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Clinical surgery can lead to severe neuroinflammation and cognitive dysfunctions. It has been reported that astrocytes mediate memory formation and postoperative cognitive dysfunction (POCD), however, the thalamic mechanism of astrocytes in mediating POCD remains unknown. Here, we report that reactive astrocytes in zona incerta (ZI) mediate surgery-induced recognition memory impairment in male mice. Immunostaining results showed that astrocytes are activated with GABA transporter-3 (GAT-3) being down-expressed, and neurons were suppressed in the ZI. Besides, our work revealed that reactive astrocytes caused increased tonic current in ZI neurons. Up-regulating the expression of GAT-3 in astrocytes ameliorates surgery-induced recognition memory impairment. Together, our work demonstrates that the reactive astrocytes in the ZI play a crucial role in surgery-induced memory impairment, which provides a new target for the treatment of surgery-induced neural dysfunctions., 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 Ltd. All rights reserved.)

Fluoxetine is often prescribed to treat depression during pregnancy. Rodent studies have shown that fluoxetine exposure during early development can induce persistent changes in the emotional behavior of the offspring. However, the effects of prenatal fluoxetine on memory have not been elucidated. This study evaluates the memory of adult male offspring from rat dams orally administered with a clinically relevant dose of 0.7 mg/kg fluoxetine from 9 weeks before pregnancy to 1 week before delivery. Hippocampal-dependent (Morris Water Maze, MWM) and non-hippocampal-dependent (Novel Object Recognition, NOR) memory paradigms were assessed. Anxiety- and depressive-like symptoms were also evaluated using the Open Field Test, Tail Suspension Test and Sucrose Preference Test. Male rats exposed to fluoxetine during gestation displayed NOR memory impairments during adulthood, as well as increased anxiety- and depressive-like symptoms. In the MWM, the offspring of fluoxetine-treated dams did not show learning deficits. However, a retention impairment was found on remote memory, 15 days after the end of training. Molecular analyses showed increased expression of NMDA subunit NR 2B , and a decrease in NR 2A -to- NR 2B ratio in the temporal cortex, but not in the hippocampus, suggesting changes in NMDA receptor composition. These results suggest that in utero exposure to fluoxetine induces detrimental effects on non-hippocampal memory and in remote retention of hippocampal-dependent memory, which is believed to be stored in the temporal cortex, possibly due to changes in cortical NMDA receptor subunit stoichiometry. The present results warrant the need for studies on potential remote memory deficits in human offspring exposed to fluoxetine in utero., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

There is increasing evidence showing that HDACs regulates BDNF (brain-derived neurotrophic factor) expression through its interaction with the Bdnf gene promoter, a key regulator to consolidate memory. Although the nuclear mechanisms regulated by HDACs that control BDNF expression have been partially described recently, the temporal events for memory consolidation remain unknown. Hence, in this work, we studied the temporal pattern for the activation of the BDNF/TrkB pathway through class I HDAC inhibition to enhance object recognition memory (ORM) consolidation. To this end, we inhibited class I HDAC into the insular cortex (IC) and a weak ORM protocol was used to assess temporal expression and function of the BDNF/TrkB pathway in the IC. We found that cortical class I HDAC inhibition enhanced long-term ORM, coincident with a clear peak of BDNF expression at 4 h after acquisition. Furthermore, the tyrosine kinase B (TrkB) receptor blockade at 4 h, but not at 8 h, impaired the consolidation of ORM. These results suggest that histone acetylation regulates the temporal expression of BDNF in cortical circuits potentiating the long-term recognition memory., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

GPR40 was utilized as the drug target to the treatment of diabetes, but the function and mechanisms ameliorating the Alzheimer's disease (AD) remain unknown. In present study, the typical APP/PS1 mouse model was applied to explore the function and mechanism of GPR40 in AD. GPR40 agonist GW9508 and antagonist GW1100 were respectively given by i.c.v. injection to activate/inhibit the GPR40 in the brain of APP/PS1 mice which illustrated the function and mechanism of GPR40 in ameliorating AD symptoms. Morris water maze test, step-through test, Y-maze spontaneous alternation test, open field test and new object recognition test were used to test the cognitive function and memory ability of mice, while molecular biology experiments such as Western blot, immunofluorescence, JC-1 were used to detect the corresponding changes of signal pathways. The results revealed that treatment with GW9508 could significantly ameliorate cognitive deficits of APP/PS1 mice, upregulate the expression levels of cAMP, p-CREB and neurotrophic factors in vivo, while GW9508 also ameliorate Aβ 1-42 -induced neuron damage and downregulate the expression levels of pathological protein such as p-JNK, JNK and apoptosis-related proteins such as IL-6, IL-1β, TNF-α and caspase-3 in vitro. Meanwhile, high-content screening also showed that GW9508 promoted the cellular differentiation of SH-SY5Y cells, while GW1100 reversed the effects of GW9508. These results suggested that GPR40 was an underlying therapeutic target for the treatment of AD and GPR40 agonist could be explored as the emerging AD therapeutic drug., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Galanin (1-15) [GAL(1-15)] participates in mood regulation and depression. GAL(1-15) is also able to enhance the antidepressant effects induced by Fluoxetine (FLX) in the forced swimming test through interaction between GALR1-GALR2 and 5-HT1A receptors that induced changes in the binding characteristics and mRNA of the 5-HT1AR in the hippocampus. Since the medial prefrontal cortex (mPFC) is a core region for the interaction between emotional processing and cognition with a high density of 5-HT1AR and GALR1 and GALR2, we have analyzed the binding characteristics and mRNA levels of 5-HT1AR in the mPFC after GAL(1-15)-FLX administration in the rats. GAL(1-15) increased the Kd and the Bmax of the 5HT1AR agonist binding in the mPFC as well as the mRNA levels of 5-HT1AR in mPFC. Moreover, GAL(1-15) reversed the effects of memory impairment induced by FLX(10 mg/kg) in the Novel Object Recognition task. GALR2 was involved in these effects, since the specific GALR2 antagonist M871 blocked GAL(1-15) mediated actions at behavioral level. On the contrary GAL(1-15) did not reverse the effect of FLX in the Object Location Memory task. In conclusion, our results describe an interactions between GAL(1-15) and FLX in the mPFC involving interactions at the 5-HT1AR receptor level in the plasma membrane with changes at the transcriptional level with implications also at functional level. The GALR1-GALR2-5-HT1A heteroreceptor could be postulated to be used to reverse some of the adverse effects of FLX on memory processes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Consistent experimental evidence supports an important role of the glutamatergic system in the etiopathogenesis of schizophrenia. Numerous studies propose that blockade of the NMDA receptor by its antagonist ketamine impairs cognition and can mimic certain aspects of positive and negative symptoms of schizophrenia in rodents. Neuroactive steroids, including dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) were shown to affect brain glutamatergic system and to be implicated in schizophrenia. BNN27 is a novel DHEA derivative, which is devoid of steroidogenic activity. The neuroprotective effects of BNN27 have been recently evidenced. The aim of the present study was to investigate the ability of BNN27 to counteract schizophrenia-like behavioural deficits produced by ketamine in rats. BNN27's ability to attenuate hypermotility, stereotypies and ataxia induced by ketamine were evaluated using a motor activity cage. To assess the efficacy of BNN27 to reverse non-spatial and spatial recognition memory deficits caused by ketamine, the object recognition task and the object location task were used. Finally, the social interaction test was utilized in order to examine the effects of BNN27 on ketamine-induced social withdrawal. BNN27 (3 and 6 mg/kg, i.p.) attenuated ketamine (10 mg/kg, i.p.)-induced ataxia and to some extent also hypermotility. BNN27 (3-6 mg/kg, i.p.) counteracted ketamine (3 mg/kg, i.p.)-induced non-spatial and spatial recognition memory deficits. Further, BNN27 (6 mg/kg, i.p.) reduced the ketamine (8 mg/kg, i.p.)-induced social isolation. Our findings show that BNN27 is sensitive to glutamate hypofunction produced by ketamine since it reduced schizophrenia-like behavioural deficits induced by this NMDA receptor antagonist in rats., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Noradrenergic degeneration in the locus coeruleus (LC) seems a convergent neuropathological marker of different neurodegenerative diseases. Herein, we investigated the temporal development of apoptotic signaling activation in the LC, noradrenergic dysfunction and behavioral impairments in rats following the noradrenergic lesion of the LC. For this purpose, the dopamine reuptake inhibitor nomifensine was administered 1 h before the stereotaxic bilateral injections of 6-hydroxydopamine (6-OHDA; 5, 10 or 20 μg/hem) into the LC. The behavioral and neurochemical analyses were performed at 7, 21 and 42 days after 6-OHDA injections. All doses of 6-OHDA induced neuronal death in LC, but only the highest dose (20 μg/hem) disrupted the motor function. 6-OHDA (5 μg/hem) injection induced short-term memory deficits in all periods, olfactory discrimination and long-term memory impairments at 7 days, and depressive-like behaviors at 21 and 42 days after injection. Moreover, 6-OHDA infusion increased Bax/Bcl2 ratio and caspase 3 levels, and decreased the dopamine β-hydroxylase immunocontent in the LC. Noradrenergic neurotransmission dysfunction was observed in the LC, olfactory bulb, prefrontal cortex, hippocampus and striatum. The intranasal (i.n.) noradrenaline (NA) infusion restored the impairments in the olfactory discrimination, short-term memory and depressive-like behavior of 6-OHDA-lesioned rats. In addition, these effects were blocked by the prior i.n. infusion of the β 3 -adrenergic receptor antagonist SR59230A. These findings indicate that the 6-OHDA injection into the LC induced the apoptosis signaling activation, noradrenergic neurotransmission dysfunction and behavioral impairments that were restored via β 3 -adrenergic receptors activation mediated by the i.n. NA administration., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Experimental evidence indicates that anesthetic doses of the non-competitive NMDA receptor antagonist ketamine impair memory abilities in rodents. The mechanism by which anesthetic ketamine produces its adverse behavioural effects is not yet clarified. In this context, it has been proposed that the effects of anesthetic ketamine on memory might be attributed to its agonistic properties on the GABA type A receptor. The present study was designed to address this issue. Thus, we investigated the ability of the benzodiazepine receptor antagonist flumazenil (1, 3, 6 mg/kg, i.p.) and the GABA A receptor antagonist bicuculline (0.5, 1.5, 3 mg/kg, i.p.) to counteract recognition memory deficits produced by anesthetic ketamine (100 mg/kg, i.p.) in rats. For this purpose, the novel object recognition task, a behavioural paradigm assessing recognition memory abilities in rodents was used. Compounds were coadministered 24 h before testing or retention. Pre (24 h before testing) or post-training (24 h before retention) administration of flumazenil (6 mg/kg, i.p.) counteracted anesthetic ketamine-induced performance deficits in the novel object recognition memory task. Conversely, bicuculline failed to attenuate the recognition memory deficits caused by anesthetic ketamine. Our findings propose a functional interaction between anesthetic ketamine and the GABA A receptor allosteric modulator flumazenil on recognition memory., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produced long-lasting behavioral alterations such as social withdrawal and cognitive impairment in the social interaction test and in the novel object recognition test, respectively. At the molecular level, an increased cannabinoid receptor type-1 (CB1) mRNA and protein expression, which might be due to reduction in DNA methylation at the gene promoter in the prefrontal cortex (PFC), coincided with deficits in the social interaction test and in the novel object recognition test in MAM rats. Both the schizophrenia-like phenotype and altered transcriptional regulation of CB1 receptors were reversed by peripubertal treatment (from PND 19 to PND 39) with the non-psychotropic phytocannabinoid cannabidiol (30 mg/kg/day), or, in part, by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day), but not with haloperidol (0.6 mg/kg/day). These results suggest that early treatment with cannabidiol may prevent both the appearance of schizophrenia-like deficits as well as CB1 alterations in the PFC at adulthood, supporting that peripubertal cannabidiol treatment might be protective against MAM insult., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

It is well established that newly acquired information is stabilized over time by processes underlying memory consolidation, these events can be impaired by many drug treatments administered shortly after learning. The consolidation hypothesis has been challenged by a memory integration hypothesis, which suggests that the processes underlying new memories are vulnerable to incorporation of the neurobiological alterations induced by amnesic drugs generating a state-dependent memory. The present experiments investigated the effects of amnesic drugs infused into the insular cortex of male Wistar rats on memory for object recognition training. The findings provide evidence that infusions of several amnesic agents including a protein synthesis inhibitor, an RNA synthesis inhibitor, or an NMDA receptor antagonist administered both after a specific period of time and before retrieval induce state-dependent recognition memory. Additionally, when amnesic drugs were infused outside the early consolidation window, there was amnesia, but the amnesia was not state-dependent. Data suggest that amnesic agents can induce state-dependent memory when administered during the early consolidation window and only if the duration of the drug effect is long enough to become integrated to the memory trace. In consequence, there are boundary conditions in order to induce state-dependent memory., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Cannabinoid derivatives have shown promising results for treating neuropsychiatric disorders, including drug addiction. Recent studies on the therapeutic effects of Cannabidiol (CBD) on drug abuse showed mixed results, especially with psychostimulant substances such as cocaine. To determine whether CBD can attenuate cocaine reinforcement, we assessed behavioural responses induced by cocaine in mice, using the behavioural sensitization, conditioned place preference and intravenous self-administration paradigms. We show that repeated CBD treatment produces anxiolytic effects in the elevated plus maze test, increases the discrimination index of the novel object recognition task and attenuates cocaine-induced conditioned place preference but does not affect behavioural sensitization. CBD reduced cocaine voluntary consumption and progressive ratio breaking point in the self-administration paradigm, but not drug-induced reinstatement. In parallel, CBD increased expression of type 1 cannabinoid receptor, MAPK-CREB phosphorylation, BDNF expression, and neural cell proliferation in the hippocampus, and reduced the GluA1/2 AMPA subunit receptor ratio in the striatum. In summary, we show that CBD can modulate some behavioural and molecular manifestations of cocaine reinforcement. Moreover, our findings show that CBD has pro-neurogenic effects also in cocaine consuming animals. Overall, this novel evidence provides new perspectives to use CBD as a therapeutic tool., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Extensive evidence indicates that noradrenergic activation of the basolateral amygdala (BLA) is essential for mediating emotional arousal effects on memory consolidation in different target regions. However, the mechanism by which BLA activation regulates such information storage processes remains largely elusive. Here we demonstrate, in male Sprague-Dawley rats, that noradrenergic activation of the BLA is critically involved in enabling facilitation of memory consolidation induced by histone acetylation, a form of chromatin modification, within the insular cortex (IC) on object recognition memory. The histone deacetylase (HDAC) inhibitor sodium butyrate (NaB) administered either systemically or directly into the anterior, but not posterior, IC immediately after object recognition training enhanced long-term memory for the identity of the object. Systemic NaB administration also enhanced memory for the location of the object. This NaB-induced enhancement of both object recognition and object location memory was selectively associated with an increased ability to assess the familiarity of the training stimulus, without affecting interaction with a novel stimulus. The β-adrenoceptor antagonist propranolol infused into the BLA concurrently abolished the NaB-induced enhancement of familiarity detection underlying both object recognition and object location memory. These findings indicate that noradrenergic activity within the BLA induced by emotional arousal interacts with chromatin modification mechanisms in its target regions to affect post-learning consolidation processes underlying long-term recognition memory and discrimination of a familiar stimulus., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Prenatal drug exposure altered cognitive function in individuals, and may also impact their offspring's susceptibility to cognitive impairment. The high incidence of methamphetamine (METH) abuse among adolescents and women of childbearing age elevates the importance to determine the influence of maternal METH exposure on cognitive functions in the descendants. We hypothesized that maternal METH exposure affects cognitive behavior in offspring mice by disrupting gene expression associated with neural development. Here, female C57BL/6 mice were exposed to intermittent escalating doses of METH or saline from adolescence to adulthood, and then continued through pregnancy. Interestingly, male but not female offspring exhibited impaired short-term recognition memory and long-term spatial memory retention in novel object recognition and Morris water maze test respectively. Additionally, maternal METH exposure altered neurodevelopmental genes in both male and female offspring, and 12 differentially expressed genes between male and female were observed in the HPC and NAc regions. These differentially expressed genes are involved in neurogenesis, axon guidance, neuron migration and synapse of neural development circuits. Our observations suggest that maternal METH exposure induced differential expression patterns of neurodevelopment-related genes in the HPC and NAc of male and female mice, which may underlie the different cognitive behavior phenotypes in both genders., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Methotrexate is a dihydrofolate reductase inhibitor widely employed in curative treatment for children with acute lymphoblastic leukemia (ALL). However, methotrexate administration is also associated with persistent cognitive deficits among long-term childhood cancer survivors. Animal models of methotrexate-induced cognitive deficits have primarily utilized adult animals. The purpose of present study is to investigate the neurotoxicity of methotrexate in juvenile rats and its relevant mechanisms. The doses and schedule of systemic and intrathecal methotrexate, given from post-natal age 3-7 weeks, were chosen to model the effects of repeated methotrexate dosing on the developing brains of young children with ALL. This methotrexate regimen had no visible acute toxicity and no effect on growth. At 15 weeks of age (8 weeks after the last methotrexate dose) both spatial pattern memory and visual recognition memory were impaired. In addition, methotrexate-treated animals demonstrated impaired performance in the set-shifting assay, indicating decreased cognitive flexibility. Histopathological analysis demonstrated decreased cell proliferation in methotrexate-treated animals compared to controls, as well as changes in length and thickness of the corpus callosum. Moreover, methotrexate suppressed microglia activation and RANTES production. In conclusion, our study demonstrated that a clinically relevant regimen of systemic and intrathecal methotrexate induces persistent deficits in spatial pattern memory, visual recognition memory and executive function, lasting at least 8 weeks after the last injection. The mechanisms behind methotrexate-induced deficits are likely multifactorial and may relate to suppression of neurogenesis, alterations in neuroinflammation and microglial activation, and structural changes in the corpus callosum., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Synthetic cathinones, frequently referred to as "bath salts", have significant abuse potential, and recent evidence suggests that these novel psychoactive substances can also produce cognitive deficits as well as cytotoxic effects. However, most of these latter findings have been obtained either using high concentrations in vitro or following non-contingent high dose administration in vivo. The present study utilized a model of long-term voluntary binge-like self-administration to determine potential detrimental effects of synthetic cathinones on cognitive function and their known underlying neural circuits, collectively referred to as neurocognitive dysfunction. Male Sprague-Dawley rats were allowed to self-administer the cocaine-like synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV, 0.03 mg/kg/infusion i.v.) in 96-hr sessions, or saline as a control. A total of five 96-hr sessions were conducted, each separated by 3 days of abstinence in the home cage. Three weeks following the last 96-hr session, animals underwent assessment of cognitive function using spatial object recognition (SOR) and novel object recognition (NOR) tasks, after which brains were harvested and assessed for neurodegeneration using FluoroJade C (FJC). Compared to animals self-administering saline, animals self-administering MDPV demonstrated (1) robust drug intake that escalated over time, (2) deficits in NOR but not SOR, and (3) neurodegeneration in the perirhinal and entorhinal cortices. These results indicate that repeated binge-like intake of MDPV can induce neurocognitive dysfunction. In addition, utilization of rodent models of extended binge-like intake may provide insight into potential mechanisms and/or approaches to prevent or reverse the detrimental effects of abused substances on cognitive and neurobiological functioning. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.', (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Patients afflicted with bipolar disorder demonstrate significant impairments in recognition and episodic memory during acute depressive and manic episodes. These impairments and the related pathophysiology may result from over-activation of the brain dopamine (DA) system. In order to model overactive DA transmission in a well-established novel object recognition (NOR) memory test, we used DA transporter knockdown (DAT-KD) mice, which exhibit reduced DAT expression and display hyper-dopaminergic phenotypes. DAT-KD mice exhibited impaired NOR memory compared to wild-type (WT) mice. This impairment was prevented by administration of FAUC365, a DA D 3 receptor (D 3 R) selective antagonist, prior to object learning. Similarly, D 3 R knockout (KO)/DAT-KD double mutant mice displayed performance in the NOR test that was comparable to WT mice, suggesting that deficiencies in NOR performance in DAT-KD mice can be compensated by diminishing D 3 R signaling. GBR12909, a DAT blocker, also impaired NOR performance in WT mice, but not in D 3 R KO mice. Impaired NOR performance in GBR12909-treated WT mice was also prevented by pretreatment with FAUC365. Together, these findings indicate that reduced DAT activity can impair recognition memory in the NOR test, and D 3 R appears to be necessary to mediate this effect., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Exposure to early-life adversity may program brain function to prepare individuals for adaptation to matching environmental contexts. In this study we tested this hypothesis in more detail by examining the effects of early-life stress - induced by raising offspring with limited nesting and bedding material from postnatal days 2-9 - in various behavioral tasks and on synaptic function in adult mice. Early-life stress impaired adult performance in the hippocampal dependent low-arousing object-in-context recognition memory task. This effect was absent when animals were exposed to a single stressor before training. Early-life stress did not alter high-arousing context and auditory fear conditioning. Early-life stress-induced behavioral modifications were not associated with alterations in the dendritic architecture of hippocampal CA1 pyramidal neurons or principal neurons of the basolateral amygdala. However, early-life stress reduced the ratio of NMDA to AMPA receptor-mediated excitatory postsynaptic currents and glutamate release probability specifically in hippocampal CA1 neurons, but not in the basolateral amygdala. These ex vivo effects in the hippocampus were abolished by acute glucocorticoid treatment. Our findings support that early-life stress can hamper object-in-context learning via pre- and postsynaptic mechanisms that affect hippocampal function but these effects are counteracted by acute stress or elevated glucocorticoid levels., (Copyright © 2018. Published by Elsevier Ltd.)

Phosphodiesterases (PDEs) are enzymes that hydrolyze and inactivate 3', 5'-cyclic adenosine monophosphate (cAMP) and/or 3', 5'-cyclic guanosine monophosphate (cGMP). The regulation of intracellular signaling pathways mediated by cyclic nucleotides is imperative to synaptic plasticity and memory in animals. Because PDEs play an important role in this regulation, PDE inhibitors are considered as candidate compounds for treating cognitive and memory disorders. In the present study, we tested whether cilostazol, a selective PDE3 inhibitor, prevents the cognitive deterioration that occurs during the course of normal aging in mice. Ten months of cilostazol administration (1.5%) in 13-month-old mice improved spatial memory when tested at 23 months of age. First, it prevented the decline in the ability of these aged mice to recognize a change in an object's location in the object recognition task. Second, spatial memory of these cilostazol-treated aged mice in the Morris water maze was comparable to that of untreated middle-aged mice (13 months old). Cilostazol administration had no effect on the emotional states and physical ability of aged mice. Thus, long-term cilostazol administration prevented hippocampus-dependent memory decline in aged mice, allowing them to achieve a level of cognitive performance similar to middle-aged mice and without negative behavioral side effects. Considering its well-established safety in other medical contexts, cilostazol may be a potential therapeutic candidate drug for staving off cognitive decline in the aging human population., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Amyloid β (Aβ) is a key mediator for synaptic dysfunction and cognitive impairment implicated in Alzheimer's disease (AD). However, the precise mechanism of the toxic effect of Aβ is still not completely understood. Moreover, there is currently no treatment for AD. Protein kinase B (PKB, also termed Akt) is known to be aberrantly regulated in the AD brain. However, its potential function as a therapeutic target for AD-associated memory impairment has not been studied. Here, we examined the role of a direct Akt activator, SC79, in hippocampus-dependent memory impairments using Aβ-injected as well as 5XFAD AD model mice. Oligomeric Aβ injections into the 3rd ventricle caused concentration-dependent and time-dependent impairments in learning/memory and synaptic plasticity. Moreover, Aβ aberrantly regulated caspase-3, GSK-3β, and Akt signaling, which interact with each other in the hippocampus. Caspase-3 and GSK-3β inhibitor ameliorated memory impairments and synaptic deficits in Aβ-injected AD model mice. We also found that pharmacological activation of Akt rescued memory impairments and aberrant synaptic plasticity in both Aβ-treated and 5XFAD mice. These results suggest that Akt could be a therapeutic target for memory impairment observed in AD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Although MDMA (3,4-methylendioxymethamphetamine, ecstasy) neurotoxicity in serotonin neurons is largely recognized in a wide variety of species including man, neurotoxicity in dopamine (DA) neurons is thought to be species-specific. MDMA is mainly consumed by adolescents, often in conjunction with caffeine (Energy Drinks) and this association has been reported to exacerbate MDMA toxic effects. In order to model these aspects of MDMA use, vis-à-vis their impact on DA neurons, we investigated the effects of adolescent exposure to low doses of MDMA (5 mg/kg for 10 days), alone or in combination with caffeine (10 mg/kg) on neuronal and functional DA indices and on recognition memory in adult rats. MDMA reduced density of tyrosine hydroxylase (TH) positive neurons in the ventral tegmental area and in the substantia nigra pars compacta, and immunoreactivity of TH and DA transporter in the nucleus accumbens (NAc) shell and core, and caudate-putamen. This same treatment caused a reduction of basal dialysate DA in the NAc core. MDMA-pretreated rats also showed behavioral sensitization to a MDMA challenge at adulthood and potentiation of MDMA-induced increase of dialysate DA in the NAc core, but not in the NAc shell. In addition, MDMA-treated rats displayed a deficit in recognition memory. Caffeine co-administration did not affect the above outcomes. Our results show that adolescent exposure of rats to low doses of MDMA induces long-lasting and widespread reduction of DA neurons indicative of a neurotoxic effect on DA neurons and suggestive of a degeneration of the same neurons., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Current drug treatments for schizophrenia (SCZ) can alleviate positive symptoms, but have little effect on the negative symptoms and cognitive deficits that are difficult to translate into preclinical models for drug development. Therefore, we aimed to determine the dose-response effects of acute phencyclidine (PCP, 1.0-5.0 mg/kg) on rat brain connectivity and detect markers for different SCZ-like symptoms. Pharmacological functional magnetic resonance imaging (phMRI) and microdialysis were used to investigate PCP-induced effects on functional connectivity (FC) and dopamine levels, respectively. Next, we evaluated the association between PCP-induced changes in imaging parameters and behavior. PCP at doses of 3.0-5.0 mg/kg induced fMRI signal changes in several brain regions associated with SCZ. Additionally, the FC was globally disturbed, dopamine levels increased, and locomotor activity increased, reflecting the manifestation of SCZ-like positive symptoms. A distinct pattern in the measures was observed at lower PCP doses (1.0-2.0 mg/kg); PCP induced fMRI signal changes in the fronto-cortical regions, and increased dopamine levels in the medial prefrontal cortex. In addition to the dysconnectivity of these regions, the hippocampal FC was disrupted. These observations are consistent with the induction of SCZ-like cognitive deficits and negative symptoms, which were observed as impaired novel object recognition and decreased social interaction. No indicators for positive symptoms were observed at lower PCP doses. We conclude that acute PCP induces SCZ-like symptom classes in a dose-dependent manner; PCP doses of 1.0-2.0 mg/kg are more suitable for modeling SCZ-like negative symptoms and cognitive deficits, while SCZ-like positive symptoms dominate at doses of 3.0-5.0 mg/kg., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Chronic cerebral hypoperfusion is an important risk factor for vascular dementia and other brain dysfunctions, for which there are currently no effective medications available. We investigated the neuroprotective and axonal outgrowth promoting effects of tetramethylpyrazine nitrone (TBN) in a permanent bilateral occlusion of the common carotid arteries (2VO) rat model and in primary hippocampal neurons exposed to oxygen glucose deprivation (OGD). At 6th week after 2VO, TBN increased the time spent in novel arms in the Y-maze test and improved the discrimination ratio in object reorganization task. TBN attenuated axonal damage, and reduced oxidative DNA injury and lipid peroxidation in white matter. TBN also attenuated the neuronal apoptosis and ameliorated accumulation of astrocytes in parietal cortex and CA1 region of hippocampus. Western blot analyses indicated that TBN increased Bcl-2 expression, decreased Bax and Caspase 3 expressions, and upregulated the phosphorylation levels of high-molecular weight neurofilament (p-NFH), Akt (p-Akt) and glycogen synthase kinase-3β (p-GSK3β) in hippocampus at 6th week after chronic hypoperfusion. In vitro, TBN rescued hippocampal neuronal viability and axonal elongation from OGD damage. The p-Akt and p-GSK3β upregulation by TBN was abolished by a specific phosphoinositide 3-kinase (PI3K) inhibitor LY294002, resulting in suppression of axonal outgrowth. Collectively, the results showed that TBN alleviated white matter lesion and impairment of cortex and hippocampus, attenuated oxidative damage and enhanced axonal outgrowth through the regulation of PI3K/Akt/GSK3β signaling pathway, leading to improved cognitive deficit in a rat chronic hypoperfusion model., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Rats injected with by d-phenylalanine, a carbonic anhydrase (CA) activator, enhanced spatial learning, whereas rats given acetazolamide, a CA inhibitor, exhibited impairments of fear memory consolidation. However, the related mechanisms are unclear. We investigated if CAs are involved in a non-spatial recognition memory task assessed using the object recognition test (ORT). Systemic administration of acetazolamide to male CD1 mice caused amnesia in the ORT and reduced CA activity in brain homogenates, while treatment with d-phenylalanine enhanced memory and increased CA activity. We provided also the first evidence that d-phenylalanine administration rapidly activated extracellular signal-regulated kinase (ERK) pathways, a critical step for memory formation, in the cortex and the hippocampus, two brain areas involved in memory processing. Effects elicited by d-phenylalanine were completely blunted by co-administration of acetazolamide, but not of 1-N-(4-sulfamoylphenyl-ethyl)-2,4,6-trimethylpyridinium perchlorate (C18), a CA inhibitor that, differently from acetazolamide, does not cross the blood brain barrier. Our results strongly suggest that brain but not peripheral CAs activation potentiates memory as a result of ERK pathway enhanced activation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Cannabinoid-mediated memory impairment is a concern in cannabinoid-based therapies. Caffeine exacerbates cannabinoid CB 1 receptor (CB 1 R)-induced memory deficits through an adenosine A 1 receptor-mediated mechanism. We now evaluated how chronic or acute blockade of adenosine A 2A receptors (A 2A Rs) affects long-term episodic memory deficits induced by a single injection of a selective CB 1 R agonist. Long-term episodic memory was assessed by the novel object recognition (NOR) test. Mice received an intraperitoneal (i.p.) injection of the CB 1 /CB 2 receptor agonist WIN 55,212-2 (1 mg/kg) immediately after the NOR training, being tested for novelty recognition 24 h later. Anxiety levels were assessed by the Elevated Plus Maze test, immediately after the NOR. Mice were also tested for exploratory behaviour at the Open Field. For chronic A 2A R blockade, KW-6002 (istradefylline) (3 mg/kg/day) was administered orally for 30 days; acute blockade of A 2A Rs was assessed by i.p. injection of SCH 58261 (1 mg/kg) administered either together with WIN 55,212-2 or only 30 min before the NOR test phase. The involvement of CB 1 Rs was assessed by using the CB 1 R antagonist, AM251 (3 mg/kg, i.p.). WIN 55,212-2 caused a disruption in NOR, an action absent in mice also receiving AM251, KW-6002 or SCH 58261 during the encoding/consolidation phase; SCH 58251 was ineffective if present during retrieval only. No effects were detected in the Elevated Plus maze or Open Field Test. The finding that CB 1 R-mediated memory disruption is prevented by antagonism of adenosine A 2A Rs, highlights a possibility to prevent cognitive side effects when therapeutic application of CB 1 R drugs is desired., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Oleanolic acid is a naturally occurring triterpenoid and is widely present in food and medicinal plants. To examine the effect of oleanolic acid on memory deficits, we employed a cholinergic blockade-induced cognitive deficit mouse model. A single administration of oleanolic acid significantly increased the latency on the passive avoidance task and affected the alternation behavior on the Y-maze task and the exploration time on the novel object recognition task, indicating that oleanolic acid reverses the cognitive impairment induced by scopolamine. In accordance with previous reports, oleanolic acid enhanced extracellular-signal-regulated kinase 1/2 (ERK1/2) and cAMP response element-binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Interestingly, ameliorating effect of oleanolic acid on scopolamine-induced memory impairment was abolished by N2-(2-{[(2-oxoazepan-3-yl)amino]carbonyl}phenyl)benzo[b]thiophene-2-carboxamide (ANA-12), a potent and specific inhibitor of tropomyosin receptor kinase B (TrkB), in the passive avoidance task. Similarly, oleanolic acid significantly evoked long-term potentiation in a dose-dependent manner, which was diminished by ANA-12 treatment as shown in the electrophysiology study. Together, these results imply that oleanolic acid ameliorates scopolamine-induced memory impairment by modulating the BDNF-ERK1/2-CREB pathway through TrkB activation in mice, suggesting that oleanolic acid would be a potential therapeutic agent for the treatment of cognitive deficits., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The cognitive impairments and negative symptoms experienced by schizophrenia patients still await effective treatment. Alpha7 nicotinic acetylcholine receptors (α7 nAChRs) have gain considerable attention in this regard. It has been recently proposed that positive allosteric modulators (PAMs) of α7 nAChRs may represent an alternative strategy to that based on orthosteric agonists. The aim of the present study is to evaluate the efficacy of PAM-2 (3-furan-2-yl-N-p-tolyl-acrylamide) against cognitive deficits and negative-like symptoms in a rat model of schizophrenia based on administration of ketamine, a NMDAR antagonist. The activity of PAM-2 was compared to that elicited by DMXBA, an α7 nAChR partial agonist. For this purpose, the attentional set-shifting task (ASST) and the novel object recognition task (NORT) were used. The efficacies of PAM-2 and DMXBA against ketamine-induced social withdrawal were assessed using the social interaction test (SIT). The results demonstrated that PAM-2 and DMXBA ameliorated ketamine-induced cognitive impairments on the ASST and NORT as well as produced pro-social activities in the SIT. Moreover, the co-administration of inactive doses of PAM-2 and antipsychotic drugs, clozapine or risperidone, reversed ketamine-induced deficits. The present findings provide further support for the concept that α7-PAMs could be used either alone or in combination with antipsychotics for schizophrenia therapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Survivors of exposure to an organophosphorus nerve agent may develop a number of complications including long-term cognitive deficits (Miyaki et al., 2005; Nishiwaki et al., 2001). We recently demonstrated that inhibition of the prostaglandin E2 receptor, EP2, attenuates neuroinflammation and neurodegeneration caused by status epilepticus (SE) induced by the soman analog, diisopropylfluorophosphate (DFP), which manifest within hours to days of the initial insult. Here, we tested the hypothesis that DFP exposure leads to a loss of cognitive function in rats that is blocked by early, transient EP2 inhibition. Adult male Sprague-Dawley rats were administered vehicle or the competitive EP2 antagonist, TG6-10-1, (ip) at various times relative to DFP-induced SE. DFP administration resulted in prolonged seizure activity as demonstrated by cortical electroencephalography (EEG). A single intraperitoneal injection of TG6-10-1 or vehicle 1 h prior to DFP did not alter the development of seizures, the latency to SE or the duration of SE. Rats administered six injections of TG6-10-1 starting 90 min after the onset of DFP-induced SE could discriminate between a novel and familiar object 6-12 weeks after SE, unlike vehicle treated rats which showed no preference for the novel object. By contrast, behavioral changes in the light-dark box and open field assays were not affected by TG6-10-1. Delayed mortality after DFP was also unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor may prevent SE-induced memory impairment in rats caused by exposure to a high dose of DFP., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The rodent hippocampus supports non-spatial object memory. Serotonin 5-HT2A receptors (5-HT2AR) are widely expressed throughout the hippocampus. We previously demonstrated that the activation of 5-HT2ARs enhanced the strength of object memory assessed 24 h after a limited (i.e., weak memory) training procedure. Here, we examined the subcellular distribution of 5-HT2ARs in the hippocampal CA1 region and underlying mechanisms of 5-HT2AR-mediated object memory consolidation. Analyses with immuno-electron microscopy revealed the presence of 5-HT2ARs on the dendritic spines and shafts of hippocampal CA1 neurons, and presynaptic terminals in the CA1 region. In an object recognition memory procedure that places higher demand on the hippocampus, only post-training systemic or intrahippocampal administration of the 5-HT2AR agonist TCB-2 enhanced object memory. Object memory enhancement by TCB-2 was blocked by the 5-HT2AR antagonist, MDL 11,937. The memory-enhancing dose of systemic TCB-2 increased extracellular glutamate levels in hippocampal dialysate samples, and increased the mean in vivo firing rate of hippocampal CA1 neurons. In summary, these data indicate a pre- and post-synaptic distribution of 5-HT2ARs, and activation of 5-HT2ARs selectively enhanced the consolidation of object memory, without affecting encoding or retrieval. The 5-HT2AR-mediated facilitation of hippocampal memory may be associated with an increase in hippocampal neuronal firing and glutamate efflux during a post-training time window in which recently encoded memories undergo consolidation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

It is well known that an impairment of learning and memory function is one of the major physiological effects caused by natural or synthetic cannabinoid consumption in rodents, nonhuman primates and in humans. JWH-018 and its halogenated derivatives (JWH-018-Cl and JWH-018-Br) are synthetic CB1/CB2 cannabinoid agonists, illegally marketed as "Spice" and "herbal blend" for their Cannabis-like psychoactive effects. In the present study the effects of acute exposure to JWH-018, JWH-018-Cl, JWH-018-Br (JWH-018-R compounds) and Δ(9)-THC (for comparison) on Novel Object Recognition test (NOR) has been investigated in mice. Moreover, to better characterize the effects of JWH-018-R compounds on memory function, in vitro electrophysiological and neurochemical studies in hippocampal preparations have been performed. JWH-018, JWH-018-Cl and JWH-018-Br dose-dependently impaired both short- and long-memory retention in mice (respectively 2 and 24 h after training session). Their effects resulted more potent respect to that evoked by Δ(9)-THC. Moreover, in vitro studies showed as JWH-018-R compounds negatively affected electrically evoked synaptic transmission, LTP and aminoacid (glutamate and GABA) release in hippocampal slices. Behavioral, electrophysiological and neurochemical effects were fully prevented by CB1 receptor antagonist AM251 pretreatment, suggesting a CB1 receptor involvement. These data support the hypothesis that synthetic JWH-018-R compounds, as Δ(9)-THC, impair cognitive function in mice by interfering with hippocampal synaptic transmission and memory mechanisms. This data outline the danger that the use and/or abuse of these synthetic cannabinoids may represent for the cognitive process in human consumer., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Nicotinic acetylcholine receptor (nAChR) subtypes containing the α4 subunit, particularly α4β2 nAChRs, play an important role in cognitive functioning. The impact of the smoking cessation aid varenicline, a selective partial α4β2 nAChR agonist, on (1) changes of central protein and mRNA expression of this receptor and (2) on memory deficits in a mouse model of cognitive impairment was investigated. Protein and mRNA expression of both the α4 and β2 receptor subunits in mouse brain endothelial and hippocampal cells as well as hippocampus and neocortex tissues were determined by western blot and realtime PCR, respectively. The β2 antibody showed low specificity, though. Tissues were examined following a 2-week oral treatment with various doses of varenicline (0.01, 0.1, 1, 3 mg/kg/day) or vehicle. In addition, episodic memory of mice was assessed following this treatment with an object recognition task using (1) normal mice and (2) animals with anticholinergic-induced memory impairment (i.p. injection of 0.5 mg/kg scopolamine). Varenicline dose-dependently increased protein expression of both the α4 and β2 subunit in cell cultures and brain tissues, respectively, but had no effect on mRNA expression of both subunits. Scopolamine injection induced a significant reduction of object memory in vehicle-treated mice. By contrast, cognitive performance was not altered by scopolamine in varenicline-treated mice. In conclusion, a 2-week oral treatment with varenicline prevented memory impairment in the scopolamine mouse model. In parallel, protein, but not mRNA expression was upregulated, suggesting a posttranscriptional mechanism. Our findings suggest a beneficial effect of varenicline on cognitive dysfunction., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Serotonin (5-HT) receptors still represent promising targets for the development of novel multireceptor or stand-alone antipsychotic drugs with a potential to ameliorate cognitive impairments and negative symptoms in schizophrenia. The 5-HT5A receptor, one of the least known members of the serotonin receptor family, has also drawn attention in this regard. Although the antipsychotic efficacy of 5-HT5A antagonists is still equivocal, recent experimental data suggest the cognitive-enhancing activity of this strategy. The aim of the present study was to evaluate pro-cognitive and pro-social efficacies of the 5-HT5A receptor antagonist in a rat pharmacological model of schizophrenia employing the administration of the NMDA receptor antagonist, ketamine. The ability of SB-699551 to reverse ketamine-induced cognitive deficits in the attentional set-shifting task (ASST) and novel object recognition task (NORT) was examined. The compound's efficacy against ketamine-induced social withdrawal was assessed in the social interaction test (SIT) and in the social choice test (SCT). The results demonstrated the efficacy of SB-699551 in ameliorating ketamine-induced impairments on the ASST and NORT. Moreover, the tested compound also enhanced set-shifting performance in cognitively unimpaired control rats and improved object recognition memory in conditions of delay-induced natural forgetting. The pro-social activity of SB-699551 was demonstrated on both employed paradigms, the SIT and SCT. The present study suggests the preclinical efficacy of a strategy based on the blockade of 5-HT5A receptors against schizophrenia-like cognitive deficits and negative symptoms. The utility of this receptor as a target for improvement of cognitive and social dysfunctions warrants further studies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Opiate use disorders are associated with impaired cognitive function and altered stress-responsive systems. The corticotropin-releasing factor (CRF) system mediates stress responses via CRF1 and CRF2 receptors and may be implicated in substance use disorders. However, the specific role for each of the two known CRF receptor subtypes in cognitive impairment induced by opiate administration and withdrawal remains to be elucidated. In the present study, CRF1-/-, CRF2-/- and their respective wild-type mice are injected with escalating doses of morphine and cognitive function assessed by the novel object recognition (NOR) memory task throughout relatively long periods of opiate withdrawal. Early (2 days) phases of opiate withdrawal impair NOR memory in wild-type, CRF1-/- and CRF2-/- mice. However, the duration of opiate withdrawal-induced NOR memory deficits is prolonged in CRF1-/- but shortened in CRF2-/- mice, as compared to their respective wild-type mice, indicating opposite roles for the two CRF receptor subtypes. Nevertheless, following apparent recovery, exposure to an environmental stressor induces the reemergence of NOR memory deficits in long-term opiate-withdrawn wild-type but not CRF1-/- or CRF2-/- mice, indicating an essential role for both CRF receptor subtypes in stress vulnerability. These findings bring initial evidence of a complex physiopathological role for the CRF system in cognitive deficits and the long-lasting vulnerability induced by opiate drugs., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Traumatic brain injury (TBI) is often a result of traffic accidents, contact sports or battlefield explosions. A mild form of traumatic brain injury (mTBI) is frequently underestimated, as the immediate physical symptoms decrease rapidly and conventional neuroimaging studies often do not show visible evidence of brain lesions. However, cognitive impairments persist for weeks, months or even years after the incident. Endogenous opioids were documented to play a role in thmodulation of mTBI pathology, whereas exogenous opioids were shown to possess neuroprotective properties. In the present study, biphalin, a dimeric enkephalin analog, improved cognitive performance in the Morris Water Maze and Novel Object Recognition tests in a mouse weight-drop model of mTBI. The effect of a single systemic injection of 10 mg/kg biphalin immediately after trauma was reversed by naltrexone, suggesting an opioid receptor-mediated mechanism. Biphalin also reduced cortical and hippocampal neurodegeneration, as shown by silver staining. Our data indicates that opioid receptor activation by biphalin may provide neuroprotection of post-traumatic neurodegeneration processes and may protect against memory impairments., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Alpha 7 nicotinic acetylcholine receptors (α7-nAChRs) have generated great interest as targets of new pharmacological treatments for cognitive dysfunction in schizophrenia. One promising recent approach is based on the use of positive allosteric modulators (PAMs) of α7-nAChRs, which demonstrate several advantages over direct agonists. Nevertheless, the efficacy of these newly introduced α7-nAChR agents has not been extensively characterised in animal models of schizophrenia. The aim of the present study was to evaluate the efficacy of type I and II PAMs, N-(5-chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)urea (PNU-120596) and N-(4-chlorophenyl)-[[(4-chlorophenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide (CCMI), respectively, and galantamine, an acetylcholinesterase inhibitor (AChE) that also allosterically modulates nAChRs, against ketamine-induced cognitive deficits and social withdrawal in rats. The orthosteric α7-nAChR agonist octahydro-2-methyl-5-(6-phenyl-3-pyridazinyl)-pyrrolo[3,4-c]pyrrole (A-582941) was used as a positive control. Additionally, the antipsychotic activities of the tested compounds were assessed using the conditioned avoidance response (CAR) test. PNU-120596, CCMI, galantamine and A-582941 reversed ketamine-induced cognitive inflexibility, as assessed in the attentional set-shifting task (ASST). The tested compounds were also effective against ketamine-induced impairment in the novel object recognition task (NORT). PNU-120596, CCMI, and A-582941 ameliorated ketamine-induced social interaction deficits, whereas galantamine was ineffective. Moreover, all tested compounds selectively suppressed the CAR. The positive allosteric modulation of α7-nAChRs demonstrates preclinical efficacy not only against schizophrenia-like cognition impairments but also positive and negative symptoms. Therefore, the use of α7-nAChR PAMs as a potential treatment strategy in schizophrenia is supported., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Cannabis continues to be the most accessible and popular illicit recreational drug. Whereas current data link adolescence cannabinoid exposure to increased risk for dependence on other drugs, depression, anxiety disorders and psychosis, the mechanism(s) underlying these adverse effects remains controversial. Here we show in a mouse model of female adolescent cannabinoid exposure deficient endocannabinoid (eCB)-mediated signaling and presynaptic forms of long-term depression at adult central glutamatergic synapses in the prefrontal cortex. Increasing endocannabinoid levels by blockade of monoacylglycerol lipase, the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol (2-AG), with the specific inhibitor JZL 184 ameliorates eCB-LTD deficits. The observed deficit in cortical presynaptic signaling may represent a neural maladaptation underlying network instability and abnormal cognitive functioning. Our study suggests that adolescent cannabinoid exposure may permanently impair brain functions, including the brain's intrinsic ability to appropriately adapt to external influences., (Published by Elsevier Ltd.)

Previous neuroprotective studies demonstrated that 1-(R)-aminoindan (AI), which is the major metabolite of the anti-Parkinsonian drug rasagiline, possesses beneficial pharmacological effects in various cell culture and animal models of neurodegeneration. The present study was aimed at investigating the possible neuroprotective effects of AI on cognitive impairments and neurochemical alterations in aged mice. Our findings provide evidence that following chronic systemic treatment with AI (5 mg/kg; daily; 3 months) of aged mice (24 months old), the compound exerted a significant positive impact on neuropsychiatric functions and cognitive behavior deficits, assessed in a variety of tasks (spatial learning and memory retention, working memory, learning abilities and nest building behavior) and produced an antidepressant-like effect. In addition, chronic AI treatment significantly enhanced expression levels of neurotrophins, including brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF), tyrosine kinase- B (Trk-B) receptor and synaptic plasticity markers, such as synapsin-1 and growth-associated protein-43 (GAP-43) in the striatum and hippocampus in aged mice. Our results also indicate that AI treatment up-regulated the expression levels of the pro-survival Bcl-2 mRNA, increased the anti-apoptotic index Bcl-2/Bax and enhanced the activity of the antioxidant enzyme catalase in the brain of aged mice. These effects of AI were also confirmed in aged rats (24 months old). Altogether, the present findings indicate that AI can induce neuroprotective effects on age-related alterations in neurobehavioral functions and exerts neurotrophic up-regulatory and anti-apoptotic properties in aged animals., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In previous studies, we have shown that phosphodiesterase type 5 inhibitors (PDE5-Is) can improve early consolidation of object memory. These conclusions were based on the timing of drug administration relative to the learning trial (i.e. before or after). However, there are very little pharmacological data available about the pharmacokinetic profile of orally administered PDE5-Is in the rat. Furthermore, there is still debate whether these effects are achieved via central or peripheral mechanisms and if acquisition processes are improved. In the current study, we tested the effects of the PDE5-I vardenafil in a cholinergic-deficit model and compared the effects after intracerebroventricular (ICV) versus oral (PO) administration. We found that PO vardenafil restored a scopolamine-induced memory impairment when dosed within 2 min after the learning trial while ICV vardenafil was able to restore memory when injected within 4 min after learning. Because the test trial was within 10 min after the learning trial, this suggests that these effects on object memory are related to acquisition processes that may still be ongoing in a time window after the learning trial. To further elucidate the extent of this acquisition window, we investigated the pharmacokinetic profile of vardenafil after PO administration where it was detected within 4 min post-dose. Taken together, our data suggest that PDE5 is involved in acquisition processes, which may linger for at least 4-6 min after learning. Further studies are needed to exclude that these effects could also be explained on basis of an effect on early consolidation processes. Additionally, the effectiveness of ICV-administered vardenafil provides further experimental evidence that PDE5-Is improve memory via a central mechanism., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

β-amyloid1-42 (Aβ1-42) is a major endogenous pathogen underlying the aetiology of Alzheimer's disease (AD). Recent evidence indicates that soluble Aβ oligomers, rather than plaques, are the major cause of synaptic dysfunction and neurodegeneration. Small molecules that suppress Aβ aggregation, reduce oligomer stability or promote off-pathway non-toxic oligomerization represent a promising alternative strategy for neuroprotection in AD. MRZ-99030 was recently identified as a dipeptide that modulates Aβ1-42 aggregation by triggering a non-amyloidogenic aggregation pathway, thereby reducing the amount of intermediate toxic soluble oligomeric Aβ species. The present study evaluated the relevance of these promising results with MRZ-99030 under pathophysiological conditions i.e. against the synaptotoxic effects of Aβ oligomers on hippocampal long term potentiation (LTP) and two different memory tasks. Aβ1-42 interferes with the glutamatergic system and with neuronal Ca(2+) signalling and abolishes the induction of LTP. Here we demonstrate that MRZ-99030 (100-500 nM) at a 10:1 stoichiometric excess to Aβ clearly reversed the synaptotoxic effects of Aβ1-42 oligomers on CA1-LTP in murine hippocampal slices. Co-application of MRZ-99030 also prevented the two-fold increase in resting Ca(2+) levels in pyramidal neuron dendrites and spines triggered by Aβ1-42 oligomers. In anaesthetized rats, pre-administration of MRZ-99030 (50 mg/kg s.c.) protected against deficits in hippocampal LTP following i.c.v. injection of oligomeric Aβ1-42. Furthermore, similar treatment significantly ameliorated cognitive deficits in an object recognition task and under an alternating lever cyclic ratio schedule after the i.c.v. application of Aβ1-42 and 7PA2 conditioned medium, respectively. Altogether, these results demonstrate the potential therapeutic benefit of MRZ-99030 in AD., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

We previously showed that activity of the large conductance calcium-activated potassium (Big-K; BK) channels is suppressed in 3xTg Alzheimer disease (AD) model mice. However, its behavioral significance is not known. In the present report, ventricular injection of the BK channel activator isopimaric acid (ISO) was conducted to examine whether BK channel activation ameliorates cognition in 3xTg mice. The novel object recognition (NOR) test revealed that chronic injection of ISO improved non-spatial memory in 3xTg mice. In the Morris water maze, the probe test demonstrated an improved spatial memory after ISO injection. Electrophysiological underpinnings of the ISO effect were then examined in slices obtained from the mice after behavior. At hippocampal CA1 synapses, the basic synaptic transmission was abnormally elevated and long-term potentiation (LTP) was partially suppressed in 3xTg mice. These were both recovered by ISO treatment. We then confirmed suppressed BK channel activity in 3xTg mice by measuring the half-width of evoked action potentials. This was also recovered by ISO treatment. We previously showed that the recovery of BK channel activity accompanies reduction of neuronal excitability in pyramidal cells. Here again, pyramidal cell excitability, as assessed by calculating the frequency of evoked spikes, was elevated in the 3xTg mouse and was normalized by ISO. ELISA experiments demonstrated an ISO-induced reduction of Aβ1-42 content in hippocampal tissue in 3xTg mice. The present study thus suggests a potential therapeutic utility of BK channel activators for AD., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Glutamatergic hyperactivity plays an important role in the pathophysiology of Parkinson's disease (PD). Ceftriaxone increases expression of glutamate transporter 1 (GLT-1) and affords neuroprotection. This study was aimed at clarifying whether ceftriaxone prevented, or reversed, behavioral and neuronal deficits in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Male Wistar rats were injected daily with either ceftriaxone starting 5 days before or 3 days after MPTP lesioning (day 0) or saline and underwent a bar-test on days 1-7, a T-maze test on days 9-11, and an object recognition test on days 12-14, then the brains were taken for histological evaluation on day 15. Dopaminergic degeneration in the substantia nigra pars compacta and striatum was observed on days 3 and 15. Motor dysfunction in the bar test was observed on day 1, but disappeared by day 7. In addition, lesioning resulted in deficits in working memory in the T-maze test and in object recognition in the object recognition task, but these were not observed in rats treated pre- or post-lesioning with ceftriaxone. Lesioning also caused neurodegeneration in the hippocampal CA1 area and induced glutamatergic hyperactivity in the subthalamic nucleus, and both changes were suppressed by ceftriaxone. Increased GLT-1 expression and its co-localization with astrocytes were observed in the striatum and hippocampus in the ceftriaxone-treated animals. To our knowledge, this is the first study showing a relationship between ceftriaxone-induced GLT-1 expression, neuroprotection, and improved cognition in a PD rat model. Ceftriaxone may have clinical potential for the prevention and treatment of dementia associated with PD., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Schizophrenia is associated with atypical multisensory integration. Rats treated sub-chronically with NMDA receptor antagonists to model schizophrenia are severely impaired on a tactile-to-visual crossmodal object recognition (CMOR) task, and this deficit is reversed by systemic nicotine. The current study assessed the receptor specificity of the ameliorative effect of nicotine in the CMOR task, as well as the potential for nicotinic receptor (nAChR) interactions with GABA and glutamate. Male Long-Evans rats were treated sub-chronically for 10 days with ketamine or saline and then tested on the CMOR task after a 10-day washout. Systemic nicotine given before the sample phase of the CMOR task reversed the ketamine-induced impairment, but this effect was blocked by co-administration of the GABAA receptor antagonist bicuculline at a dosage that itself did not cause impairment. Pre-sample systemic co-administration of the NMDA receptor antagonist MK-801 did not block the remediating effect of nicotine in ketamine-treated rats. The selective α7 nAChR agonist GTS-21 and α4β2 nAChR agonist ABT-418 were also tested, with only the latter reversing the ketamine impairment dose-dependently; bicuculline also blocked this effect. Similarly, infusions of nicotine or ABT-418 into the orbitofrontal cortex (OFC) reversed the CMOR impairment in ketamine-treated rats, and systemic bicuculline blocked the effect of intra-OFC ABT-418. These results suggest that nicotine-induced agonism of α4β2 nAChRs within the OFC ameliorates CMOR deficits in ketamine-treated rats via stimulation of the GABAergic system. The findings of this research may have important implications for understanding the nature and potential treatment of cognitive impairment in schizophrenia., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders, antidepressants that target key 5-HT (serotonin) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility. Vortioxetine is a multimodal antidepressant that inhibits 5-HT1D, 5-HT3, 5-HT7 receptor activity, 5-HT reuptake, and enhances the activity of 5-HT1A and 5-HT1B receptors. In this study, we investigated the effects of vortioxetine on the period length of PER2::LUC expression, circadian behavior, and episodic memory, using tissue explants from genetically modified PER2::LUC mice, locomotor activity rhythm monitoring, and the object recognition test, respectively. Incubation of tissue explants from the suprachiasmatic nucleus of PER2::LUC mice with 0.1 μM vortioxetine increased the period length of PER2 bioluminescence. Monitoring of daily wheel-running activity of Sprague-Dawley rats treated with vortioxetine (10 mg/kg, s.c.), alone or in combination with the 5-HT1A receptor agonist flesinoxan (2.5 mg/kg, s.c.) or the 5-HT7 receptor antagonist SB269970 (30 mg/kg, s.c.), just prior to activity onset revealed significant delays in wheel-running behavior. The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the 5-HT7 receptor partial agonist AS19. Finally, in the object recognition test, vortioxetine (10 mg/kg, i.p.) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 (5 mg/kg, i.p.). In conclusion, the present study shows that vortioxetine, partly via its 5-HT7 receptor antagonism, induced a significant effect on circadian rhythm and presented promnesic properties in rodents.

Chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans and in animal models. Modafinil is a wake-promoting compound approved for the treatment of sleeping disorders. It is also prescribed off label to treat METH dependence. In the present study, we investigated whether modafinil could improve cognitive deficits induced by sub-chronic METH treatment in mice by measuring visual retention in a Novel Object Recognition (NOR) task. After sub-chronic METH treatment (1 mg/kg, once a day for 7 days), mice performed the NOR task, which consisted of habituation to the object recognition arena (5 min a day, 3 consecutive days), training session (2 equal objects, 10 min, day 4), and a retention session (1 novel object, 5 min, day 5). One hour before the training session, mice were given a single dose of modafinil (30 or 90 mg/kg). METH-treated mice showed impairments in visual memory retention, evidenced by equal preference of familiar and novel objects during the retention session. The lower dose of modafinil (30 mg/kg) had no effect on visual retention scores in METH-treated mice, while the higher dose (90 mg/kg) rescued visual memory retention to control values. We also measured extracellular signal-regulated kinase (ERK) phosphorylation in medial prefrontal cortex (mPFC), hippocampus, and nucleus accumbens (NAc) of METH- and vehicle-treated mice that received modafinil 1 h before exposure to novel objects in the training session, compared to mice placed in the arena without objects. Elevated ERK phosphorylation was found in the mPFC of vehicle-treated mice, but not in METH-treated mice, exposed to objects. The lower dose of modafinil had no effect on ERK phosphorylation in METH-treated mice, while 90 mg/kg modafinil treatment restored the ERK phosphorylation induced by novelty in METH-treated mice to values comparable to controls. We found neither a novelty nor treatment effect on ERK phosphorylation in hippocampus or NAc of vehicle- and METH-treated mice receiving acute 90 mg/kg modafinil treatment. Our results showed a palliative role of modafinil against METH-induced visual cognitive impairments, possibly by normalizing ERK signaling pathways in mPFC. Modafinil may be a valuable pharmacological tool for the treatment of cognitive deficits observed in human METH abusers as well as in other neuropsychiatric conditions. This article is part of the Special Issue entitled 'CNS Stimulants'., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Cognitive dysfunction is more common in individuals with type 2 diabetes (T2DM). Currently, glucagon-like peptide-1 (GLP-1) and metformin are important therapeutic options for patients with T2DM. However, their potential effects on cognitive function, including underlying mechanisms, are yet to be fully determined. We have compared the individual and combined effects of treatment for 20 days with (Val(8))GLP-1(GluPAL), an enzymatically stable GLP-1-receptor agonist, and metformin on metabolic control and aspects of learning and memory in high fat fed mice. (Val(8))GLP-1(GluPAL) treatment for 20 days alone, or in combination with metformin, improved (p < 0.05) the recognition index in high fat mice, indicating enhanced learning and memory. In addition, these mice exhibited a complete reversal of the deleterious effects of prolonged high-fat feeding on long-term potentiation in the hippocampal CA1 region. This was linked to reduced hippocampal levels of 8-oxoguanine (p < 0.01) and glial fibriallary acidic protein (p < 0.001), indicating decreased oxidative stress and inflammation; respectively. Expression of fundamental hippocampal genes including mTOR, VEGF, NTRK2 and SIRT1 was also increased significantly (p < 0.001) by all treatments. (Val(8))GLP-1(GluPAL) monotherapy, or in combination with metformin, reduced circulating glucose (p < 0.05) and increased insulin (p < 0.05 to p < 0.01) concentrations, as well as improving glucose tolerance (p < 0.001) and glucose-stimulated insulin secretion (p < 0.05 to p < 0.01). Insulin sensitivity and measurements of energy regulation and metabolic rate were not altered. These studies highlight the neuroprotective properties of (Val(8))GLP-1(GluPAL), alone and in combination with metformin, in T2DM., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Type 2 diabetes is a risk factor for developing Alzheimer's disease (AD). In the brains of AD patients, insulin signalling is desensitised. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and analogues such as liraglutide are on the market as treatments for type 2 diabetes. We have previously shown that liraglutide showed neuroprotective effects in the APPswe/PS1ΔE9 mouse model of AD. Here, we test the GLP-1 receptor agonist lixisenatide in the same mouse model and compare the effects to liraglutide. After ten weeks of daily i.p. injections with liraglutide (2.5 or 25 nmol/kg) or lixisenatide (1 or 10 nmol/kg) or saline of APP/PS1 mice at an age when amyloid plaques had already formed, performance in an object recognition task was improved in APP/PS1 mice by both drugs at all doses tested. When analysing synaptic plasticity in the hippocampus, LTP was strongly increased in APP/PS1 mice by either drug. Lixisenatide (1 nmol/kg) was most effective. The reduction of synapse numbers seen in APP/PS1 mice was prevented by the drugs. The amyloid plaque load and dense-core Congo red positive plaque load in the cortex was reduced by both drugs at all doses. The chronic inflammation response (microglial activation) was also reduced by all treatments. The results demonstrate that the GLP-1 receptor agonists liraglutide and lixisenatide which are on the market as treatments for type 2 diabetes show promise as potential drug treatments of AD. Lixisenatide was equally effective at a lower dose compared to liraglutide in some of the parameters measured., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Schizophrenia is a severe neuropsychiatric disorder that is characterized by core psychiatric symptoms, including positive, negative, and cognitive symptoms. Current treatments for schizophrenia have an effect on positive symptoms but have a limited efficacy on negative or cognitive symptoms. Oleanolic acid is a plant-derived pentacyclic terpenoid that is known to exhibit anti-oxidative and anti-inflammatory activities. Here, we investigated the effects of oleanolic acid on schizophrenia-like behaviors in mice elicited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. A single administration of oleanolic acid blocked MK-801-induced hyperlocomotion in the open field test. In the acoustic startle response test, oleanolic acid itself did not have any effects on the acoustic startle response or prepulse inhibition (PPI) level, whereas the MK-801-induced PPI deficit was ameliorated by oleanolic acid. In the novel object recognition test, the attention and recognition memory impairments induced by MK-801 were reversed by a single administration of oleanolic acid. Additionally, oleanolic acid normalized the MK-801-induced alterations of signaling molecules including phosphorylation levels of Akt and GSK-3β in the frontal cortex. These results suggest that oleanolic acid could be a candidate for the treatment of several symptoms of schizophrenia, including positive symptoms, sensorimotor gating disruption, and cognitive impairments., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Memory loss is one of the key features of cognitive impairment in either aging, Mild Cognitive Impairment (MCI) or dementia. Pharmacological treatments for memory loss are today focused on addressing symptomatology. One of these approved compounds is memantine, a partial NMDA receptor antagonist that has proved its beneficial effects in cognition. The Octodon degus (O. degus) has been recently proposed as a potential model relevant for neurodegenerative diseases. However, there are no previous studies investigating the effect of pharmacological treatments for age-related cognitive impairment in this rodent. In this work we aimed to evaluate the effect of memantine on sleep deprivation (SD)-induced memory impairment in young and old O. degus. Young and old animals were trained in different behavioral paradigms validated for memory evaluation, and randomly assigned to a control (CTL, n=14) or an SD (n=14) condition, and treated with vehicle or memantine (10-mg/Kg i.p.) before the SD started. We demonstrate that SD impairs memory in both young and old animals, although the effect in the old group was significantly more severe (P<0.05). Memantine pretreatment was able to prevent the cognitive impairment caused by SD in both age groups, while it had no negative effect on CTL animals. The positive effect of memantine in counteracting the negative effect of SD on the retrieval process even in the aged O. degus further supports the translational potential of both the challenge and the species, and will enable a better understanding of the behavioral features of memantine effects, especially related with reference and working memories., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Experimental evidence indicates that the non competitive N-methyl-d-aspartate (NMDA) receptor antagonist ketamine and the mixed dopamine (DA) D1/D2 receptor agonist apomorphine induce schizophrenia-like symptoms in rodents, including cognitive deficits. Activation of Group II metabotropic glutamate 2/3 (mGlu2/3) receptors reduces the excessive glutamate release that is hypothesized to be associated with psychiatric disorders. Thus, mGlu2/3 receptor agonists may reverse deficits induced by excessive glutamate or DA release induced by administration of NMDA receptor antagonists and DA receptor agonists, respectively, and potentially those seen in schizophrenia. LY379268 is a selective mGlu2/3 receptor agonist that has shown to be effective in several animal models of stroke, epilepsy, and drug abuse. The present study investigated whether LY379268 antagonizes non-spatial and spatial recognition memory deficits induced by ketamine and apomorphine administration in rats. To assess the effects of the compounds on non-spatial and spatial recognition memory, the object recognition task and object location task were used. Post-training administration of LY379268 (1-3 mg/kg, i.p.) counteracted ketamine (3 mg/kg, i.p.) and apomorphine (1 mg/kg, i.p.)-induced performance deficits in the object recognition task. In contrast, LY379268 (1-3 mg/kg, i.p.) did not attenuate spatial recognition memory deficits produced by ketamine (3 mg/kg, i.p.) or apomorphine (1 mg/kg, i.p.) in the object location task. The present data show that the mGlu2/3 receptor agonist LY379268 reversed non-spatial, but not spatial, recognition memory deficits induced by NMDA receptor blockade or DA receptor agonism in rodents. Thus, such mGlu2/3 receptor agonists may be efficacious in reversing some memory deficits seen in schizophrenia patients., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Emotionally arousing events like encounter with an unfamiliar con-species produce strong and vivid memories, whereby the hippocampus and amygdala play a crucial role. It is less understood, however, which neurotransmitter systems regulate the strength of social memories, which have a strong emotional component. It was shown previously that dynorphin signalling is involved in the formation and extinction of fear memories, therefore we asked if it influences social memories as well. Mice with a genetic deletion of the prodynorphin gene Pdyn (Pdyn(-/-)) showed a superior partner recognition ability, whereas their performance in the object recognition test was identical as in wild-type mice. Pharmacological blockade of kappa opioid receptors (KORs) led to an enhanced social memory in wild-type animals, whereas activation of KORs reduced the recognition ability of Pdyn(-/-) mice. Partner recognition test situation induced higher elevation in dynorphin A levels in the central and basolateral amygdala as well as in the hippocampus, and also higher dynorphin B levels in the hippocampus than the object recognition test situation. Our result suggests that dynorphin system activity is increased in emotionally arousing situation and it decreases the formation of social memories. Thus, dynorphin signalling is involved in the formation of social memories by diminishing the emotional component of the experience., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Currently, several studies addresses the novel link between sleep and dopaminergic neurotransmission, focusing most closely on the mechanisms by which Parkinson's disease (PD) and sleep may be intertwined. Therefore, variations in the activity of afferents during the sleep cycles, either at the level of DA cell bodies in the ventral tegmental area (VTA) and/or substantia nigra pars compacta (SNpc) or at the level of dopamine (DA) terminals in limbic areas may impact functions such as memory. Accordingly, we performed striatal and hippocampal neurochemical quantifications of DA, serotonin (5-HT) and metabolites of rats intraperitoneally treated with haloperidol (1.5 mg/kg) or piribedil (8 mg/kg) and submitted to REM sleep deprivation (REMSD) and sleep rebound (REB). Also, we evaluated the effects of REMSD on motor and cognitive parameters and SNpc c-Fos neuronal immunoreactivity. The results indicated that DA release was strongly enhanced by piribedil in the REMSD group. In opposite, haloperidol prevented that alteration. A c-Fos activation characteristic of REMSD was affected in a synergic manner by piribedil, indicating a strong positive correlation between striatal DA levels and nigral c-Fos activation. Hence, we suggest that memory process is severely impacted by both D2 blockade and REMSD and was even more by its combination. Conversely, the activation of D2 receptor counteracted such memory impairment. Therefore, the present evidence reinforce that the D2 receptor is a key player in the SNpc neuronal activation mediated by REMSD, as a consequence these changes may have direct impact for cognitive and sleep abnormalities found in patients with PD. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'., (Copyright © 2013 Elsevier Ltd. All rights reserved.)