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Alcohol-Related Brain Damage (ARBD) manifests predominantly as cognitive impairment and brain atrophy with the hippocampus showing particular vulnerability. Fasudil, a Rho kinase (ROCK) inhibitor, has established neuroprotective properties; however, its impact on alcohol-induced cognitive dysfunction and hippocampal structural damage remains unelucidated. This study probes Fasudil's neuroprotective potential and identifies its mechanism of action in an in vivo context. Male C57BL/6 J mice were exposed to 30% (v/v, 6.0 g/kg) ethanol by intragastric administration for four weeks. Concurrently, these mice received a co-treatment with Fasudil through intraperitoneal injections at a dosage of 10 mg/kg/day. Fasudil was found to mitigate alcohol-induced spatial and recognition memory deficits, which were quantified using Y maze, Morris water maze, and novel object recognition tests. Concurrently, Fasudil attenuated hippocampal structural damage prompted by chronic alcohol exposure. Notably, Fasudil moderated alcohol-induced disassembly of the actin cytoskeleton and microtubules-mechanisms central to the maintenance of hippocampal synaptic integrity. Collectively, our findings indicate that Fasudil partially reverses alcohol-induced cognitive and morphological detriments by modulating cytoskeletal dynamics, offering insights into potential therapeutic strategies for ARBD., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD), the most frequent neurodegenerative disease within dementias, affects the CNS, leading to gradual memory issues and cognitive dysfunction. Oxidative stress in AD contributes to ongoing neuronal loss and hastens disease progression. Notably, the potent antioxidant compounds morin and hesperidin have demonstrated significant effectiveness in addressing oxidative stress. This study explores the impact of morin and hesperidin on behavior and oxidative stress in the streptozotocin (STZ)-induced AD rat model. The experiment involved five groups: control, STZ, STZ+morin, STZ+hesperidin, and STZ+morin+hesperidin. The rat model of AD was created by injecting STZ with the stereotaxic surgery. Morin and hesperidin were applied to the groups for 7-days. After the applications, the Morris water maze (MWM) and novel object recognition (NOR) tests were used and the rats were sacrificed. Malondialdehyde (MDA), glutathione (GSH), nitric oxide (NOx), and protein carbonyl (PC) levels were measured. In the STZ group, the levels of NOx and PC exhibited a noteworthy increase compared to the control. Conversely, the application of morin and/or hesperidin treatments reduced NOx and PC levels compared to the STZ group. The co-administration of morin and hesperidin improved the antioxidant status and decreased lipid peroxidation in STZ-induced rats. In the STZ group, serum advanced oxidation protein products (AOPP) levels were statistically elevated compared to the control. However, in the treatment groups, morin and/or hesperidin successfully decreased AOPP levels to those observed in the control. The combined use of these flavonoids may have a neuroprotective effect regarding memory problems and decreasing oxidative/nitrosative stress., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Both dopamine (DA) and serotonin (5-HT) play key roles in numerous functions including motor control, stress response and learning. So far, there is scarce or conflicting evidence about the effects of 5-HT1A and 5-HT2A receptor (R) agonists and antagonists on recognition memory in the rat. This also holds for their effect on cerebral DA as well as 5-HT release. In the present study, we assessed the effects of the 5-HT 1A R agonist 8-OH-DPAT and antagonist WAY100,635 and the 5-HT 2A R agonist DOI and antagonist altanserin (ALT) on rat behaviors. Moreover, we investigated their impact on monoamine efflux by measuring monoamine transporter binding in various regions of the rat brain. After injection of either 8-OH-DPAT (3 mg/kg), WAY100,635 (0.4 mg/kg), DOI (0.1 mg/kg), ALT (1 mg/kg) or the respective vehicle (saline, DMSO), rats underwent an object and place recognition memory test in the open field. Upon the assessment of object exploration, motor/exploratory parameters and feces excretion, rats were administered the monoamine transporter radioligand N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[ 123 I]iodophenyl)-nortropane ([ 123 I]-FP-CIT; 8.9 ± 2.6 MBq) into the tail vein. Regional radioactivity accumulations in the rat brain were determined post mortem. Compared vehicle, administration of 8-OH-DPAT impaired memory for place, decreased rearing behavior, and increased ambulation as well as head-shoulder movements. DOI administration led to a reduction in rearing behavior but an increase in head-shoulder motility relative to vehicle. Feces excretion was diminished after ALT relative to vehicle. Dopamine transporter (DAT) binding was increased in the caudateputamen (CP), but decreased in the nucleus accumbens (NAC) after 8-OH-DPAT relative to vehicle. Moreover, DAT binding was decreased in the NAC after ALT relative to vehicle. Findings indicate that 5-HT 1A R inhibition and 5-HT 2A R activation may impair memory for place. Furthermore, results imply associations not only between recognition memory, motor/exploratory behavior and emotionality but also between the respective parameters and the levels of available DA in CP and NAC., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interest (either financial or non-financial)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Tamsulosin is an α 1 -adrenoceptor antagonist used to treat benign prostatic hyperplasia. This drug exhibits high affinity for α 1A - and α 1D -adrenoceptor subtypes, which are also expressed in the brain. While dementia symptoms have been reported after administration of tamsulosin in humans, studies on its effects on the rodent brain are still rare. The present study investigated the effects of tamsulosin (and biperiden, an amnesic drug) on cognitive performance in the object recognition task (ORT). Tamsulosin (0.001-0.01 mg/kg) was orally administrated in mice at three distinct time points: pre-training, post-training and pre-test session. Tamsulosin 0.01 mg/kg impaired object recognition regardless of when it was injected, whereas at lower doses did not affect mouse performance in the ORT. Biperiden also impaired acquisition and consolidation of object recognition in mice. Furthermore, the effects of tamsulosin on locomotion, motivation and anxiety were excluded as potential confounding factors. At all doses tested, tamsulosin did not alter distance moved, time spent exploring objects in the ORT, and anxiety-related behaviors in the elevated plus-maze test. By contrast, diazepam evoked a significant reduction of anxiety-like behaviours. In conclusion, tamsulosin impaired memory acquisition, consolidation and retrieval in an object recognition task in mice, thus affecting memory performance in a non-specific phase manner. These findings contribute to our understanding of the potential adverse effects of tamsulosin, and shed light on the role played by α 1 -adrenoceptors, particularly α 1A - subtype, in cognitive processes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study explores the under-researched domain of long-term stimulant treatment in children and adolescents diagnosed with attention deficit hyperactivity disorder (ADHD). The necessity for extended treatment duration, often accompanied by safety concerns and side effects leading to treatment discontinuation, underscores the significance of this investigation. Concurrently, comparative studies have revealed adverse impacts on vulnerable regions within the hippocampal formation, accompanied by behavioral perturbations. We employed computerized tests and virtual reality to assess spatial memory, pattern separation, and object recognition memory in a cohort of children diagnosed with ADHD receiving stimulant treatment. We compared their performance to a group of neurotypical peers. Our findings indicate that the ADHD group exhibited a lower performance in spatial memory, pattern separation, and object recognition memory than ND group. Intriguingly, a positive relationship emerged between the duration of stimulant treatment and performance in these variables. Notably, this improvement was not immediate to MPH treatment but becomes significant after 24 months of treatment. In contrast to previous comparative investigations, our study did not reveal a detrimental impact on spatial navigation, object recognition memory, or pattern separation, despite the known interplay of these cognitive processes with the hippocampal formation. These results shed new light on the nuanced effects of stimulant treatment in ADHD, underscoring the need for a more comprehensive understanding of long-term treatment outcomes., Competing Interests: Declaration of Competing All authors certify that they have no affiliations with or involvement in any organization or entity with any financial or nonfinancial interest in the subject matter or materials discussed in this manuscript., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In long-term spaceflight, astronauts will face unique cognitive loads and social challenges which will be complicated by communication delays with Earth. It is important to understand the central nervous system (CNS) effects of deep spaceflight and the associated unavoidable exposure to galactic cosmic radiation (GCR). Rodent studies show single- or simple-particle combination exposure alters CNS endpoints, including hippocampal-dependent behavior. An even better Earth-based simulation of GCR is now available, consisting of a 33-beam (33-GCR) exposure. However, the effect of whole-body 33-GCR exposure on rodent behavior is unknown, and no 33-GCR CNS countermeasures have been tested. Here astronaut-age-equivalent (6mo-old) C57BL/6J male mice were exposed to 33-GCR (75cGy, a Mars mission dose). Pre-/during/post-Sham or 33-GCR exposure, mice received a diet containing a 'vehicle' formulation alone or with the antioxidant/anti-inflammatory compound CDDO-EA as a potential countermeasure. Behavioral testing beginning 4mo post-irradiation suggested radiation and diet did not affect measures of exploration/anxiety-like behaviors (open field, elevated plus maze) or recognition of a novel object. However, in 3-Chamber Social Interaction (3-CSI), CDDO-EA/33-GCR mice failed to spend more time exploring a holder containing a novel mouse vs. a novel object (empty holder), suggesting sociability deficits. Also, Vehicle/33-GCR and CDDO-EA/Sham mice failed to discriminate between a novel stranger vs. familiarized stranger mouse, suggesting blunted preference for social novelty. CDDO-EA given pre-/during/post-irradiation did not attenuate the 33-GCR-induced blunting of preference for social novelty. Future elucidation of the mechanisms underlying 33-GCR-induced blunting of preference for social novelty will improve risk analysis for astronauts which may in-turn improve countermeasures., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Patients with chronic pain often complain about memory impairments. Experimental studies have shown neuroprotective effects of Carbamylated erythropoietin (Cepo-Fc) in the treatment of cognitive dysfunctions. However, little is currently known about its precise molecular mechanisms in a model of inflammatory pain. Therefore, this study aimed to investigate neuroprotective effects of Cepo-Fc against cognitive impairment induced by the inflammatory model of Complete Freund's Adjuvant (CFA). Carbamylated erythropoietin was administrated Intraperitoneally (i.p) on the day CFA injection, continued for a 21-days period. After conducting the behavioral tests (thermal hyperalgesia and novel object recognition test), western blot and ELISA were further preformed on days 0, 7, and 21. The results of this study indicate that Cepo-Fc can effectively reverse the CFA induced thermal hyperalgesia and recognition memory impairment. Additionally, Cepo-Fc noticeably decreased the hippocampal microglial expression, production of hippocampal IL-1β, and hippocampal apoptosis and necroptosis induced by the inflammatory pain. Therefore, our findings suggest that neuroprotective effects of Cepo-Fc in the treatment of pain related recognition memory impairment may be mediated through reducing hippocampal microglial expression as well as IL-1β production., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Positive allosteric modulators (PAMs) of α5GABA A receptors (α5GABAARs) are emerging as potential therapeutics for a range of neuropsychiatric disorders. However, their role in memory processing of healthy animals is not sufficiently examined. We tested the effects of MP-III-022 (1 mg/kg, 2.5 mg/kg and 10 mg/kg), a PAM known to be selective for α5GABAARs and devoid of prominent side-effects, in different behavioral paradigms (Morris water maze, novel object recognition test and social novelty discrimination) and on GABRA5 expression in Wistar rats, 30 min and 24 h after intraperitoneal treatment administration. The lowest dose tested worsened short-term object memory. The same dose, administered two times in a span of 24 h, improved spatial and impaired object and, at a trend level, social memory. The highest dose had a detrimental effect on all types of long-term memory (object memory at a trend level) and short-term spatial memory, but improved short-term object and social memory. Distinct sets of expression changes were detected in both prefrontal cortex and two regions of the hippocampus, but the latter ones could be assessed as more consequential. An increase of GABRA5 mRNA in CA2 occurred in parallel with improvement of object and social, but impairment of spatial memory, while the opposite happened with a trend level change in CA1. Our study demonstrates the variability of the roles of the α5GABAAR based on its level of expression and localization, in dependence on the type and protocol of cognitive tasks, as well as the respective timing of pharmacological modulation and testing., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Reserpine (RES) is an irreversible inhibitor of VMAT2 used to study Parkinson's disease (PD) and screening for antiparkinsonian treatments in rodents. Recently, the repeated treatment with a low dose of reserpine was proposed as a model capable of emulating progressive neurochemical, motor and non-motor impairments in PD. Conversely, compared to Wistar rats, Spontaneously Hypertensive Rats (SHR) are resistant to motor changes induced by repeated treatment with a low dose of RES. However, such resistance has not yet been investigated for RES-induced non-motor impairments. We aimed to assess whether SHR would have differential susceptibility to the object recognition deficit induced by repeated low-dose reserpine treatment. We submitted male Wistar and SHR rats to repeated RES treatment (15 s.c. injections of 0.1 mg/kg, every other day) and assessed object memory acquisition and retrieval 48 h after the 6 th RES injection (immediately before the appearance of motor impairments). Only RES Wistar rats displayed memory impairment after reserpine treatment. On the other hand, untreated SHR rats displayed object recognition memory deficit, but RES treatment restored such deficits. We also performed immunohistochemistry for tyrosine hydroxylase (TH) and α-synuclein (α-syn) 48 h after the last RES injection. In a different set of animals submitted to the same treatment, we quantified DA, 5-HT and products of lipid peroxidation in the prefrontal cortex (PFC) and hippocampus (HPC). SHR presented increased constitutive levels of DA in the PFC and reduced immunoreactivity to TH in the medial PFC and dorsal HPC. Corroborating the behavioral findings, RES treatment restored those constitutive alterations in SHR. These findings indicate that the neurochemical, molecular and genetic differences in the SHR strain are potentially relevant targets to the study of susceptibility to diseases related to dopaminergic alterations., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Ghrelin (Ghrl) is an orexigenic peptide with potential roles in the modulation of anxiety- and depressive-like symptoms induced by bilateral olfactory bulbectomy (OB) in rodents. In the present work, we assessed whether intrahippocampal Ghrl could reverse OB-induced depressive-like and amnesic effects by regulating molecular mechanisms related to neuroplasticity. Adult female albino Swiss mice were divided into sham and OB groups, and infused with saline (S) or Ghrl 0.03 nmol/μl, 0.3 nmol/μl, or 3 nmol/μl into the hippocampus before exposition to open-field test (OFT) and tail suspension test (TST) or immediately after training in the object recognition test (ORT). After test phase in ORT, animals were euthanized and their hippocampi were dissected to study the expression of genes related to memory. The OB-S animals presented hyperlocomotion in OFT, increased immobility in TST and memory impairment compared to sham-S (p < 0.05), but acute intrahippocampal infusion of Ghrl 0.3 nmol/μl produced an improvement on these parameters in OB animals (p < 0.05). In addition, this dose of Ghrl reversed OB-induced low expression of NMDA1 and MAPK1 iso1 and up-regulated the expression of CaMKIIa iso1 and iso2, and MAPK1 iso2 (p < 0.05). These results extend the existing literature regarding OB-induced behavioral and neurochemical changes, and provide mechanisms that could underlie the antidepressant effect of Ghrl in this model., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The α7 nicotinic acetylcholine receptor (α7 nAChR) is a potential target for the treatment of cognitive decline in patients with schizophrenia, Alzheimer's disease, and attention-deficit/hyperactivity disorder. Here we examined the promnesic activity of the α7 nAChR agonist (A582941), the type I (CCMI), and the type II (PNU120596) positive allosteric modulators (PAMs) in rats following single and repeated (once daily for seven days) treatment. To determine the neuronal mechanisms underlying the procognitive activity of the tested compounds, levels of the extracellular signal-regulated kinases (Erk1/2) and the activity-regulated cytoskeleton-associated protein (Arc) mRNAs were assessed in the frontal cortical and hippocampal brain regions. Using the novel object recognition test, we demonstrate that the lower doses of A582941 (0.1 mg/kg), CCMI (1 mg/kg), and PNU120596 (0.3 mg/kg) improved recognition memory after repeated but not single administration, suggesting a cumulative effect of repeated dosing. In contrast, the higher doses of A582941 (0.3 mg/kg), CCMI (3 mg/kg) and PNU120596 (1 mg/kg) demonstrated promnesic efficacy following both single and repeated administration. Subsequent in situ hybridization revealed that repeated treatment with A582941 and CCMI, but not PNU120596 enhanced mRNA expression of the Erk1/2 and Arc in the frontal cortex and hippocampus. Present data suggest that both the α7 nAChR agonist and PAMs exhibit procognitive effects after single and repeated administration. The increased level of the Erk1/2 and Arc genes is likely to be at least partially involved in this effect., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The symptoms of human depression often include cognitive deficits. However, cognition is not frequently included in the behavioral assessments conducted in preclinical models of depression. For example, it is well known that repeated corticosterone (CORT) injections in rodents produce depression-like behavior as measured by the forced swim test, sucrose preference test, and tail suspension test, but the cognitive impairments produced by repeated CORT have not been thoroughly examined. The purpose of this experiment was to assess the effect of repeated CORT injections on several versions of object recognition memory and modulation of the acoustic startle response by relatively low intensity prepulses, along with the more traditional assessment of depression-like behavior using the forced swim test. Rats received 21 days of CORT (40 mg/kg) or vehicle injections followed by a battery of behavioral tests. Importantly, during behavioral testing CORT treatment did not occur (CORT withdrawal). Corticosterone decreased body weight, increased immobility in the forced swim test, lowered startle amplitudes, and facilitated responding to trials with a short interval (30 ms) between the prepulse and pulse. Corticosterone also impaired both object location and object-in-place recognition memory, while sparing performance on object recognition memory. Collectively, our data suggest that CORT produces selective disruptions in prepulse facilitation, object location, and object-in-place recognition memory, and that these impairments should be considered as part of the phenotype produced by repeated CORT, and perhaps chronic stress., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is the foremost cause of dementia among other neurodegenerative diseases, leading to memory loss and cognitive deficits. AD has gained extensive attention in research for exploring possible interventions. One promising field is natural substances and compounds that could provide a wide range of neuroprotection against AD. This study aimed to investigate the possible effects of melatonin (MEL) and resveratrol (RES) in improving memory deficits in a sporadic mouse model of AD. Memory deficit was induced using AlCl 3 and d-galactose for generating an AD mouse model. Mice were randomly distributed into five groups (n = 13): control, AD, AD + MEL (AD mice treated with 80 mg/kg of MEL), AD + RES (AD mice treated with 40 mg/kg of RES), and AD + Combination)AD mice that received 80 mg/kg MEL and 40 mg/kg RES). A novel object recognition task (NORT) and passive avoidance task (PAT) were used for assessing memory. Moreover, acetylcholinesterase (AChE) level, brain-derived neurotrophic factor (BDNF), and cAMP-response element binding (CREB) protein expression were measured in the prefrontal cortex tissue. Our results showed that MEL significantly improved memory deficits in both the NORT and PAT of the AD model, while RES improved the PAT only in the AD model. Co-treatment with MEL and RES exerted beneficial additive effects on recognition memory impairment in the AD mouse model. Moreover, our results demonstrated that both MEL and RES enhanced the cholinergic system and BDNF and CREB signaling pathways in the prefrontal cortex in an AD mouse model., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The majority of schizophrenia patients have cognitive deficits as a separate symptom cluster independent of positive or negative symptoms. Current medicines, unfortunately, cannot provide clear benefits for cognitive symptoms in patients. Recent findings showed decreased α7 nicotinic acetylcholine receptor (nAChR) expressions in subjects with schizophrenia. α7 nAChR full/partial agonists and positive allosteric modulators (PAMs) may be valuable drug candidates to treat cognitive deficits of disease. This study comparatively investigated the effect of α7 nAChR agonist (A-582941), type I PAM (CCMI), type II PAM (PNU-120596), and the antipsychotic drug (clozapine) on behavioral, molecular, and immunohistochemical parameters in a subchronic MK-801 model of schizophrenia in male rats. Novel object recognition (NOR) and Morris water maze (MWM) tests were performed to evaluate recognition and spatial memories, respectively. Gene and protein expressions of parvalbumin, glutamic acid decarboxylase-67 (GAD67), and α7 nAChR were examined in the rats' hippocampal tissue. The subchronic MK-801 administration produced cognitive deficits in the NOR and MWM tests. It also decreased the protein and gene expressions of parvalbumin, GAD67, and α7 nAChR in the hippocampus. Clozapine, A-582941, and PNU-120596 but not CCMI increased the parvalbumin and α7 nAChR expressions and provided benefits in recognition memory. Interestingly, clozapine and CCMI restored the MK-801 induced deficits on GAD1 expression and spatial memory while A-582941 and PNU-120596 were ineffective. These results indicated that α7 nAChR agonist, type I and type II PAMs may provide benefits in different types of cognitive deficits rather than a complete treatment in schizophrenia., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Monoclonal anti-proprotein convertase subtilisin/kexin type 9 (PSCK9) neutralizing antibodies effectively lower plasma cholesterol levels and decrease cardiovascular events but also raised some concern that cognitive function could worsen as a side effect. Here, we performed experiments in mice to characterize the effect of anti-PCSK9 antibodies on behavior and cognitive function in detail. APOE*3Leiden.CETP mice and B6129SF1/J wildtype mice were fed a Western type diet and treated with the fully human anti-PCSK9 antibody CmAb1 (PL-45134; 10mg*kg -1 s.c.) or vehicle for 6 weeks. Locomotor activity, anxiety levels, recognition memory, and spatial learning were investigated using the open field, novel object recognition test, and Morris water maze, respectively. Serum cholesterol levels in APOE*3Leiden.CETP mice after treatment with anti-PCSK9 antibody were significantly lower compared to controls whereas cholesterol levels in B6129SF1/J wildtype mice remained unchanged at low levels. No apparent differences were found regarding locomotor activity, anxiety, recognition memory, and spatial learning between animals treated with anti-PCSK9 antibody or vehicle in APOE*3Leiden.CETP and B6129SF1/J wildtype mice. In this study, we found no evidence that treatment with anti-PCSK9 antibodies lead to differences in behavior or changes of cognition in mice., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Early postnatal neuroactive steroids (NAS) play a significant role in the neurodevelopment. Their alteration can modify adult behavior, such as anxiety or learning. For this reason, we set out to observe if neonatal NAS levels alteration affects two types of learning implying low or high levels of emotional content, such as recognition memory and aversive learning respectively. Thus, we tested allopregnanolone or finasteride administered from postnatal days 5-9. In adulthood, recognition memory was assessed using the object recognition test, as well as aversive learning throughout the passive avoidance test (PA). Because of the important emotional component of PA, which can be influencing learning, we evaluated anxiety-like behavior by means of the open field test (OF). The results indicated that those animals administered with finasteride showed higher recognition levels of a familiar object. On the other hand, they showed an impairment in a stressful learning, such as PA. However, no effects of finasteride were observed on anxiety-like behavior in OF, despite it has been reported that neonatal finasteride treatment can promote an anxiety-like profile in the elevated plus-maze test in adulthood. Regarding neonatal allopregnanolone, animals showed higher levels in OF exploration only when they were already familiar with the apparatus. Furthermore, neonatal allopregnanolone did not affect recognition memory or aversive learning. In conclusion, the neonatal NAS manipulation by means of finasteride differently affected two types of learning implying distinct stress levels. Altogether, the results show the importance of the emotional content to explain the effects of neonatal NAS manipulation on learning., (Copyright © 2020 Elsevier B.V. All rights reserved.)

According to preclinical and clinical studies, the antidepressant-induced increase in the activity of atypical antipsychotics may efficiently improve the treatment of negative and some cognitive symptoms of schizophrenia. In the present study, we aimed to evaluate the effects of the antidepressants escitalopram and mirtazapine and the atypical antipsychotic drug aripiprazole, administered separately or in combination, on the MK-801-induced deficits in the recognition memory test and on the extracellular levels of monoamines and their metabolites in the rat frontal cortex. Based on the results of the behavioral tests, co-treatment with an ineffective dose of aripiprazole (0.1 mg/kg) and escitalopram (2.5 and 5 mg/kg) or mirtazapine (5 mg/kg) abolished the deficits evoked by MK-801 in the novel object recognition test, and those effects were blocked by the 5-HT 1A receptor antagonist (WAY 100,635) or the dopamine D 1 receptor antagonist (SCH 23,390). Moreover, co-treatment with aripiprazole (0.3 mg/kg) and escitalopram (5 mg/kg) significantly increased the levels of noradrenaline and serotonin, decreased the level of its metabolite, and did not alter level of dopamine, but decreased the levels of its metabolites. In addition, co-treatment with aripiprazole (0.3 mg/kg) and mirtazapine (10 mg/kg) significantly increased the level of noradrenaline, did not change the levels of dopamine and serotonin, but increased the levels of their metabolites. Based on these results, the increase in the extracellular levels of noradrenaline or serotonin in the cortex induced by co-treatment with an antidepressant and aripiprazole may be very important for the pharmacotherapy of negative and some cognitive symptoms of schizophrenia., Competing Interests: Declaration of Competing Interest Declarations of interest: none., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Several lines of evidence indicate that anesthetic doses of the non-competitive N-methyl-D-aspartate receptor antagonist ketamine disrupt memory functions in rodents. The mechanism by which anesthetic ketamine produces its adverse behavioural effects is not yet clarified. The implication of nicotinic acetylcholine receptor as a potential site of action of anesthetic ketamine adverse effects on memory is proposed. We investigated the ability of α4β2 nicotinic receptor agonist ABT-418 (0.01, 0.03, 0.1 mg/kg, i.p.) and α7 nicotinic receptor agonist GTS-21 (0.3, 1, 3 mg/kg, i.p.) to counteract recognition memory deficits produced by acute post-training administration of anesthetic ketamine (100 mg/kg, i.p.) in rats. For this purpose, the novel object recognition test, a behavioural paradigm assessing recognition memory abilities in rodents was used. Post-training acute administration of GTS-21 (3 mg/kg) counteracted anesthetic ketamine-induced performance deficits in the novel object recognition memory task. By contrast, ABT-418 failed to reverse the recognition memory deficits caused by anesthetic ketamine. The present findings propose that an α7 nicotinic receptor component might modulate anesthetic ketamine's adverse effects on recognition memory., Competing Interests: Declaration of Competing Interest The author reports no financial conflict of interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Taste recognition memory in rodents is evident as taste neophobia disappears upon repeated taste exposures without aversive consequences, thus increasing the consumption of familiar edibles. The attenuation of taste neophobia (AN) induced by taste familiarity is auditory context-dependent in mice since neophobia to a familiar taste reappears with a novel auditory background. This effect depends on the integrity of the dorsal hippocampus but the potential role of dopamine has remained unexplored. In order to explore the involvement of dopamine through D1 dopamine receptors in AN, C57BL/6 mice were exposed to a 3% vinegar taste solution for 10 min throughout several consecutive days. An experimentally-controlled auditory background was used to define a context, which could either change or remain constant throughout all the drinking sessions. Systemic administration of the D1 dopamine receptor antagonist SCH-23390 induced a similar effect to that of an auditory context change while it was kept constant and systemic administration of SKF-81297 prevented the contextual modulation of AN when the auditory context changed. Additionally, SCH-23390 injection on the following day to the auditory context change further impaired AN, thus suggesting the relevance of dopamine in the consolidation of the context dependency of taste recognition memory. We conclude that the context dependency of the AN involves dopaminergic activity mediated by D1 receptors which might be responsible for proper acquisition of safe taste recognition memory., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Individuals who begin drug use during early adolescence experience more adverse consequences compared to those initiating later, especially if they are female. The mechanisms for these age and gender differences remain obscure, but studies in rodents suggest that psychostimulants may disrupt the normal ontogeny of dopamine and glutamate systems in the prefrontal cortex (PFC). Here, we studied Sprague-Dawley rats of both sexes who began methamphetamine (METH, i.v.) self-administration in adolescence (postnatal [P] day 41) or adulthood (P91). Rats received seven daily 2-h self-administration sessions with METH or saccharin as the reinforcer, followed by 14 daily long access (LgA; 6 h) sessions. After 7 and 14 days of abstinence, novel object (NOR) or object-in-place (OiP) recognition was assessed. PFC and nucleus accumbens were collected 7 days after the final cognitive test and NMDA receptor subunits and dopamine D 1 receptor expression was measured. We found that during LgA sessions, adolescent-onset rats escalated METH intake more rapidly than adult-onset rats, with adolescent-onset females earning the most infusions. Adolescent-onset rats with a history of METH self-administration exhibited modest deficits in OiP compared to their adult-onset counterparts, but there was no sex difference and self-administration groups did not differ from naïve control rats. All rats displayed intact novel object recognition memory. We found no group differences in D 1 and NMDA receptor expression, suggesting no long-lasting alteration of ontogenetic expression profiles. Our findings suggest that adolescent-onset drug use is more likely to lead to compulsive-like patterns of drug-taking and modest dysfunction in PFC-dependent cognition., Competing Interests: Declaration of Competing Interest All authors report they have no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Positive allosteric modulators (PAMs) of alpha 7 nicotinic acetylcholine receptors (α7-nAChRs) may represent a novel approach to attenuate cognitive decline in Alzheimer's disease (AD). One possible scenario for the use of this class of compounds is their combination with currently approved anti-AD drugs. We thus evaluated the efficacy of co-administration of inactive doses of type I and type II α7-nAChR PAMs (CCMI and PNU-120596, respectively) with acetylcholinesterase inhibitors (AChEIs), donepezil and galantamine, or with a non-competitive glutamate N-methyl-D-aspartate receptor antagonist, memantine, in ameliorating scopolamine-induced memory deficits in the novel object recognition test in rats. Both CCMI and PNU-120596 as well as donepezil, galantamine and memantine attenuated the scopolamine-induced recognition impairments. Interestingly, the combined administration of previously established sub-effective doses of the tested PAMs (0.1 mg/kg) with either AChEIs, donepezil (0.3 mg/kg) and galantamine (0.1 mg/kg), or memantine (0.3 mg/kg) also restored object recognition memory in scopolamine-treated animals. These findings suggest the therapeutic potential of α7-nAChR PAMs as an augmentation strategy for cognitive enhancement in AD., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Experimental evidence shows that the phenylpyrazole pesticide fipronil exerts neurotoxic effects at central level in rodents, and in particular on nigrostriatal dopaminergic neurons, whose degeneration is well known to cause motor and non-motor deficits in animals and in humans. In order to characterize better the central neurotoxic effect of fipronil, we injected fipronil (15 and 25 μg) dissolved in dimethyl sulfoxide (DMSO) unilaterally into the substantia nigra of male rats. Male rats injected with DMSO unilaterally into the substantia nigra were used as controls. Control and fipronil-treated rats were then tested in different motor (i.e., open field arena, rotarod, tail flick) and non motor tests (novel object recognition, social interaction) 15 days after injection. A systemic challenge dose of the dopamine-agonist apomorphine was also used to study the presence of a rotational behavior. Sixteen days after fipronil or DMSO injection into the substantia nigra, rats were sacrificed, and either striatal dopamine content or substantia nigra tyrosine hydroxylase (TH) immunoreactivity were measured. The results confirm that the unilateral injection of fipronil into the substantia nigra caused the degeneration of nigrostriatal dopaminergic neurons, which leads to a decrease around 50 % in striatal dopamine content and substantia nigra TH imunoreactivity. This occurred together with changes in motor activity and coordination, and in nociception but not in recognition memory and in social interaction, as revealed by the results of the behavioral experiments performed in fipronil-treated rats compared to vehicle-treated rats 15 days after treatment, as found with other compounds that destroy nigrostriatal dopaminergic neurons., Competing Interests: Declaration of Competing Interest The authors have nothing to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In recent years, there has been a growing appreciation that 17β-estradiol (E2) can rapidly modulate learning and memory processes by binding to membrane estrogen receptors and cause the activation of a number of signaling cascades within the central nervous system. In this study, we sought to investigate the effects of post-training administration of E2 (100 ng/g, 1 μg/g, 10 μg/g) and involvement of the estrogen receptors (ERs) using selective ER agonists on the consolidation of object recognition (OR) and object placement memory (OP) in adult male zebrafish. The general activation of ERs with the highest E2 dose improved consolidation of memory in both learning tasks within 1.45 h of administration. Activation of classical ERs (ERα and ERβ) improved consolidation of OR memory, but had no effect on fish performance in OP task. On the other hand, activation of G protein-coupled ER1 impaired and enhanced consolidation of OR and OP memories, respectively. Memory improvement in both tasks was accompanied by a marked up-regulation in the expression of genes encoding ionotropic and metabotropic glutamate receptors in a task-dependent manner. In contrast, the down-regulation in the expression of certain ionotropic glutamate receptors was observed in fish with impaired OR memory. Moreover, our study also revealed an increase in the transcript abundance of genes associated with synaptic protein synthesis (brain-derived neurotrophic factor, synaptophysin, and the mechanistic target of rapamycin). These results suggest that E2 may affect consolidation of memory in zebrafish likely through rapid changes in synaptic morphology and function., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The systemic administration of low reserpine (RES) doses (0.1-1.0 mg/kg) has been proposed as a valuable rat model for the study of non-motor symptoms of Parkinson's disease (PD). Here, we investigated the temporal-dependent effects of RES (1 mg/kg, s.c.) on short-term memory and locomotion, as well as, the levels of dopamine, serotonin and its metabolites in the striatum, hippocampus and prefrontal cortex at 3, 24 or 72 h after RES administration. RES administrations resulted in social and object recognition memory impairment and increased dopamine turnover in the striatum, without changes in the rat spontaneous locomotor activity, 3 h after RES administration. Altogether, these results provide new insights for the use of RES administration as an experimental design for the study of PD non-motor symptoms in rats., Competing Interests: Declaration of Competing Interest The authors have no financial or personal conflict of interest related to this work., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A survey of the literature indicates that both rapid eye movement sleep deprivation (RSD) and activation of cannabinoid CB 1 receptor (CB 1 R) may impair novel object recognition (NOR) memory in rodents. To our knowledge, so far, no previous study has investigated the probable effects of RSD on the different phases of NOR memory. Moreover, far too little attention has been paid to the potential role of the CB 1 R in the effects of RSD on object memory. Therefore, the major objective of this study was to investigate the probable role of the CB 1 R in the acquisition, consolidation, retrieval, and reconsolidation of NOR memory in the RSD rats. A 12-h paradigm of RSD using the multiple platform method did not affect acquisition, but it impaired the consolidation, retrieval, and reconsolidation of NOR memory. Administration of the CB 1 R antagonist rimonabant (1 or 3 mg/kg, i.p.) did not have significant effects on the acquisition and reconsolidation, but it improved RSD-induced impairment of the consolidation and retrieval of object memory, especially at the dose of 3 mg/kg. In addition, the RSD paradigm did not affect the levels of plasma corticosterone as an important marker of stress in rat. The results revealed that RSD may have different effects on the different phases of NOR memory which may not be attributable to the effects of stress. Our findings would seem to suggest that the CB 1 R can be targeted to, at least partially, modulate the adverse effects of RSD on the process of NOR memory., (Copyright © 2019. Published by Elsevier B.V.)

Previously we demonstrated that a single physical exercise session promotes the persistence of object recognition (OR) memory and this effect involves the activation of the noradrenergic system. Here, using adult male Wistar rats (3 months old) we confirm that an aerobic single physical exercise session (30 min of treadmill running at an intensity of 60-70 % of indirect VO 2 max.) after OR learning promotes memory persistence. We also demonstrate that this effect involves the dopaminergic system, since it is blocked when a D1-family receptor antagonist (SCH-23390, 1μg/μl) is infused into the hippocampus after the physical exercise session. Additionally, through HPLC experiments we demonstrate that a physical exercise session increases the hippocampal dopamine levels. Taken together, our results demonstrate that acute post-learning physical exercise is able to promote the persistence of OR memory, inducing the release of dopamine in hippocampus, which is necessary for the modulation of memory persistence. This work brings new evidences on the benefit of a single physical exercise session to memory, as well as suggests that catecholaminergic mechanisms are behind this effect., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Chlorpyrifos (CPF) is an extensively used organophosphate pesticide. Exposure to CPF has been related to neurobehavioral disorders, particularly during neurodevelopment. Apolipoprotein E (apoE) is a lipid and cholesterol carrier and a susceptibility factor for cognitive impairment which can influence the response to toxic exposures. The study was aimed at assessing the effects of postnatal exposure to CPF on object recognition memory and its modulation by sex and APOE genotype. Human apoE3 and apoE4 targeted replacement mice and C57BL/6 mice were postnatally exposed to 0 or 1 mg/kg/day of CPF. Recognition memory was evaluated in an Object Recognition Test (ORT). In order to study the contribution of cholinergic and GABAergic neurotransmitter systems to recognition memory, a pharmacological challenge was included. Sex, genotype and postnatal exposure to CPF were key factors throughout the testing period. Specifically, CPF increased exploratory behavior and impaired discrimination performance. We observed that administering scopolamine, a cholinergic antagonist, was detrimental to recognition memory. However, discrimination in C57BL/6 and apoE4 males improved with the administration of the cholinergic agonist rivastigmine, but the same drug worsened retention in apoE4 females. Finally, the GABAergic agonist alprazolam altered performance in a sex- and genotype-dependent manner. Overall, these results suggest complex interactions between sex, APOE genotype and postnatal CPF exposure and indicate a different functioning of both the cholinergic and GABAergic neurotransmitter system between groups., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Nitric oxide (NO) plays a leading role in learning and memory processes. Previously, we showed its ability to modify the deleterious effect of immunotoxin 192 IgG-saporin (192-IgG-SAP) in the cholinergic system. The aim of this study was to analyze the potential of a NO donor (molsidomine, MOLS) to prevent the recognition memory deficits resulting from the septal cholinergic denervation by 192 IgG-SAP in rats. Quantification of neuronal and endothelial nitric oxide synthase (nNOS and eNOS, respectively) expression was evaluated in striatum, prefrontal cortex, and hippocampus. In addition, a choline acetyltransferase immunohistochemical analysis was performed in medial septum and assessed the effect of MOLS treatment on the spatial working memory of rats through a recognition memory test. Results showed that 192-IgG-SAP reduced the immunoreactivity of cholinergic septal neurons (41%), compared with PBS-receiving control rats (p < 0.05). Treatment with MOLS alone failed to antagonize the septal neuron population loss but prevented the progressive abnormal morphological changes of neurons. Those animals exposed to 192-IgG-SAP immunotoxin exhibited a reduction of cortical nNOS expression against the control group, whereas expression was enhanced in the 192-IgG-SAP + MOLS group. The most relevant finding was the recovering of the discrimination index exhibited by the 192-IgG-SAP + MOLS group. When compared with the rats exposed to the 192-IgG-SAP immunotoxin, they reached values similar to those observed in the PBS group. Our results show that although MOLS failed to block the cholinergic neurons loss induced by 192-IgG-SAP, it avoided the neuronal damage progression., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is characterized by the presence of amyloid-β (Aβ), oxidative damage and neuronal degeneration, which, together with other pathological events, promote progressive memory loss and cognitive decline. Non-pharmacological strategies have been study to provide some protection against the development of AD. Considering that physical exercise neuroprotective effects on prevention of cognitive deficits are well elucidate, it is important clarify the effects of cognitive training, and verify if they are similar or comparable to those observed for physical exercise. Here we divided male adult Wistar rats in six groups: control, which rats were not submitted to any intervention; Aβ, which rats were submitted to hippocampal infusion of Aβ; physical exercise (PE), which rats were submitted to 4 weeks of PE training; PE + Aβ, which rats were submitted to 4 weeks of PE training followed by hippocampal infusion of Aβ; cognitive exercise (CE), which rats were submitted to 4 weeks of CE training; and, CE + Aβ, which rats were submitted to 4 weeks of CE training followed by hippocampal infusion of Aβ. Ten days after Aβ infusion, short (STM) and long-term (LTM) object recognition memory, as well as hippocampal oxidative stress (ROS levels by DCFH test), lipid peroxidation (TBARS), total antioxidant capacity (FRAP) and hippocampal histology were evaluated. Both PE and CE were effective in protect cognitive function against memory deficits related to Aβ neurotoxicity, preventing oxidative stress and damage and hippocampal cellular disorganization. So, cognitive training seems to be as good as physical training in the prevention of memory deficits related to Aβ and seems to share some mechanisms of actions, as oxidative stress prevention., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Current models suggest that neuropeptide oxytocin modulates the salience of emotional/social stimuli and consequently influences perceptual, attentional and learning processes that underlie social behaviour. Therefore, oxytocin has been considered as a potential treatment in managing social and communication deficits in neuropsychological disorders. Recent studies indicate that effects of oxytocin on social and cognitive functions greatly vary and even lead to opposite outcomes. The factors leading to such variabilities in behavioural effects of oxytocin and their underlying mechanisms remain unclear. Here, we examined the effects of exogenously administered (intranasal) oxytocin (48 IU) on cognitive functions of macaque monkeys within a controlled experimental condition in a randomized crossover study. Monkeys performed a working memory task in which they memorized and subsequently matched stimuli with different emotional/social content (positive, negative, and neutral) at different levels of cognitive difficulties (delay period). Monkeys' accuracy was lower at longer delay intervals indicating that higher cognitive demands adversely affected their performance. There was a significant difference in accuracy and response time between the three emotional conditions. The effects of oxytocin on monkeys' performance were dependent on the emotional content of stimuli so that oxytocin enhanced the adverse effects of negative stimuli, however, moderated the effects of positive stimuli. Our findings in monkeys do not support models suggesting a general effect of oxytocin in enhancing salience or heightening of attention to social stimuli and instead suggest that the cognitive effects of oxytocin depend on the emotional valence of contextual factors., (Copyright © 2018. Published by Elsevier B.V.)

Diminished dopamine D1 stimulation may contribute to cognitive impairment in Alzheimer's and Parkinson's diseases, schizophrenia, and other neuropsychiatric disorders. However, orthosteric D1 receptor (D1R) agonists produce receptor desensitization and an inverted U-shaped dose-response curve, but positive allosteric modulators (PAMs) do not. We examined the cognitive effects of DETQ, a D1R PAM, in mice genetically modified to express the human D1 receptor ("hD1 mice"). Phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate receptor antagonist, dosed seven days (subchronic), followed by withdrawal, produced a prolonged deficit in novel object recognition (NOR) memory, which was reversed by acute treatment with DETQ, with no evidence for an inverted U-shaped response. This was blocked by the D1R antagonist, SCH391660. Single doses of D1R agonists, SKF38393 and SKF82958, and the acetylcholinesterase inhibitor, rivastigmine, alone and the combination of subeffective doses of both DETQ and rivastigmine, also restored NOR in both subchronic PCP-treated in hD1 mice. DETQ increased cortical and hippocampal acetylcholine efflux after both acute and subchronic dosing in hD1 mice. Subchronic but not acute DETQ, inhibited glutamate and GABA efflux. DETQ-induced acetylcholine efflux was absent in subchronic PCP-treated mice, indicating that restoration of NOR in subchronic PCP-treated mice does not require cortical acetylcholine efflux. This is additional evidence that DETQ stimulates D1R without producing an inverted-U-shaped response curve and increases neurotransmitter release in the mPFC and HIP without causing tolerance. The ability of D1 PAMs to improve cognition in humans with neuropsychiatric disorders without evidence of tolerance or an inverted-U-shaped response curve needs to be established clinically., (Copyright © 2018. Published by Elsevier B.V.)

This study aims to investigate the contribution of nigral dopaminergic (DA) cell loss, repeated exposure to DA medication and the combination of both to the development of neuropsychiatric symptoms observed in Parkinson's disease (PD). A bilateral 6-OHDA lesion of the substantia nigra pars compacta (SNc) was performed in rats. A set of animals was repeatedly administered with L-dopa (20 mg/kg/day) and benserazide (5 mg/kg/day) over 10 days starting from day 11 post-lesion. Behavioural testing was performed in week 3 post-lesion: novel object recognition (NOR), elevated plus maze (EPM) social interaction (SI) tests, and amphetamine-induced hyperlocomotion (AIH). Immunohistochemical analysis revealed a significant partial lesion (48%) in 6-OHDA versus sham rats. This lesion was not associated with motor impairment. However, lesioned rats displayed a significant deficit in the NOR, which was reversed by acute treatment with l-dopa/benserazide (12.5 mg/kg and 15 mg/kg respectively). Lesioned rats also displayed a deficit in the EPM which was not reversed by acute treatment with l-dopa. No difference was observed in the SI test or in the AIH assay. In all assays, no effect of chronic l-dopa exposure was observed. This study provides new insights into the neuropathophysiology associated with neuropsychiatric symptoms of PD. Our data strongly emphasises a not previously clearly identified critical role in cognition for the SNc. The results suggest that DA pathways were less directly involved in lesion-induced anxiety-like behaviour. We did not report any effect of chronic l-dopa exposure in the context of partial nigral cell loss., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Sleep deprivation (SD) negatively caused cognitive deficit, which was associated with oxidative stress induced damage. Ginsenoside Rh2 had the ability to protect against damage caused by reactive oxygen species in vitro, showing antioxidant property. Therefore, it was hypothesized that Ginsenoside Rh2 could prevent SD-induced cognitive deficit via its antioxidant properties. In this study, the effect of Ginsenoside Rh2 on memory impairment induced by sleep deprivation was investigated. The mice were sleep deprived continuously for 14 days using our self-made Sleep Interruption Apparatus (SIA). Ginsenoside Rh2 was administered intraperitoneally at two doses (20 and 40 μmol/kg) for 20 days. Thereafter, behavioral studies were conducted to test the learning and memory ability using object location recognition (OLR) experiment and passive avoidance (PA) test. Additionally, the oxidative stress parameters in the serum and the brain tissues (cortex and hippocampus) were assessed, including the superoxide dismutase (SOD) enzyme activity, the total antioxidant reactivity (TAR), the malondialdehyde (MDA) level, the glutathione (GSH) level, and the lipid peroxidation (LPO) content. The results revealed that SD impaired both spatial and non-spatial memory (P < 0.05). Treatment with Ginsenoside Rh2 at both doses prevented memory impairment induced by SD. Moreover, Ginsenoside Rh2 normalized the reduction of SOD and TAR activities in the serum (P < 0.01) and the decrease of GSH content in both the cortex and hippocampus (P < 0.05) induced by SD. Furthermore, Ginsenoside Rh2 significantly decreased the MDA level in the serum (P < 0.05) and the LPO content in both the cortex and hippocampus (P < 0.05) compared to SD group. In conclusion, sleep deprivation impaired both spatial and non-spatial memory and Ginsenoside Rh2 reversed this impairment, probably by preventing the oxidative stress damage in the body, including the serum and brain during sleep deprivation., (Copyright © 2018. Published by Elsevier B.V.)

Systemic inflammation induces cognitive impairment, yet the mechanism involved in this process is unclear. Neurotrophin receptor p75 (p75 NTR ) signaling is a key pathological factor contributing to neurobehavioral abnormalities in many neurodegenerative diseases. However, the role of p75 NTR signaling in the regulation of sepsis-induced cognitive impairment remains largely to be elucidated. In this study, systemic inflammation was induced by cecal ligation and puncture (CLP). Neurobehavioral performances were evaluated by open field, novel object recognition, and fear conditioning tests. The expressions of proinflammatory cytokines (tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), IL-6, IL-10), apoptosis marker cleaved caspase-3, ionized calcium binding adaptor molecule 1 (IBA1), proBDNF, p75 NTR , c-Jun N-terminal kinase (JNK), and pJNK in the hippocampus were determined by enzyme-linked immunosorbent assay, western blot analysis, and immunofluorescence. The synaptic marker in the CA1 region of the hippocampus was assessed by Golgi staining. In the present study, we showed that systemic inflammation induced cognitive impairment, which was accompanied by increased expressions of hippocampcal proBDNF and p75 NTR . Of note, we found that LM11A-31, an orally available, blood-brain barrier-permeant small-molecule p75 NTR signaling modulator significantly reversed the sepsis-induced cognitive impairment and restored most of the abnormal biochemical parameters. Taken together, our study suggests that proBDNF/p75 NTR signaling pathway might play a key role in the development of sepsis-induced cognitive impairment, whereas specific p75 NTR inhibitor may provide a novel therapeutic approach for this disorder and possible other neurodegenerative diseases., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The capacity to recognize objects from different view-points or angles, referred to as view-invariance, is an essential process that humans engage in daily. Currently, the ability to investigate the neurobiological underpinnings of this phenomenon is limited, as few ethologically valid view-invariant object recognition tasks exist for rodents. Here, we report two complementary, novel view-invariant object recognition tasks in which rodents physically interact with three-dimensional objects. Prior to experimentation, rats and mice were given extensive experience with a set of 'pre-exposure' objects. In a variant of the spontaneous object recognition task, novelty preference for pre-exposed or new objects was assessed at various angles of rotation (45°, 90° or 180°); unlike control rodents, for whom the objects were novel, rats and mice tested with pre-exposed objects did not discriminate between rotated and un-rotated objects in the choice phase, indicating substantial view-invariant object recognition. Secondly, using automated operant touchscreen chambers, rats were tested on pre-exposed or novel objects in a pairwise discrimination task, where the rewarded stimulus (S+) was rotated (180°) once rats had reached acquisition criterion; rats tested with pre-exposed objects re-acquired the pairwise discrimination following S+ rotation more effectively than those tested with new objects. Systemic scopolamine impaired performance on both tasks, suggesting involvement of acetylcholine at muscarinic receptors in view-invariant object processing. These tasks present novel means of studying the behavioral and neural bases of view-invariant object recognition in rodents., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Abnormalities in prefrontal cortical and hippocampal GABAergic function are postulated to be major causes of the cognitive impairment associated with schizophrenia (CIAS). There are conflicting views on whether diminished or enhanced GABAergic activity contributes to the deficit in short-term novel object recognition (NOR) in the sub-chronic phencyclidine (scPCP) rodent model of CIAS. This study assessed the role of GABA A signaling in the medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC) in NOR in saline (scSAL)- and scPCP-treated rats., Methods: The effects of local administration of a GABA A agonist (muscimol) into the vHPC or mPFC and an antagonist (bicuculline) or a GABA A /benzodiazepine partial agonist (bretazenil) into the vHPC on NOR in scSAL and scPCP-treated rats were determined., Results: In scSAL-treated rats, injection of muscimol into the vHPC, but not mPFC, induced a deficit in NOR. The scPCP-induced NOR deficit was significantly reversed by intra-vHPC bicuculline, while intra-vHPC bretazenil produced a non-significant trend for reversal (p = .06). scPCP treatment increased mRNA expression of GABA A γ 2 in PFC and GABA A α 5 and GABA A β 1 in the HPC. However, GABA concentration in the PFC or HPC was not altered., Conclusions: These findings indicate that the scPCP-induced NOR deficit can be rescued by reducing GABA A receptor stimulation in vHPC, indicating that increased vHPC GABA A inhibition may contribute to the scPCP-induced NOR deficit in rats. These results also indicate that excessive GABA A receptor signalling in the vHPC has a deleterious effect on NOR in normal rats., (Copyright © 2017. Published by Elsevier B.V.)

Hearing and cognition are commonly involved in both normal and pathological aging. Current clinical interest lies in whether peripheral hearing loss promotes cognitive decline. In our previous publication, the authors have shown a causal relationship between hearing and cognitive impairments in C57BL/6 mice. Here we extended the follow-up to 12 months to determine the long-term effects of hearing loss on cognition and to observe hippocampal p-tau and lipofuscin. One month old male mice were randomly allocated into two groups, the control (n = 12) and noise-induced hearing loss (NIHL) (n = 12). After baseline hearing and cognitive measurements, the mice in the NIHL group were exposed to 110 dB SPL white noise for 1 h every day for 20 consecutive days. Cognitive function was assessed by radial arm maze and novel object recognition tests. p-Tau was observed by the western blot, immunofluorescence, and immunogold staining. The mice in the NIHL group showed elevated auditory brainstem response thresholds and poorer performances in spatial working and recognition memories than the controls. They exhibited more p-tau and lipofuscin in the hippocampus. The cognitive impact of hearing loss varied with the types of memory. Working memory impairment was reversible, whereas recognition memory impairment was permanent. Our results provide behavioral and histopathological evidence for hearing-related cognitive decline. Early hearing loss is suggested to be one of the important determinants between normal and pathological cognitive aging., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Working memory (WM) is the ability to temporarily store information for use and manipulation. Working memory is thought to depend on a distributed set of higher cortical areas including the prefrontal and parietal cortex in primates while relatively little research has been conducted in rodents to elucidate the exact role of the parietal cortex (PC) in WM, particularly in relation to the construct of WM capacity. Previous work in our lab demonstrates that performance of the odour span task (OST), an olfactory incremental delayed nonmatching-to-sample task, relies on the medial prefrontal cortex (mPFC). However, the effects of inactivating the PC on the OST have not been studied. Therefore, the present experiment assessed the effects of inactivating the PC with the GABA receptor agonists muscimol/baclofen on performance of the OST. Infusions of muscimol/baclofen did not disrupt working memory performance, assessed by the mean number of odours each rat could remember before making an error on each day of testing. In contrast, performance of a positive control task, spontaneous cross-modal object recognition, was impaired by inactivating the PC. These results suggest that performance of the OST does not depend on the PC in rats. Our results are notable given past research demonstrating the importance of the parietal cortex for attentional processes and working memory in other tasks., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Traumatic brain injury (TBI) causes sustained disability due to compromised neurorepair mechanisms. Crucial to neurorepair and functional recovery following both TBI and stroke is hypoxia-inducible factor-1 alpha (HIF-1α). Based on reports that HIF-1α could be stabilized via S-nitrosylation, we tested the hypothesis that the S-nitrosylating agent S-nitrosoglutathione (GSNO) would stabilize HIF-1α, thereby stimulating neurorepair mechanisms and aiding in functional recovery. TBI was induced by controlled cortical impact (CCI) in adult rats. GSNO (0.05mg/kg) was administered at two hours after CCI. The treatment was repeated daily until the 14th day after CCI. Functional recovery was assessed by motor and cognitive functions, and the recovery was compared with the expression of HIF-1α. The mechanisms of GSNO-mediated S-nitrosylation of HIF-1α were determined using brain endothelial cells. While non-treated TBI animals showed sustained neurobehavioral deficits, GSNO treatment of TBI improved neurobehavioral functions. GSNO also increased the expression of HIF-1α and VEGF. The beneficial effects of GSNO on neurobehavioral functions in TBI animals were blocked by treatment with the HIF-1α inhibitor 2-methoxyestradiol (2-ME). The stimulatory effect of GSNO on VEGF was reversed not only by 2-ME but also by the denitrosylating agent dithiothreitol, confirming our hypothesis that GSNO's benefits are mediated by the stabilization of HIF-1α via S-nitrosylation. GSNO's S-nitrosylation of HIF-1α was further confirmed using a biotin switch assay in endothelial cells. The data provide evidence that GSNO treatment of TBI aids functional recovery through stabilizing HIF-1α via S-nitrosylation. GSNO is a natural component of the human brain/body, and its exogenous administration has not shown adverse effects in humans. Therefore, the translational potential of GSNO therapy in TBI is high., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The insular cortex (IC) receives projections from prefrontal, entorhinal and cingulate cortex, olfactory bulb and basal nuclei and has reciprocal connections with the amygdala and entorhinal cortex. These connections suggest a possible involvement in memory processes; this has been borne out by data on several behaviors. Social recognition memory (SRM) is essential to form social groups and to establish hierarchies and social and affective ties. Despite its importance, knowledge about the brain structures and the neurotransmitter mechanisms involved in its processing is still scarce. Here we study the participation of NMDA-glutamatergic, D1/D5-dopaminergic, H2-histaminergic, β-adrenergic and 5-HT 1A -serotoninergic receptors of the IC in the consolidation of SRM. Male Wistar rats received intra-IC infusions of substances acting on these receptors immediately after the sample phase of a social discrimination task and 24h later were exposed to a 5-min retention test. The intra-IC infusion of antagonists of D1/D5, β-adrenergic or 5-HT 1A receptors immediately after the sample phase impaired the consolidation of SRM. These effects were blocked by the concomitant intra-IC infusion of agonists of these receptors. Antagonists and agonists of NMDA and H2 receptors had no effect on SRM. The results suggest that the dopaminergic D1/D5, β-adrenergic and serotonergic 5-HT 1A receptors in the IC, but not glutamatergic NMDA and the histaminergic H2 receptors, participate in the consolidation of SRM in the IC., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Atorvastatin (Ator), competitive inhibitors of 3-hydroxymethyl-3-glutaryl-coenzyme-A reductase, is a cholesterol lowering drug. Ator has been shown to have neuroprotective, antioxidant and anti-inflammatory properties making that a potential candidate for the treatment of central nervous system (CNS) disorders. Here we assessed the effect of Ator on the d-galactose (d-gal)-induced aging in mice. For this purpose, Ator (0.1 and 1mg/kg/p.o.), was administrated daily in d-gal-received (500mg/kg/p.o.) mice model of aging for six weeks. Anxiety-like behaviors and cognitive functions were evaluated by the elevated plus-maze and novel object recognition tasks, respectively. Physical power was assessed by forced swimming capacity test. Animals brains were analyzed for the superoxide dismutase (SOD) and brain-derived neurotrophic factor (BDNF). We found that Ator decreases the anxiety-like behaviors in d-gal-treated mice. Also, our behavioral tests showed that Ator reverses the d-gal induced learning and memory impairment. Furthermore, we found that Ator increases the physical power of d-gal-treated mice. Our results indicated that the neuroprotective effect of Ator on d-gal induced neurotoxicity is mediated, at least in part, by an increase in the SOD and BDNF levels. The results of present study suggest that Ator could be used as a novel therapeutic strategy for the treatment of age-related conditions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Chemotherapy can cause serious neurotoxic side effects, such as painful peripheral neuropathies and disabling cognitive impairments. Four experiments examined whether Ibudilast, a clinically approved neuroimmune therapy, would reduce tactile allodynia and memory impairments caused by oxaliplatin in laboratory rats. Rats received an intraperitoneal injection of oxaliplatin (6mg/kg i.p.) or vehicle and were assessed for tactile allodynia 3 or 5days after injection, memory impairments in the novel object and novel location recognition tests 10-12days after injection, and fear conditioning 14days after injection. Ibudilast (7.5mg/kg) or vehicle was administered prior to oxaliplatin (Experiments 1 and 3) or prior to behavioural testing (Experiments 2 and 4). Ibudilast treatment prior to oxaliplatin prevented the development of tactile allodynia and memory impairments. Ibudilast treatment prior to behavioural testing reduced oxaliplatin-induced tactile allodynia, memory impairments, and impaired renewal of fear conditioning. These results suggest that Ibudilast could be an effective treatment against oxaliplatin-induced neuropathies and cognitive impairments., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Zinc and copper are essential trace elements. Dyshomeostasis in these two metals has been observed in Alzheimer's disease, which causes profound cognitive impairment. Insulin therapy has been shown to enhance cognitive performance; however, recent data suggest that this effect may be at least in part due to the inclusion of zinc in the insulin formulation used. Zinc plays a key role in regulation of neuronal glutamate signaling, suggesting a possible link between zinc and memory processes. Consistent with this, zinc deficiency causes cognitive impairments in children. The effect of zinc supplementation on short- and long-term recognition memory, and on spatial working memory, was explored in young and adult male Sprague Dawley rats. After behavioral testing, hippocampal and plasma zinc and copper were measured. Age increased hippocampal zinc and copper, as well as plasma copper, and decreased plasma zinc. An interaction between age and treatment affecting plasma copper was also found, with zinc supplementation reversing elevated plasma copper concentration in adult rats. Zinc supplementation enhanced cognitive performance across tasks. These data support zinc as a plausible therapeutic intervention to ameliorate cognitive impairment in disorders characterized by alterations in zinc and copper, such as Alzheimer's disease., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is characterized by motor dysfunction, which is preceded by a number of non-motor symptoms including olfactory deficits. Aggregation of α-synuclein (α-syn) gives rise to Lewy bodies in dopaminergic neurons and is thought to play a central role in PD pathology. However, whether amyloid fibrils or soluble oligomers of α-syn are the main neurotoxic species in PD remains controversial. Here, we performed a single intracerebroventricular (i.c.v.) infusion of α-syn oligomers (α-SYOs) in mice and evaluated motor and non-motor symptoms. Familiar bedding and vanillin essence discrimination tasks showed that α-SYOs impaired olfactory performance of mice, and decreased TH and dopamine levels in the olfactory bulb early after infusion. The olfactory deficit persisted until 45days post-infusion (dpi). α- SYO-infused mice behaved normally in the object recognition and forced swim tests, but showed increased anxiety-like behavior in the open field and elevated plus maze tests 20 dpi. Finally, administration of α-SYOs induced late motor impairment in the pole test and rotarod paradigms, along with reduced TH and dopamine content in the caudate putamen, 45 dpi. Reduced number of TH-positive cells was also seen in the substantia nigra of α-SYO-injected mice compared to control. In conclusion, i.c.v. infusion of α-SYOs recapitulated some of PD-associated non-motor symptoms, such as increased anxiety and olfactory dysfunction, but failed to recapitulate memory impairment and depressive-like behavior typical of the disease. Moreover, α-SYOs i.c.v. administration induced motor deficits and loss of TH and dopamine levels, key features of PD. Results point to α-syn oligomers as the proximal neurotoxins responsible for early non-motor and motor deficits in PD and suggest that the i.c.v. infusion model characterized here may comprise a useful tool for identification of PD novel therapeutic targets and drug screening., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The hippocampus is thought to be involved in object location recognition memory, yet the contribution of hippocampal NMDA receptors to the memory processes, such as encoding, retention and retrieval, is unknown. First, we confirmed that hippocampal infusion of a competitive NMDA receptor antagonist, AP5 (2-amino-5-phosphonopentanoic acid, 20-40nmol), impaired performance of spontaneous object location recognition test but not that of novel object recognition test in Wistar rats. Next, the effects of hippocampal AP5 treatment on each process of object location recognition memory were examined with three different injection times using a 120min delay-interposed test: 15min before the sample phase (Time I), immediately after the sample phase (Time II), and 15min before the test phase (Time III). The blockade of hippocampal NMDA receptors before and immediately after the sample phase, but not before the test phase, markedly impaired performance of object location recognition test, suggesting that hippocampal NMDA receptors play an important role in encoding and consolidation/retention, but not retrieval, of spontaneous object location memory., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Prenatal ethanol exposure (PAE) in humans results in a spectrum of disorders including deficits in learning and memory. Animal models to date have typically used high ethanol doses but have not identified the biochemical changes underlying the cognitive deficit. This study used treatment of mouse breeding harems with 5% ethanol via drinking water throughout pregnancy and lactation and explored the behavioural consequences in the progeny at 3-6 months of age using the open field test, novel object recognition test and elevated plus maze to measure anxiety and memory consolidation. The effects of angiotensin IV on behaviour of the progeny were also determined. The results indicated that PAE increased anxiety-like behaviour as determined in the open field test in male but not female progeny. In control animals, angiotensin IV enhanced memory consolidation in males, but this effect was abolished by PAE. The abolition of the pro-cognitive effect of angiotensin IV was not a consequence of increased anxiety, and there was some evidence of a long-lasting anxiolytic effect of angiotensin IV in the male PAE progeny. These results suggest that PAE may act via alteration of the actions of the brain renin-angiotensin system to impair memory consolidation, but these effects may be partially sex-dependent., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Patients with schizophrenia display impaired cognitive functioning and increased sensitivity to psychomimetic drugs. The neurodevelopmental hypothesis of schizophrenia posits that disruption of the developing brain predisposes neural networks to lasting structural and functional abnormalities resulting in the emergence of such symptoms in adulthood. Given the critical role of the glutamatergic system in early brain development, we investigated whether chronic prenatal exposure to the glutamate NMDA receptor antagonist, MK-801, induces schizophrenia-like behavioural and neurochemical changes in juvenile and adult rats., Methods: Pregnant Long-Evans rats were administered saline or MK-801 (0.1mg/kg; s.c.) at gestation day 7-19. Object recognition memory and cognitive flexibility were assessed in the male offspring using a novel object preference task and a maze-based set-shifting procedure, respectively. Locomotor-activating effects of acute amphetamine and MK-801 were also assessed., Results: Adult, but not juvenile, prenatally MK-801-treated rats failed to show novel object preference after a 90min delay, suggesting that object recognition memory may have been impaired. In addition, the set-shifting task revealed impaired acquisition of a new rule in adult prenatally MK-801-treated rats compared to controls. This deficit appeared to be driven by regression to the previously learned behaviour. There were no significant differences in drug-induced locomotor activity in juvenile offspring or in adult offspring following acute amphetamine challenges. Unexpectedly, MK-801-induced locomotor activity in adult prenatally MK-801-treated rats was lower compared to controls., Conclusions: Glutamate transmission dysfunction during early development may modify behavioural parameters in adulthood, though these parameters do not appear to model deficits observed in schizophrenia., (Copyright © 2017 Elsevier B.V. All rights reserved.)

It is widely thought that inactivation of the glutamatergic system impairs recognition memory in rodents. However, we previously demonstrated that systemic administration of riluzole, which blocks the glutamatergic system, enhances recognition memory in the rat novel object recognition (NOR) test. The mechanisms underlying this paradoxical effect of riluzole on recognition memory remain unclear. In the present study, adult male Wistar rats were bilaterally cannulated in the basolateral amygdala (BLA) to examine the effects of intra-BLA administration of riluzole. We also compared the effects of riluzole with those of d-cycloserine, a partial agonist at the glycine binding site on the N-methyl-d-aspartate (NMDA) receptor. The BLA plays a critical role not only in recognition memory, but also in the regulation of anxiety. In the present study, intra-BLA administration of riluzole or d-cycloserine enhanced recognition memory in the NOR test. It was previously suggested that recognition memory can be strongly affected by the state of anxiety in rodents. Interestingly, intra-BLA administration of riluzole, but not d-cycloserine, produced a potent anxiolytic-like effect in the elevated plus-maze test. Thus, the enhancement of recognition memory by riluzole might be an indirect effect resulting from the anxiolytic-like action of the intra-BLA administration of the drug, and may not be directly related to inhibition of the glutamatergic system. Further studies are needed to clarify the mechanisms underlying the memory enhancing effect of riluzole., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The neurotoxic effects of methamphetamine (MA) exposure in the developing and adult brain can lead to behavioral alterations and cognitive deficits in adults. Previous increases in the rates of adolescent MA use necessitate that we understand the behavioral and cognitive effects of MA exposure during adolescence on the adolescent brain. Adolescents using MA exhibit high rates of nicotine (NIC) use, but the effects of concurrent MA and NIC in the adolescent brain have not been examined, and it is unknown if NIC mediates any of the effects of MA in the adolescent. In this study, the long-term effects of a neurotoxic dose of MA with or without NIC exposure during early adolescence (postnatal day 30-31) were examined later in adolescence (postnatal day 41-50) in male C57BL/6J mice. Effects on behavioral performance in the open field, Porsolt forced swim test, and conditioned place preference test, and cognitive performance in the novel object recognition test and Morris water maze were assessed. Additionally, the effects of MA and/or NIC on levels of microtubule associated-2 (MAP-2) protein in the nucleus accumbens and plasma corticosterone were examined. MA and NIC exposure during early adolescence separately decreased anxiety-like behavior in the open field test, which was not seen following co-administration of MA/NIC. There was no significant effect of early adolescent MA and/or NIC exposure on the intensity of MAP-2 immunoreactivity in the nucleus accumbens or on plasma corticosterone levels. These results show that early adolescent MA and NIC exposure separately decrease anxiety-like behavior in the open field, and that concurrent MA and NIC exposure does not induce the same behavioral change as either drug alone., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Although N-methyl-d-aspartate receptor antagonists-induced hypoglutamate rodent models are the most well-established models for preclinical studies of schizophrenia-related deficits, they also evoke a wide spectrum of psychotomimetic side effects. It is significant to increase the specificity of hypoglutamate rodent models. In this study, the recognition memory was evaluated in rats by object recognition test (ORT), sensorimotor gating was evaluated by prepulse inhibition of the startle reflex (PPI), and locomotor activity was measured using open field test. High-performance liquid chromatography was used to measure neurotransmitters content in the medial prefrontal cortex (mPFC) and thalamus (THA). Total Akt and phospho-Akt protein was measured by Western blots. Results showed that 0.3mg/kg of MK-801 was most effective in inducing locomotion. 0.3mg/kg of MK-801 was most effective in decreasing PPI. 0.03mg/kg of MK-801 was most effective in decreasing object memory while not affecting exploration manners in the training session. 0.03mg/kg of MK-801 significantly increased HVA and Glu content in the mPFC. 0.1mg/kg of MK-801 significantly decreased GABA content in the THA. 0.03mg/kg of MK-801 significantly decreased Akt phosphorylation in the mPFC, which was related to the ORT index. In conclusion, a dose of 0.03mg/kg MK-801 can establish a "pure" memory impairment model without contaminations of sensorimotor gating and locomotor activity. MK-801-induced cognitive deficits is associated with increased DA metabolites and glutamate content in the mPFC and decreased GABA content in the THA as well as decrease in Akt phosphorylation in the mPFC., (Copyright © 2016. Published by Elsevier B.V.)