etiológico. Esto coincide con lo reportado por otros estudios que han determinado que la incidencia de leptospirosis aumenta durante la época de lluvia y que esta enfermedad se relaciona con actividades de recreación en zonas tropicales. Conclusiones La leptospirosis es una enfermedad zoonótica emergente de gran importancia en México, que se presenta con mayor frecuencia en época de lluvias. Los estados de Sinaloa y Tabasco son los más afectados.(AU)

ABSTRACT Objetive To determine the temporal and spatial behavior of leptospirosis in Mexico during the period 2013-2019. Materials and Methods It was used the information deposited in the epidemiological bulletins of National System of Epidemiological Surveillance of Mexico. To determine spatial behavior, endemic channels and time series analyzes were constructed. The spatial statistical model Scan was used to determine the spatial behavior. Results It was determined that leptospirosis cases in Mexico occur throughout the year, however endemic peaks were observed during the months of August, September and October. Regarding to spatial behavior, it was not statistically determined any aggrupation, nevertheless the States with the highest prevalence were Sinaloa with 146.7 cases per million of habitants and Tabasco with 142 cases per million of habitants. Discussion Leptospirosis is a disease which is affected by habits and customs of the populations, as well as by climatological events, favoring the contact with the etiological agent, which coincides with that reported in other studies, in which it was determined that leptospirosis incidence increases during the rainy season, likewise, it was reported that this disease is related to recreational activities in tropical areas. Conclusions To date leptospirosis is an important emerging zoonotic disease in Mexico, the disease occurs more frequently during rainy season, being Sinaloa and Tabasco the most affected States by this disease.(AU)

Delayed effects of a single-dose whole-brain radiation therapy on glucose metabolism and myelin density: a longitudinal PET study.

PURPOSE: Radiotherapy is an important treatment option for brain tumors, but the unavoidable irradiation of normal brain tissue can lead to delayed cognitive impairment. The mechanisms involved are still not well explained and, therefore, new tools to investigate the processes leading to the delayed symptoms of brain irradiation are warranted. In this study, positron emission tomography (PET) is used to explore delayed functional changes induced by brain irradiation. MATERIALS AND METHODS: Male Wistar rats were subjected to a single 25-Gy dose of whole brain X-ray irradiation, or sham-irradiation. To investigate delayed effects of radiation on cerebral glucose metabolism and myelin density, 18F-fluorodeoxyglucose (18F-FDG) PET scans were performed at baseline and on day 64 and 94, whereas N-11C-methyl-4,4'-diaminostilbene (11C-MeDAS) PET scans were performed at baseline and on day 60 and 90 post-irradiation. In addition, the open field test (OFT) and novel spatial recognition (NSR) test were performed at baseline and on days 59 and 89 to investigate whether whole brain irradiation induces behavioral changes. RESULTS: Whole-brain irradiation caused loss of bodyweight and delayed cerebral hypometabolism, with 18F-FDG uptake in all brain regions being significantly decreased in irradiated rat on day 64 while it remained unchanged in control animals. Only amygdala and cortical brain regions of irradiated rats still showed reduced 18F-FDG uptake on day 94. 11C-MeDAS uptake in control animals was significantly lower on days 60 and 90 than at the baseline, suggesting a reduction in myelin density in young adults. In irradiated animals, 11C-MeDAS uptake was similarly reduced on day 60, but on day 90 tracer uptake was somewhat increased and not significantly different from baseline anymore. Behavioral tests showed a similar pattern in control and irradiated animals. In both groups, the OFT showed significantly reduced mobility on days 59 and 89, whereas the NSR did not reveal any significant changes in spatial memory over time. Interestingly, a positive correlation between the NSR and 11C-MeDAS uptake was observed in irradiated rats. CONCLUSIONS: Whole-brain irradiation causes delayed brain hypometabolism, which is not accompanied by white matter loss. Irradiated animals showed similar behavioral changes over time as control animals and, therefore, cerebral hypometabolism could not be linked to behavioral abnormalities. However, spatial memory seems to be associated with myelin density in irradiated rats.

An Efficient Single-session Spatial Skill Trainer for Robot-assisted Surgery: A Randomized Trial.

STUDY OBJECTIVE: To introduce and examine a single session of spatial skill training as an efficient means of improving surgical suturing performance in robot-assisted surgery. DESIGN: A randomized, controlled trial. SETTING: A tertiary university medical center in Israel. PARTICIPANTS: A purposive sample composed of 41 residents with no robotic suturing skills. INTERVENTIONS: A computer-based simulator training of spatial skills. MEASUREMENTS AND MAIN RESULTS: Participants were randomly assigned to training (n = 21: mean age of 34 years [standard deviation (SD) = 1.92]) and control (n = 20: mean age of 32 years [SD = 3.17]) conditions. The training group underwent a session of spatial skills training, whereas the control group engaged in a neutral activity. After 1 participant was lost to the follow-up of the posttraining performance test, data of 40 participants were analyzed. Robotic suturing task performance with the da Vinci Skills Simulator (Intuitive Surgical, Sunnyvale, CA) was evaluated using the da Vinci Skills Simulator built-in measure of "excess tissue piercing" and an expert rating of "tissue tearing." The mean number of excess tissue piercing after training (but not after the neutral activity) was significantly lower than before training (3.25 [SD = 1.996] vs 6.75 [SD = 3.68], respectively; p <.001), reflecting an improvement of 52% (decreasing the mean number of excess tissue piercing in a single suture by 3.5 excess piercing trials). After the interventions, the extent of tissue tearing was rated lower in the training group (p = .01), and there was no change in the control group (p = .14). CONCLUSION: We showed the efficiency of a training approach that focuses on spatial skills critical in robot-assisted surgery. We showed that surgeons who received a 1 session spatial skill training with a cognitive spatial skill trainer immediately improved the performance of a robotic suturing task compared with surgeons who did not receive such training.

The right look for the job: decoding cognitive processes involved in the task from spatial eye-movement patterns.

The aim of the study was not only to demonstrate whether eye-movement-based task decoding was possible but also to investigate whether eye-movement patterns can be used to identify cognitive processes behind the tasks. We compared eye-movement patterns elicited under different task conditions, with tasks differing systematically with regard to the types of cognitive processes involved in solving them. We used four tasks, differing along two dimensions: spatial (global vs. local) processing (Navon, Cognit Psychol, 9(3):353-383 1977) and semantic (deep vs. shallow) processing (Craik and Lockhart, J Verbal Learn Verbal Behav, 11(6):671-684 1972). We used eye-movement patterns obtained from two time periods: fixation cross preceding the target stimulus and the target stimulus. We found significant effects of both spatial and semantic processing, but in case of the latter, the effect might be an artefact of insufficient task control. We found above chance task classification accuracy for both time periods: 51.4% for the period of stimulus presentation and 34.8% for the period of fixation cross presentation. Therefore, we show that task can be to some extent decoded from the preparatory eye-movements before the stimulus is displayed. This suggests that anticipatory eye-movements reflect the visual scanning strategy employed for the task at hand. Finally, this study also demonstrates that decoding is possible even from very scant eye-movement data similar to Coco and Keller, J Vis 14(3):11-11 (2014). This means that task decoding is not limited to tasks that naturally take longer to perform and yield multi-second eye-movement recordings.

Melatonin rescued methotrexate-induced spatial deficit and hyperhomocysteinemia and increased asymmetric dimethylarginine in plasma and dorsal hippocampus in developing rats.

AIMS: With the improvement of the survival rates in children acute lymphoblastic leukemia (ALL), some children ALL survivors show impaired cognitive function. Methotrexate (MTX), an essential component in ALL treatment, has been reported to be related to neurologic sequelae and to increased oxidative stress through its interactions with enzymes in the folate pathway. Asymmetric dimethylarginine (ADMA) is the main endogenous inhibitor of nitric oxide synthase, and increased ADMA may result from increased oxidants. Melatonin is an antioxidant; however, its role in MTX neuropathy is not well studied. We developed a rat model mimicking child ALL treatment to explore peripheral and central homocysteine and ADMA regulation after MTX and found potential treatment choice. MAIN METHODS: Preweaning male Sprague-Dawley rats were used in this study. Experiment 1 evaluated spatial performance in rats with intrathecal (IT) MTX, intraperitoneal (IP) MTX, or combined IT and IP MTX, protocols mimicking ALL treatment in children. Experiment 2 focused on rats with combined IT and IP MTX, evaluating spatial performance and plasma and dorsal hippocampal homocysteine and ADMA levels, their regulation, and the protective effect of melatonin. KEY FINDINGS: Combined IT and IP MTX treatment caused in spatial deficits in developing rats, and melatonin restored the spatial performance. Alterations in peripheral and central homocysteine and ADMA concentrations and their regulation were found and could be alleviated by melatonin treatment. SIGNIFICANCES: Combined IP and IT MTX treatment caused spatial deficits in developing rats. Melatonin could restore spatial performance through alleviating the effects on the imbalance of oxidative stress.

Time scales and wave formation in non-linear spatial public goods games.

The co-evolutionary dynamics of competing populations can be strongly affected by frequency-dependent selection and spatial population structure. As co-evolving populations grow into a spatial domain, their initial spatial arrangement and their growth rate differences are important factors that determine the long-term outcome. We here model producer and free-rider co-evolution in the context of a diffusive public good (PG) that is produced by the producers at a cost but evokes local concentration-dependent growth benefits to all. The benefit of the PG can be non-linearly dependent on public good concentration. We consider the spatial growth dynamics of producers and free-riders in one, two and three dimensions by modeling producer cell, free-rider cell and public good densities in space, driven by the processes of birth, death and diffusion (cell movement and public good distribution). Typically, one population goes extinct, but the time-scale of this process varies with initial conditions and the growth rate functions. We establish that spatial variation is transient regardless of dimensionality, and that structured initial conditions lead to increasing times to get close to an extinction state, called ε-extinction time. Further, we find that uncorrelated initial spatial structures do not influence this ε-extinction time in comparison to a corresponding well-mixed (non-spatial) system. In order to estimate the ε-extinction time of either free-riders or producers we derive a slow manifold solution. For invading populations, i.e. for populations that are initially highly segregated, we observe a traveling wave, whose speed can be calculated. Our results provide quantitative predictions for the transient spatial dynamics of cooperative traits under pressure of extinction.

Understanding children's spatiality in cancer care environments: Untangling everyday practices around an IV-stand in a paediatric day-care ward.

Since the turn of the 21st century we see a renewed interest in the impact of hospital environments on children's well-being. In this article, we study the spatiality of children affected by cancer, i.e., their encounters with the day-care ward they are situated in. First we elaborate on these encounters through Schatzki's practice theory and Gibson's theory of affordances. Then we clarify our thinking in a case study and turn as empirical focus to a 'thing', an intravenous-pump and stand (IV-stand). The data used are field notes and videos shot by two children in a day-care ward, tinged with examples from literature and coincidental encounters with the IV-stand. Through carefully untangling everyday practices around the IV-stand, we show their complexity and offer a more nuanced understanding of child-friendly environments.

The kisspeptin derivative kissorphin reduces the acquisition, expression, and reinstatement of ethanol-induced conditioned place preference in rats.

Research has shown that opioids are involved in the rewarding effects of ethanol. Neuropeptide FF (NPFF) has been described as an anti-opioid peptide because, in many cases, it inhibits opioid and ethanol effects in rodents. Kissorphin (KSO) is a new peptide derived from kisspeptin-10 with structural similarities to NPFF. This peptide possesses NPFF-like biological activity in vitro. The aim of the current study was to investigate whether KSO (Tyr-Asn-Trp-Asn-Ser-Phe-NH2) influences the acquisition, expression, and reinstatement of ethanol-induced conditioned place preference (ethanol-CPP) in rats. The ethanol-CPP was established (conditioning for 5 days) by intraperitoneal (i.p.) administration of ethanol (1 g/kg, 20%, w/v) using an unbiased procedure. After that, one group of rats was used in final post-conditioning testing (expression of CPP) and the other group received a priming injection of ethanol after 10 days of extinction (reinstatement of CPP). Our experiments showed that KSO, given intravenously (i.v.) at the doses of 1, 3, and 10 nmol before every ethanol administration, inhibited the acquisition and, given acutely before the post-conditioning test or before the priming dose of ethanol, inhibited the expression and reinstatement of ethanol-CPP, respectively, in a dose-dependent manner. KSO given by itself neither induced place preference nor aversion and did not alter locomotor activity and coordination of rats. These results suggest that KSO can alter rewarding/motivational effects of ethanol. These data suggest this peptide possesses an anti-opioid character.

Inhibition of N-acylethanolamine acid amidase reduces nicotine-induced dopamine activation and reward.

Tobacco smoke is the leading preventable cause of death in the world and treatments aimed to increase success rate in smoking cessation by reducing nicotine dependence are sought. Activation of peroxisome proliferator-activated receptor-alpha (PPARα) by synthetic or endogenous agonists was shown to suppress nicotine-induced activation of mesolimbic dopamine system, one of the major neurobiological substrates of nicotine dependence, and nicotine-seeking behavior in rats and monkeys. An alternative indirect way to activate PPARα is inhibition of N-acylethanolamine acid amidase (NAAA), one of the major hydrolyzing enzyme for its endogenous agonists palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). We synthetized a novel specific brain permeable NAAA inhibitor, AM11095. We administered AM11095 to rats and carried out brain lipid analysis, a functional observational battery (FOB) to assess toxicity, in vivo electrophysiological recording from dopamine cells in the ventral tegmental area, brain microdialysis in the nucleus accumbens shell and behavioral experiments to assess its effect on nicotine -induced conditioned place preference (CPP). AM11095 (5 and 25 mg/kg, i.p.) was devoid of neurotoxic and behavioral effects and did not affect motor behavior and coordination. This NAAA inhibitor (5 mg/kg i.p.) increased OEA and PEA levels in the hippocampus and cortex, prevented nicotine-induced activation of mesolimbic dopamine neurons in the ventral tegmental area, nicotine-induced elevation of dopamine levels in the nucleus accumbens shell and decreased the expression of nicotine CPP. Our results indicate that NAAA inhibitors represent a new class of pharmacological tools to modulate brain PEA/PPARα signalling and show potential in the treatment of nicotine dependence.

Akt3 deletion in mice impairs spatial cognition and hippocampal CA1 long long-term potentiation through downregulation of mTOR.

AIM: Loss-of-function mutation of Akt3 in humans has been associated with microcephaly and cognitive defects. Two Akt isoforms, Akt1 and Akt3, are highly expressed in hippocampal pyramidal cells. We explored the roles of Akt1 and Akt3, respectively, in spatial cognition and underlying mechanisms. METHODS: We used Akt1 knockout (Akt1-KO) and Akt3 knockout (Akt3-KO) mice to examine the influence of Akt1 and Akt3 deficiency on spatial memory, as well as induction and maintenance of hippocampal CA1 NMDA receptor-dependent and protein synthesis-dependent long-term potentiation (LTP). RESULTS: Long-term spatial memory was impaired in Akt3-KO mice, but not in Akt1-KO mice, as assessed by the Morris water maze task. Akt3-KO and Akt1-KO mice displayed reductions in brain size without concurrent changes in the number of pyramidal cells or basal properties of synaptic transmission. One-train high-frequency stimulation (HFS × 1) induced NMDA receptor-dependent LTP in Akt3-KO mice and Akt1-KO mice. Four-train HFS (HFS × 4) induced rapamycin-sensitive long-LTP in Akt1-KO mice, but not Akt3-KO mice. Basal level of mTOR phosphorylation was reduced in Akt3-KO mice rather than Akt1-KO mice. HFS × 4 induced an elevation of mTOR and p70S6K phosphorylation in Akt1-KO mice, which led to enhanced 4EBP2 and eIF4E phosphorylation along with an increase in AMPA receptor protein. However, the same protocol of HFS × 4 failed to trigger the mTOR-p70S6K signalling cascade or increase 4EBP2 and eIF4E phosphorylation in Akt3-KO mice. CONCLUSION: The Akt3 deficiency via inactivation of mTOR suppresses HFS × 4-induced mTOR-p70S6K signalling to reduce phosphorylation of 4EBP and eIF4E, which impairs protein synthesis-dependent long-LTP and long-term spatial cognitive function.

5-HIAA induces neprilysin to ameliorate pathophysiology and symptoms in a mouse model for Alzheimer's disease.

Serotoninergic activation which decreases brain Aß peptides is considered beneficial in mouse models for Alzheimer's disease (AD), but the mechanisms involved remain unclear. Because growing evidence suggested that the stimulation of proteases digesting Aß, especially the endopeptidase neprilysin (NEP) may be effective for AD therapy/prevention, we explored the involvement of serotonin precursors and derivatives in NEP regulation. We found that 5-hydroxyindolacetic acid (5-HIAA), the final metabolite of serotonin, considered until now as a dead-end and inactive product of serotonin catabolism, significantly reduces brain Aß in the transgenic APPSWE mouse model for AD-related Aß pathology and in the phosphoramidon-induced cerebral NEP inhibition mouse model. 5-HIAA treatment improves memory performance in APPSWE mice. Furthermore, 5-HIAA and its precursors increase NEP level in vivo and in neuroblastoma cells. Inhibition of ERK 1/2 cascade by 5-HIAA or SCH772984 enhanced NEP levels, suggesting MAP-kinase pathway involvement in 5-HIAA-induced regulation of NEP expression. Our results provide the first demonstration that 5-HIAA is an active serotonin metabolite that increases brain Aß degradation/clearance and improves symptoms in the APPSWE mouse model for AD.

Rapid effects of sex steroids on zebra finch (Taeniopygia guttata) pair maintenance.

Although steroids are widely known to affect behavior through activation of nuclear/cytosolic receptors ("genomic" effects), steroids can also rapidly affect behavior via modulation of signal transduction pathways ("nongenomic," fast actions, or rapid effects). In zebra finches, there is evidence that sex steroids have context-specific effects on pair-maintenance behavior, on both acute and chronic timescales. Here, we quantified the effects of orally administered testosterone and 17ß-estradiol (E2) on pair-maintenance behavior. We show that E2 rapidly affects female, but not male, affiliative behavior profiles during a partner separation and reunion paradigm. More specifically, E2 rapidly (within 5-15 min of administration) increased females' spatial proximity to a partner. This effect was present regardless of breeding condition (water restriction or water ad libitum). Combined, these results contribute to a growing body of evidence implicating sex steroids in the regulation of prosocial behavior. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Electroacupuncture Ameliorates Cognitive Impairment and Spontaneous Low-Frequency Brain Activity in Rats with Ischemic Stroke.

BACKGROUND: To evaluate whether electroacupuncture (EA) at Baihui (DU20) and Shenting (DU24) acupoints could improve cognitive function and enhance spontaneous low-frequency brain activity in rats with ischemic stroke. METHODS: Total 36 rats were randomly divided into 3 groups-the sham surgery (Sham) group, the middle cerebral artery occlusion induced cognitive deficit (MICD) group, and the MICD with EA (MICD + EA) treatment group. The rats in MICD + EA group received EA treatment at DU20 and DU24 acupoints for 14 consecutive days after the surgery. The Morris water maze test was performed to assess the spatial learning and memory ability of the rats. Magnetic resonance imaging (MRI) was used to investigate the infarction volume and spontaneous low-frequency brain activity of each group. RESULTS: After EA for 14 days, the learning and memory ability of the MICD rats was improved, and the brain infarction volume was reduced. Furthermore, basing on the fMRI amplitude of low-frequency fluctuation (ALFF) analysis, the decreased ALFF of the MICD rats was found in auditory cortex, cingulate gyrus, lateral nucleus group of dorsal thalamus, hippocampus, motor cortex, prelimbic cortex, retrosplenial cortex, and sensory cortex compared with the rats in sham group. However, these suppressive regions were notably attenuated after EA treatment. CONCLUSIONS: Our results suggested that EA at DU20 and DU24 acupoints could ameliorate cognitive impairment in rats with ischemic stroke, and the protective effect of EA may attribute to reactivating the cognition-related brain regions, such as hippocampus, retrosplenial cortex, cingulate gyrus, prelimbic cortex, and sensory cortex.