Spatial Reversal Research Articles

Indomethacin restores loss of hippocampal neurogenesis and cholinergic innervation and reduces innate immune expression and reversal learning deficits in adult male and female rats following adolescent ethanol exposure.

Adolescent intermittent ethanol (AIE) exposure causes long-term changes in the brain and behavior of adult male rodents, including persistent induction of innate immune pathways, reductions in hippocampal neurogenic and forebrain cholinergic neuronal markers, and reversal learning deficits. The current study tests the hypothesis that proinflammatory induction mediates AIE-induced (1) loss of adult neurogenesis (i.e., doublecortin (DCX) expressing immature neurons), (2) reductions in forebrain and hippocampal cholinergic markers, and (3) reversal learning deficits. Male and female rats underwent AIE (5.0g/kg/day ethanol or water, i.g., 2 day-on/2 day-off from postnatal day (PND) 25-54), followed by a 2-week regimen of the anti-inflammatory compound indomethacin (4.0g/kg/day, PND 56-69) or vehicle, after which one cohort was euthanized for immunohistochemical markers (PND 70) and the second underwent the Morris water maze to assess reversal learning. AIE reduced adult (PND 70) DCX+ immunoreactivity (IR) and increased hippocampal expression of the innate immune signal's high-mobility group box protein 1 (HMGB1 + IR) and cyclooxygenase-2 (COX-2+ IR) in adult male and female rats. AIE also reduced choline acetyltransferase (ChAT+IR) in the basal forebrain and co-labeling of hippocampal vesicular acetylcholine transporter (VAChT+) cholinergic terminals on DCX + IR neurons. Indomethacin treatment after AIE restored molecular endpoints to control levels and rescued AIE-induced reversal learning deficits in the Morris water maze in both sexes. Of note, indomethacin produced several adverse effects selectively in control conditions, highlighting the uniquely beneficial effect of indomethacin in AIE rats. These data suggest that in males and females, (1) AIE persistent neuroimmune induction mediates both the loss of adult hippocampal DCX and loss of basal forebrain cholinergic neurons and their innervation to hippocampal targets, and (2) anti-inflammatory indomethacin treatment following AIE that restores these persistent molecular pathologies also restores spatial reversal learning deficits.

Emergent optical nonreciprocity and chirality-controlled magneto-optical resonance in a hybrid magneto–chiral metamaterial

Broken spatial and time reversal symmetries in materials often give rise to new emergent phenomena in the interaction between light and matter. The combination of chirality and broken time reversal symmetry in a magnetic field leads to magneto–chiral phenomena, such as the nonreciprocity of transmission. Here, we construct a terahertz hybrid metamaterial that combines the natural optical activity of a chiral metallic gammadion bilayer and the magneto-optical activity of semiconductor indium antimonide in a magnetic field. We report a resonant magneto–chiral effect that leads to polarization-independent nonreciprocal optical transmittance. Furthermore, we discover a magneto-optical Faraday effect that is resonantly controlled by the natural optical activity of the chiral gammadion bilayer. Unlike optical activity due to chirality, the novel Faraday effect is odd under time reversal. Both phenomena are activated by a modest magnetic field, which may open doors for their potential applications in polarization-independent optical isolation and highly efficient polarization control at terahertz frequencies.

Revenues of Russian Subfederal Budgets under the Pandemic: A Spatial Reversal

Revenues of Russian Subfederal Budgets under the Pandemic: A Spatial Reversal

The novel FKBP51‐Hsp90 interaction inhibitor attenuates high‐fat diet induced cognitive impairment

AbstractBackgroundObesity increases the risk of several chronic diseases, such as type 2 diabetes mellitus, insulin resistance, and Alzheimer disease. As one of the co‐chaperones of heat shock protein 90 (Hsp90), FK506‐binding protein 51 (FKBP51) is an important regulator of metabolic and cognitive dysfunction. FKBP51 knockout mice are resistant to diet‐induced obesity, exhibit elevated glucose and insulin tolerance and have less endogenous tau. FKBP51 overexpression preserves tau and impairs spatial reversal learning and memory. Our group has identified a new family of FKBP51 inhibitors that can disrupt FKBP51‐Hsp90 interactions. Previous study has shown that our inhibitors can dose‐dependently reduce lipid accumulation in adipocytes differentiated from primary human mesenchymal stem cells and stimulate neurite outgrowth in differentiated neuroblastoma SH‐SY5Y cells. This study aims to investigate the potential roles of our inhibitors on metabolic and cognitive dysfunction in vivo.MethodsPharmacokinetic studies have been performed at first. Plasma and brain samples were collected and analyzed by liquid chromatography‐mass spectrometry. Male C57BL/6J mice were fed either the control or high‐fat diet (HFD) for 4 weeks and then treated with vehicle or inhibitor E8 (20 mg/kg, s.c.) and their respective diets for another 4 weeks. Behaviors, body composition measuremnets by EchoMRI, fasting glucose/insulin detections and glucose/insulin tolerance tests were performed during the last week. Hippocampus was collected for western blot, RNA sequencing and quantitative real‐time PCR analysis.ResultsAfter subcutaneous injection, E8 can be quickly absorbed into the blood and penetrate the blood‐brain barrier. In HFD model, E8 can attenuate the impairment of locomotor activity and short‐term memory. But it could neither reduce body weight gain nor improve insulin sensitivity and glucose/insulin tolerance. In the hippocampus, E8 reduces the elevated p‐tau (Ser214)/tau levels induced by HFD but does not show any effects on insulin signaling. It suggests that E8 reverses the behavioral impairments independently of metabolic regulation in vivo. The underlying mechanisms were further investigated by RNA sequencing and quantitative real‐time PCR analysis.ConclusionWe showed that inhibiting FKBP51‐Hsp90 interactions with small molecules provides novel therapeutic targets on cognitive dysfunction in obesity.

Sexual dimorphism in spatial learning and brain metabolism after exposure to a western diet and early life stress in rats

Prolonged daily intake of Western-type diet rich in saturated fats and sugars, and exposure to early life stress have been independently linked to impaired neurodevelopment and behaviour in animal models. However, sex-specific effects of both environmental factors combined on spatial learning and memory, behavioural flexibility, and brain oxidative capacity have still not been addressed. The current study aimed to evaluate the impact of maternal and postnatal exposure to a high-fat and high-sugar diet (HFS), and exposure to early life stress by maternal separation in adult male and female Wistar rats. For this purpose, spatial learning and memory and behavioural flexibility were evaluated in the Morris water maze, and regional brain oxidative capacity and oxidative stress levels were measured in the hippocampus and medial prefrontal cortex. Spatial memory, regional brain oxidative metabolism, and levels of oxidative stress differed between females and males, suggesting sexual dimorphism in the effects of a HFS diet and early life stress. Males fed the HFS diet performed better than all other experimental groups independently of early life stress exposure. However, behavioural flexibility evaluated in the spatial reversal leaning task was impaired in males fed the HFS diet. In addition, exposure to maternal separation or the HFS diet increased the metabolic capacity of the prefrontal cortex and dorsal hippocampus in males and females. Levels of oxidative stress measured in the latter brain regions were also increased in groups fed the HFS diet, but maternal separation seemed to dampen regional brain oxidative stress levels. Therefore, these results suggest a compensatory effect resulting from the interaction between prolonged exposure to a HFS diet and early life stress.

Prenatal stress and fluoxetine exposure in mice differentially affect repetitive behaviors and synaptic plasticity in adult male and female offspring

Autism spectrum disorder (ASD) is characterized by social communication impairments with restricted and repetitive behaviors (RRBs). The increase in prevalence of ASD and the heterogeneity of symptom severity may arise from a complex interaction of environmental and genetic factors that alter synaptic plasticity. Maternal stress during pregnancy, which is linked to depression, may be one risk factor for an ASD phenotype in offspring. Selective serotonin reuptake inhibitor (SSRI) treatment can be effective in alleviating maternal depression but prenatal SSRI exposure itself may be a risk factor for autism in offspring. The present study investigated in C57BL/6J pregnant mice whether restraint stress (G4–18) and/or treatment with the SSRI fluoxetine (G8–18) affects autism-related behaviors and hippocampal synaptic plasticity in male and female offspring. The findings indicate that restraint stress reduces preference for sucrose reward in pregnant dams that is reversed by fluoxetine. In adult male offspring, combined prenatal stress and SSRI exposure increased self-grooming and impaired spatial reversal learning. In adult female offspring, the prenatal experiences did not affect self-grooming, but restraint stress alone or SSRI exposure alone impaired spatial reversal learning. Prenatal stress reduced anxiety-related behavior in male and female offspring. Further, LTP induced by theta-burst stimulation of Schaffer-commissural afferents in field CA1 was significantly reduced in female offspring exposed to prenatal stress alone or combination with fluoxetine. Together, these findings suggest that exposure to prenatal stress, SSRI treatment or the combination differentially affects male and female offspring in autism-like behaviors and synaptic plasticity.

Impairments in operant probabilistic reversal learning in BTBR T+tf/J male and female mice

Autism spectrum disorder (ASD) presents with two core symptoms, impairments in social communication and the presence of restricted, repetitive behaviors (RRBs). RRBs are commonly linked to a lack of behavioral flexibility, having a significant negative impact on daily functioning for ASD individuals and their caregivers. Commonly utilized tests of behavioral flexibility employ a traditional deterministic reward approach where choices are either correct or incorrect throughout testing. The incorporation of an 80 %/20 % probabilistic reversal learning paradigm allows for the examination of flexible behavior in the face of variable outcomes, a more ecologically relevant approach. In this task, one specific choice is reinforced on 80 % of trials and the opposite or incorrect choice is reinforced on 20% of trials. Upon successful discrimination learning, the reward contingencies are switched so that the correct choice is now reinforced 20% of trials and the incorrect choice reinforced 80 % of trials, making it the new optimal choice. This translational task has been previously validated in ASD individuals and animal models of ASD, including the BTBR T + tf/J strain. Our lab and others have demonstrated that male BTBR T + tf/J mice have higher expression of lower order RRBs and display deficits in spatial probabilistic reversal learning tasks using a T-maze apparatus. Instead, female BTBR mice do not express the same lower order RRBs and results are mixed on whether females demonstrate similar probabilistic reversal learning deficits in a T-maze. Therefore, the purpose of this study was to assess the validity of using operant chambers to examine BTBR mouse performance on an 80 %/20 % probabilistic reversal learning task and to also examine the sex-specific differences in reversal learning performance in both mouse strains. Results show that BTBR mice, irrespective of sex, were impaired on the reversal learning, requiring more days and trials to reach reversal criterion compared to C57BL/6J mice. These results parallel previous strain findings in the spatial dependent T-maze task in male mice. Further error analysis showed that the impaired behavioral flexibility was due to elevated regressive errors and lose-shift probabilities. BTBR mice have more difficulty maintaining new choice patterns compared to C57BL/6J mice, which supports findings utilizing a spatial T-maze task. Together, these findings further support the use of the BTBR mouse as preclinical models of ASD due to their validity as an ASD model.

Impacts of neonatal methylmercury on behavioral flexibility and learning in spatial discrimination reversal and visual signal detection tasks

Early postnatal development in rodents is sensitive to neurotoxic effects of the environmental contaminant, methylmercury. While juvenile and adolescent exposure also produce long-term impairments in behavior, the outcome of neonatal exposure is less understood. Neural development during the neonatal period in rodents is akin to that seen in humans during the third trimester of pregnancy but methylmercury exposure occurring during the neonatal period has not been modeled, partly because breast milk is a poor source of bioavailable methylmercury. To examine this developmental period, male Long-Evans rats were exposed to 0, 80, or 350 µg/kg/day methylmercuric chloride from postnatal days 1–10, the rodent neonatal period. As adults, behavioral flexibility, attention, memory, and expression of the dopamine transporter in these rats was assessed. Rats exhibited changes in behavioral flexibility assessed in a spatial discrimination reversal procedure. Those rats exposed to the highest dose of methylmercury displayed subtly altered patterns of perseveration compared to control animals. During acquisition of the attention/memory procedure, rats exposed to this dose also had slower acquisition, and achieved lower overall accuracy during training, compared to controls despite neither attention nor memory being affected once the task was acquired. Finally, dopamine transporter expression in the striatum, prefrontal cortex, and hippocampus was unchanged in these adult rats. The results of this study replicate the trend of findings seen with exposure during gestation or during adolescence.

Baseline-Free Damage Imaging Algorithm Using Spatial Frequency Domain Virtual Time Reversal

Structural health monitoring techniques are widely used in industry applications to guarantee the integrity of several types of components. This article proposes a baseline-free damage imaging algorithm based on Spatial Frequency Domain Virtual Time Reversal (SFD-VTR). Virtual time reversal (VTR) is an alternative to traditional time reversal as it reduces the burden of physically back-propagating re-emitted signals by applying signal operations between the transmitted and received waveforms. However, VTR rely on the reconstruction of the emitted signal in the time domain, which involves significant data manipulation causing sampling errors of reconstructed signals. Novel SFD-VTR damage indices were here proposed to enhance defect detection as they do not require the time domain reconstruction of re-emitted signals. Experimental results showed that the proposed algorithm was able to localise material flaws and can be use as Human Machine Interface (HMI).

Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's disease.

SummaryDysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex several years before amyloid deposition. We find the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astrocytic calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral disruptions. In conclusion, we show that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.

Well-developed spatial reversal learning abilities in harbor seals (Phoca vitulina)

In this study, behavioral plasticity in harbor seals was investigated in spatial reversal learning tasks of varying complexities. We started with a classic spatial reversal learning experiment with no more than one reversal per day. The seals quickly learned the task and showed progressive improvement over reversals, one seal even reaching one-trial performance. In a second approach, one seal could complete multiple reversals occurring within a session. Again, a number of reversals were finished with only one error occurring at the beginning of a session as in experiment 1 which provides evidence that the seal adopted a strategy. In a final approach, reversals within a session were marked by an external cue. This way, an errorless performance of the experimental animal was achieved in up to three consecutive reversals. In conclusion, harbor seals master spatial, in contrast to visual, reversal learning experiments with ease. The underlying behavioral flexibility can help to optimize behaviors in fluctuating or changing environments.

Sphingolipids and DHA Improve Cognitive Deficits in Aged Beagle Dogs

Canine cognitive dysfunction syndrome (CDS) is a disorder found in senior dogs that is typically defined by the development of specific behavioral signs which are attributed to pathological brain aging and no other medical causes. One way of objectively characterizing CDS is with the use of validated neuropsychological test batteries in aged Beagle dogs, which are a natural model of this condition. This study used a series of neuropsychological tests to evaluate the effectiveness of supplementation with a novel lipid extract containing porcine brain-derived sphingolipids (Biosfeen®) and docosahexaenoic acid (DHA) for attenuating cognitive deficits in aged Beagles. Two groups (n = 12), balanced for baseline cognitive test performance, received a daily oral dose of either test supplement, or placebo over a 6-month treatment phase. Cognitive function was evaluated using the following tasks: delayed non-matching to position (DNMP), selective attention, discrimination learning retention, discrimination reversal learning, and spatial discrimination acquisition and reversal learning. The effect of the supplement on brain metabolism using magnetic resonance spectroscopy (MRS) was also examined. A significant decline (p = 0.02) in DNMP performance was seen in placebo-treated dogs, but not in dogs receiving the supplement, suggesting attenuation of working memory performance decline. Compared to placebo, the supplemented group also demonstrated significantly improved (p = 0.01) performance on the most difficult pattern of the spatial discrimination task and on reversal learning of the same pattern (p = 0.01), potentially reflecting improved spatial recognition and executive function, respectively. MRS revealed a significant increase (p = 0.048) in frontal lobe glutamate and glutamine in the treatment group compared to placebo, indicating a physiological change which may be attributed to the supplement. Decreased levels of glutamate and glutamine have been correlated with cognitive decline, suggesting the observed increase in these metabolites might be linked to the positive cognitive effects found in the present study. Results of this study suggest the novel lipid extract may be beneficial for counteracting age-dependent deficits in Beagle dogs and supports further investigation into its use for treatment of CDS. Additionally, due to parallels between canine and human aging, these results might also have applicability for the use of the supplement in human cognitive health.

Hippocampal signals modify orbitofrontal representations to learn new paths

We often remember the consequences of past choices to adapt to changing circumstances. Recalling past events requires the hippocampus (HPC), and using stimuli to anticipate outcome values requires the orbitofrontal cortex (OFC).1-3 Spatial reversal tasks require both structures to navigate newly rewarded paths.4,5 Both HPC place6 and OFC value cells7,8 fire in phase with theta (4-12Hz) oscillations. Both structures are described as cognitive maps: HPC maps space9 and OFC maps task states.10 These similarities imply that OFC-HPC interactions are crucial for using memory to predict outcomes when circumstances change, but the mechanisms remain largely unknown. To investigate possible interactions, we simultaneously recorded ensembles in OFC and CA1 as rats learned spatial reversals in a plus maze. Striking interactions occurred only while rats learned their first reversal: CA1 population vectors predicted changes in OFC activity but not vice versa, OFC spikes phase locked to hippocampal theta oscillations, mixed pairs of CA1 and OFC neurons fired together within single theta cycles, and CA1 led OFC spikes by ∼30ms. After the new contingency became familiar, CA1 ensembles stably represented distinct spatial paths, whereas OFC ensembles developed more generalized goal arm representations in different paths to identical rewards. These frontotemporal interactions, engaged selectively when new task features inform decision-making, suggest a mechanism for linking novel episodes with expected outcomes, when HPC signals trigger "cognitive remapping" by OFC.11.

The origins of cognitive flexibility in chimpanzees.

Cognitive flexibility is a core component of executive function, a suite of cognitive capacities that enables individuals to update their behavior in dynamic environments. Human executive functions are proposed to be enhanced compared to other species, but this inference is based primarily on neuroanatomical studies. To address this, we examined the nature and origins of cognitive flexibility in chimpanzees, our closest living relatives. Across three studies, we examined different components of cognitive flexibility using reversal learning tasks where individuals first learned one contingency and then had to shift responses when contingencies flipped. In Study 1, we tested n=82 chimpanzees ranging from juvenility to adulthood on a spatial reversal task, to characterize the development of basic shifting skills. In Study 2, we tested how n=24 chimpanzees use spatial versus arbitrary perceptual information to shift, a proposed difference between human and nonhuman cognition. In Study 3, we tested n=40 chimpanzees on a probabilistic reversal task. We found an extended developmental trajectory for basic shifting and shifting in response to probabilistic feedback-chimpanzees did not reach mature performance until late in ontogeny. Additionally, females were faster to shift than males were. We also found that chimpanzees were much more successful when using spatial versus perceptual cues, and highly perseverative when faced with probabilistic versus consistent outcomes. These results identify both core features of chimpanzee cognitive flexibility that are shared with humans, as well as constraints on chimpanzee cognitive flexibility that may represent evolutionary changes in human cognitive development.

Initial assessment of the spatial learning, reversal, and sequencing task capabilities of knock-in rats with humanizing mutations in the Aβ-coding region of App.

Model organisms mimicking the pathogenesis of human diseases are useful for identifying pathogenic mechanisms and testing therapeutic efficacy of compounds targeting them. Models of Alzheimer's disease (AD) and related dementias (ADRD) aim to reproduce the brain pathology associated with these neurodegenerative disorders. Transgenic models, which involve random insertion of disease-causing genes under the control of artificial promoters, are efficient means of doing so. There are confounding factors associated with transgenic approaches, however, including target gene overexpression, dysregulation of endogenous gene expression at transgenes' integration sites, and limitations in mimicking loss-of-function mechanisms. Furthermore, the choice of species is important, and there are anatomical, physiological, and cognitive reasons for favoring the rat over the mouse, which has been the standard for models of neurodegeneration and dementia. We report an initial assessment of the spatial learning, reversal, and sequencing task capabilities of knock-in (KI) Long-Evans rats with humanizing mutations in the Aβ-coding region of App, which encodes amyloid precursor protein (Apph/h rats), using the IntelliCage, an automated operant social home cage system, at 6-8 weeks of age, then again at 4-5 months of age. These rats were previously generated as control organisms for studies on neurodegeneration involving other knock-in rat models from our lab. Apph/h rats of either sex can acquire place learning and reversal tasks. They can also acquire a diagonal sequencing task by 6-8 weeks of age, but not a more advanced serial reversal task involving alternating diagonals, even by 4-5 months of age. Thus, longitudinal behavioral analysis with the IntelliCage system can be useful to determine, in follow-up studies, whether KI rat models of Familial AD (FAD), sporadic late onset AD (LOAD), and of ADRD develop aging-dependent learning and memory deficits.

Disrupted-in-schizophrenia 1 Protein Misassembly Impairs Cognitive Flexibility and Social Behaviors in a Transgenic Rat Model

Alterations in cognitive functions, social behaviors and stress reactions are commonly diagnosed in chronic mental illnesses (CMI). Animal models expressing mutant genes associated to CMI represent either rare mutations or those contributing only minimally to genetic risk. Non-genetic causes of CMI can be modeled by disturbing downstream signaling pathways, for example by inducing protein misassembly or aggregation. The Disrupted-in-Schizophrenia 1 (DISC1) gene was identified to be disrupted and thereby haploinsufficient in a large pedigree where it was associated with CMI. In a subset of CMI patients, the DISC1 protein misassembles to an insoluble protein. This has been modeled in a rat (tgDISC1 rat) where the full-length, non mutant human transgene was overexpressed and cognitive impairments were observed. Here, we investigated the scope of effects of DISC1 protein misassembly by investigating spatial memory, social behavior and stress resilience. In water maze tasks, the tgDISC1 rats showed intact spatial learning and memory, but were deficient in flexible adaptation to spatial reversal learning compared to littermate controls. They also displayed less social interaction. Additionally, there was a trend towards increased corticosterone levels after restraint stress in the tgDISC1 rats. Our findings suggest that DISC1 protein misassembly leads to disturbances of cognitive flexibility and social behaviors, and might also be involved in stress sensitization. Since the observed behavioral features resemble symptoms of CMI, the tgDISC1 rat may be a valuable model for the investigation of cognitive, social and – possibly – also stress-related symptoms of major mental illnesses.

A room temperature polar magnetic metal

The emergence of long-range magnetic order in noncentrosymmetric compounds has stimulated interest in the possibility of exotic spin transport phenomena and topologically protected spin textures for applications in next-generation spintronics. Polar magnets, with broken symmetries of spatial inversion and time reversal, usually host chiral spin textures. This work reports on a wurtzite-structure polar magnetic metal, identified as AA′-stacked (Fe0.5Co0.5)5GeTe2, which exhibits a Néel-type skyrmion lattice as well as a Rashba-Edelstein effect at room temperature. Atomic resolution imaging of the structure reveals a structural transition as a function of Co-substitution, leading to the emergence of the polar phase at 50% Co. This discovery reveals an unprecedented layered polar magnetic system for investigating intriguing spin topologies, and it ushers in a promising new framework for spintronics.Received 16 October 2021Accepted 8 March 2022DOI:https://doi.org/10.1103/PhysRevMaterials.6.044403©2022 American Physical SocietyPhysics Subject Headings (PhySH)Research AreasMagnetotransportSkyrmionsSpintronicsPhysical SystemsTransition metal dichalcogenidesCondensed Matter, Materials & Applied Physics

Curcumin improves reversal learning in middle-aged rhesus monkeys.

Age-related impairments in cognitive function occur in multiple animal species including humans and nonhuman primates. Humans and rhesus monkeys exhibit a similar pattern of cognitive decline beginning in middle age, particularly within the domain of executive function. The prefrontal cortex is the brain region most closely associated with mediating executive function. Previous studies in rhesus monkeys have demonstrated that normal aging leads to an increase in myelin degradation in the prefrontal regions that correlates with cognitive decline. This myelin deterioration is thought to result, at least in part, from the age-related emergence of chronic low levels of inflammation. One therapeutic that may arrest the deleterious effects of neuroinflammation is curcumin (CUR), the primary component of the spice turmeric. CUR has been shown to be a potent anti-inflammatory and antioxidant and improves performance on tasks for working memory and motor function. In the present study, middle-aged monkeys (12-21 years old) were given daily dietary supplementation of 500 mg of curcumin or vehicle over a period of 3-4 years. Here, we present data from a series of both object and spatial reversal tasks. Compared to vehicle, the CUR group showed enhanced performance on object, but not spatial reversal learning. These findings suggest that curcumin may improve specific aspects of executive function. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Acute serotonin 1B/1A receptor activation impairs behavioral flexibility in C57BL/6J mice

Pharmacological activation of the serotonin (5-HT) 1B and 5-HT1A receptors has been shown to induce OCD-like perseverative circling and locomotor stereotypy in rodents. Although, several studies have examined how activation of these receptors facilitates these motor-associated OCD-like behaviors, it is not known how acute 5-HT1B and 5-HT1A activation impacts behavioral inflexibility, a common trait related to OCD. The current study examined how acute 5-HT1B/1A receptor agonist RU24969 treatment at 0.01, 0.1, and 1.0 mg/kg impacted behavioral flexibility in both female and male C57BL/6J mice. Behavioral flexibility was tested using a spatial reversal learning task, with probabilistic reward contingencies. In addition, locomotor activity and anxiety-like behaviors were also measured. RU24969 at 0.1 and 1.0 mg/kg impaired behavioral flexibility in both female and male C57BL/6J mice. RU24969 treatment at 1.0 mg/kg reduced locomotor activity in male mice, although RU24969 treatment did not significantly reduce locomotor activity in female mice. In the open field, 1.0 mg/kg elevated anxiety-like behavior in male mice only. Overall, these results demonstrate that acute 5-HT1B and 5-HT1A receptor activation leads to impairments in behavioral flexibility, a common trait associated with OCD.

Neurobehavioral and neurobiochemical effect of atomoxetine and N-acetylcysteine in streptozotocin diabetes induced endothelial dysfunction and related dementia

Metabolic conditions like diabetes, is a major risk factor for the development of dementia of vascular origin. This study investigates the efficacy of atomoxetine (ATX) and N-acetylcysteine (NAC) in streptozotocin (STZ) diabetes induced vascular endothelium dysfunction and related dementia. Single dose STZ (50 mg/kg i.p) was administered to Albino Wistar rats (male, 200–250 g) by dissolving in citrate buffer. Morris water maze (MWM) and attentional set shifting tests (ASST) were used to assess the spatial learning, memory, reversal learning, and executive functioning in animals. Body weight, serum glucose, serum nitrite/nitrate, vascular endothelial function, aortic superoxide anion, brains’ oxidative markers (thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT), inflammatory markers (IL-6, IL-10, TNF-α, and myeloperoxidase-MPO), acetylcholinesterase activity-AChE and histopathological changes were also assessed. Atomoxetine - ATX (2 mg kg−1/ 4 mg kg−1) and N-acetylcysteine- NAC (250 mg kg−1/ 500 mg kg−1) were used alone as well as in combination, as the treatment drugs. Donepezil (0.5 mg kg-1) was used as a positive control. STZ administered rats showed increase in serum glucose levels and decrease in body weight. Rats administered with STZ also showed reduction in learning, memory, reversal learning, executive functioning, impairment in endothelial function, increase in brains’ oxidative stress, inflammation, AChE activity and histopathological changes. Administration of ATX and NAC in two different doses as well as in combination, significantly attenuated the STZ induced diabetes induced impairments in the behavioral, endothelial, biochemical parameters and histopathological changes. Co-treatment of ATX and NAC was better in comparison to the doses when given alone. Hence, STZ administration caused diabetes induced dementia of vascular origin which was attenuated by the administration of ATX and NAC. Therefore, these agents may be studied further for the assessment of their full potential in diabetes induced dementia of vascular origin conditions.