Step-down Inhibitory Avoidance Research Articles

Distinct Chrna5 mutations link excessive alcohol use to types I/II vulnerability profiles and IPN GABAergic neurons

Genome wide association and animal studies have implicated genetic variations in CHRNΑ5, encoding the α5 subunit-containing nicotinic acetylcholine receptors (α5*nAChRs), as a risk factor for developing alcohol use disorders (AUDs). To understand how α5*nAChR mutations may influence alcohol (EtOH) drinking behavior, we used a two-bottle choice procedure with intermittent access to alcohol in male and female transgenic mice expressing either the highly frequent human single nucleotide polymorphism (α5SNP/rs16969968) or a deletion of the Chrna5 gene (α5KO). AUDs-related preconsommatory traits (anxiety, sensation-seeking and impulsivity) were assessed with a battery of relevant tasks (elevated-plus maze, novel place preference and step-down inhibitory avoidance). The implication of the α5-expressing IPN GABAergic neurons in AUDs and related behavioral traits was verified using neurospecific lentiviral (LV)-induced reexpression of the α5 subunit in α5KOxGAD-Cre mice. Both α5SNP and α5KO mice showed over-consumption of EtOH, but displayed opposite vulnerability profiles consistent with Cloninger’s subtypes of human AUDs. α5SNP mice showed Type I-like characteristics, i.e., high anxiety, novelty avoidance, whereas α5KOs exhibited Type II-like features such as low anxiety and high impulsivity. LV re-expression of the α5 subunit in IPN GABAergic neurons restored the control of EtOH intake and improved the impulsive phenotype. We demonstrate that the SNP (rs16969968) or null mutation of Chrna5 result in increased volitional EtOH consumption but opposite effects on anxiety, novelty-seeking and impulsive-like behaviors that match Cloninger type I and II of AUDs, including sex-related variations. IPN GABAergic neurons expressing α5*nAChRs play a key role in limiting both EtOH drinking and motor impulsivity.

New curcumin-loaded nanocapsules as a therapeutic alternative in an amnesia model.

This study aimed to investigate the action of two different formulations of curcumin (Cur)-loaded nanocapsules (Nc) (Eudragit [EUD] and poly (ɛ-caprolactone) [PCL]) in an amnesia mice model. We also investigated the formulations' effects on scopolamine-induced (SCO) depressive- and anxiety-like comorbidities, the cholinergic system, oxidative parameters, and inflammatory markers. Male Swiss mice were randomly divided into five groups (n = 8): group I (control), group II (Cur PCL Nc 10mg/kg), group III (Cur EUD Nc 10mg/kg), group IV (free Cur 10mg/kg), and group V (SCO). Treatments with Nc or Cur (free) were performed daily or on alternate days. After 30min of treatment, the animals received the SCO and were subjected to behavioral tests 30min later (Barnes maze, open-field, object recognition, elevated plus maze, tail suspension tests, and step-down inhibitory avoidance tasks). The animals were then euthanized and tissue was removed for biochemical assays. Our results demonstrated that Cur treatment (Nc or free) protected against SCO-induced amnesia and depressive-like behavior. The ex vivo assays revealed lower acetylcholinesterase (AChE) and catalase (CAT) activity, reduced thiobarbituric species (TBARS), reactive species (RS), and non-protein thiols (NSPH) levels, and reduced interleukin-6 (IL-6) and tumor necrosis factor (TNF) expression. The treatments did not change hepatic markers in the plasma of mice. After treatments on alternate days, Cur Nc had a more significant effect than the free Cur protocol, implying that Cur may have prolonged action in Nc. This finding supports the concept that it is possible to achieve beneficial effects in nanoformulations, and treatment on alternate days differs from the free Cur protocol regarding anti-amnesic effects in mice.

Cross state-dependent memory retrieval between tramadol and ethanol: involvement of dorsal hippocampal GABAA receptors.

Tramadol and ethanol, as psychoactive agents, are often abused. Discovering the molecular pathways of drug-induced memory creation may contribute to preventing drug addiction and relapse. The tramadol- and ethanol-induced state-dependent memory (SDM) and cross-SDM retrieval between tramadol and ethanol were examined in this study. Moreover, because of the confirmed involvement of GABAA receptors and GABAergic neurotransmission in memory retrieval impairment, we assessed cross-SDM retrieval between tramadol and ethanol with a specific emphasis on the role of the GABAA receptors. The first hypothesis of this study was the presence of cross-SDM between tramadol and ethanol, and the second hypothesis was related to possible role of GABAA receptors in memory retrieval impairment within the dorsal hippocampus. The cannulae were inserted into the hippocampal CA1 area of NMRI mice, and a step-down inhibitory avoidance test was used to evaluate state dependence and memory recovery. The post-training and/or pre-test administration of tramadol (2.5 and 5 mg/kg, i.p.) and/or ethanol (0.5 and 1 g/kg, i.p.) induced amnesia, which was restored after the administration of the drugs 24 h later during the pre-test period, proposing ethanol and tramadol SDM. The pre-test injection of ethanol (0.25 and 0.5 g/kg, i.p.) with tramadol at an ineffective dose (1.25 mg/kg) enhanced tramadol SDM. Moreover, tramadol injection (1.25 and 2.5 mg/kg) with ethanol at the ineffective dose (0.25 g/kg) promoted ethanol SDM. Furthermore, the pre-test intra-CA1 injection of bicuculline (0.0625, 0.125, and 0.25 μg/mouse), a GABAA receptor antagonist, 5 min before the injection of tramadol (5 mg/kg) or ethanol (1 g/kg) inhibited tramadol- and ethanol-induced SDM dose-dependently. The findings strongly confirmed cross-SDM between tramadol and ethanol and the critical role of dorsal hippocampal GABAA receptors in the cross-SDM between tramadol and ethanol.

Antisense oligonucleotides targeting basal forebrain ATXN2 enhances spatial memory and ameliorates sleep deprivation-induced fear memory impairment in mice.

Regulation of brain-derived neurotrophic factor (BDNF) in the basal forebrain ameliorates sleep deprivation-induced fear memory impairments in rodents. Antisense oligonucleotides (ASOs) targeting ATXN2 was a potential therapy for spinocerebellar ataxia, whose pathogenic mechanism associates with reduced BDNF expression. We tested the hypothesis that ASO7 targeting ATXN2 could affect BDNF levels in mouse basal forebrain and ameliorate sleep deprivation-induced fear memory impairments. Adult male C57BL/6 mice were used to evaluate the effects of ASO7 targeting ATXN2 microinjected into the bilateral basal forebrain (1 μg, 0.5 μL, each side) on spatial memory, fear memory and sleep deprivation-induced fear memory impairments. Spatial memory and fear memory were detected by the Morris water maze and step-down inhibitory avoidance test, respectively. Immunohistochemistry, RT-PCR, and Western blot were used to evaluate the changes of levels of BDNF, ATXN2, and postsynaptic density 95 (PSD95) protein as well as ATXN2 mRNA. The morphological changes in neurons in the hippocampal CA1 region were detected by HE staining and Nissl staining. ASO7 targeting ATXN2 microinjected into the basal forebrain could suppress ATXN2 mRNA and protein expression for more than 1 month and enhance spatial memory but not fear memory in mice. BDNF mRNA and protein expression in basal forebrain and hippocampus was increased by ASO7. Moreover, PSD95 expression and synapse formation were increased in the hippocampus. Furthermore, ASO7 microinjected into the basal forebrain increased BDNF and PSD95 protein expression in the basal forebrain of sleep-deprived mice and counteracted sleep deprivation-induced fear memory impairments. ASOs targeting ATXN2 may provide effective interventions for sleep deprivation-induced cognitive impairments.

Hippocampal cholinergic receptors and the mTOR participation in fear-motivated inhibitory avoidance extinction memory

Evidence has demonstrated the hippocampal cholinergic system and the mammalian target of rapamycin (mTOR) participation during the memory formation of aversive events. This study assessed the role of these systems in the hippocampus for the extinction memory process by submitting male Wistar rats to fear-motivated step-down inhibitory avoidance (IA). The post-extinction session administration of the nicotinic and muscarinic cholinergic receptor antagonists, mecamylamine and scopolamine, respectively, both at doses of 2 µg/µl/side, and rapamycin, an mTOR inhibitor (0.02 µg/µl/side), into the CA1 region of the dorsal hippocampus, impaired the IA extinction memory. Furthermore, the nicotinic and muscarinic cholinergic receptor agonists, nicotine and muscarine, respectively, had a dose-dependent effect on the IA extinction memory when administered intra-CA1, immediately after the extinction session. Nicotine (0.6 µg/µl/side) and muscarine (0.02 µg/µl/side), respectively, had no effect, while the higher doses (6 and 2 µg/µl/side, respectively) impaired the IA extinction memory. Interestingly, the co-administration of muscarine at the lower dose blocked the impairment that was induced by rapamycin. This effect was not observed when nicotine at the lower dose was co-administered. These results have demonstrated the participation of the cholinergic receptors and mTOR in the hippocampus for IA extinction, and that the cholinergic agonists had a dose-dependent effect on the IA extinction memory. This study provides insights related to the behavioural aspects and the neurobiological properties underlying the early stage of fear-motivated IA extinction memory consolidation and suggests that there is hippocampal muscarinic receptor participation independent of mTOR in this memory process.

Neuroprotective effect of derris indica seed extract attenuates amyloid beta plaques induce Alzheimer’s in mice model

The progression of Alzheimer's disease type dementia is carried on by the neurotoxic effects of amyloid beta (Aβ25-35) peptide accumulation. The hypothalamic-pituitary-adrenal(HPA) axis malfunctions and leads to higher levels of amyloid beta(Aβ) accumulation. In this work, we looked at how Derris indica extract affected mice brains that had undergone neurodegeneration caused by the Aβ. Derris indica seed extract(DISE) were administered to mice over the course of 21 days in two dosages (50 mg/kg and 100 mg/kg). On the 21st day, tests for spatial learning, habituation memory, short-and long-term memory, and stepdown inhibitory responses were carried out. Pro-and anti-inflammatory cytokines and antioxidants were assessed in brain tissues. A significant (p<0.01) improvement in habituation memory and the step-down inhibitory avoidance test was seen after receiving the DISE therapy, reduced escape delay considerably (p<0.01) enhanced cognitive progress in spatial learning. DISE may have an impact on neuroprotection as seen by the significant (p<0.01) decrease in proinflammatory and enhancement in IL-10 along with improved antioxidant indicators. According to investigations, the DISE enhance cognition by controlling neuro-inflammation and neuroimmune function, which are both controlled by the HPA axis, which mitigates stress. DISE might be promising therapeutics for neurodegeneration disorders such as AD.

Cross state-dependent memory retrieval between cannabinoid CB1 and serotonergic 5-HT1A receptor agonists in the mouse dorsal hippocampus

Understanding the neurobiological mechanisms of drug-related learning and memory formation may help the treatment of cognitive disorders. Dysfunction of the cannabinoid and serotonergic systems has been demonstrated in learning and memory disorders.The present paper investigates the phenomenon called state-dependent memory (SDM) induced by ACPA (a selective cannabinoid CB1 receptor agonist) and 8-OH-DPAT (a nonselective 5-HT1A receptor agonist) with special focus on the role of the 5-HT1A receptor in the effects of both ACPA and 8-OH-DPAT SDM and cross state-dependent memory retrieval between ACPA and 8-OH-DPAT in a step-down inhibitory avoidance task.The dorsal hippocampal CA1 regions of adult male NMRI mice were bilaterally cannulated, and all drugs were microinjected into the intended injection sites. A single-trial step-down inhibitory avoidance task was used to assess memory retrieval and state-dependence.Post-training and/or pre-test microinjections of ACPA (1 and 2 ng/mouse) and 8-OH-DPAT (0.5 and 1 μg/mouse) dose-dependently induced amnesia. Pre-test administration of the same doses of ACPA and 8-OH-DPAT reversed the post-training ACPA- and 8-OH-DPAT-induced amnesia, respectively. This phenomenon has been named SDM. 8-OH-DPAT (1 μg/mouse) reversed the amnesia induced by ACPA (0.5, 1, and 2 ng/mouse) and induced ACPA SDM. ACPA (2 ng/mouse) reversed the amnesia induced by 8-OH-DPAT (0.25, 0.5, and 1 μg/mouse) and induced 8-OH-DPAT SDM. Pre-test administration of a 5-HT1A receptor antagonist, (S)-WAY 100,135 (0.25 and 0.5 μg/mouse), 5 min before ACPA and 8-OH-DPAT dose-dependently inhibited ACPA- and 8-OH-DPAT-induced SDM, respectively.The present study results demonstrated ACPA- and 8-OH-DPAT- induced SDM. Overall, the data revealed that dorsal hippocampal 5-HT1A receptor mechanisms play a pivotal role in modulating cross state-dependent memory retrieval between ACPA and 8-OH-DPAT.

Inhibitory Metaplasticity in Juvenile Stressed Rats Restores Associative Memory in Adulthood by Regulating Epigenetic Complex G9a/GLP.

BackgroundExposure to juvenile stress was found to have long-term effects on the plasticity and quality of associative memory in adulthood, but the underlying mechanisms are still poorly understood.MethodsThree- to four week-old male Wistar rats were subjected to a 3-day juvenile stress paradigm. Their electrophysiological correlates of memory using the adult hippocampal slice were inspected to detect alterations in long-term potentiation and synaptic tagging and capture model of associativity. These cellular alterations were tied in with the behavioral outcome by subjecting the rats to a step-down inhibitory avoidance paradigm to measure strength in their memory. Given the role of epigenetic response in altering plasticity as a repercussion of juvenile stress, we aimed to chart out the possible epigenetic marker and its regulation in the long-term memory mechanisms using quantitative reverse transcription polymerase chain reaction.ResultsWe demonstrate that even long after the elimination of actual stressors, an inhibitory metaplastic state is evident, which promotes synaptic competition over synaptic cooperation and decline in latency of associative memory in the behavioral paradigm despite the exposure to novelty. Mechanistically, juvenile stress led to a heightened expression of the epigenetic marker G9a/GLP complex, which is thus far ascribed to transcriptional silencing and goal-directed behavior.ConclusionsThe blockade of the G9a/GLP complex was found to alleviate deficits in long-term plasticity and associative memory during the adulthood of animals exposed to juvenile stress. Our data provide insights on the long-term effects of juvenile stress that involve epigenetic mechanisms, which directly impact long-term plasticity, synaptic tagging and capture, and associative memory.

EFFECT OF HEPTRAL ON THE COGNITIVE FUNCTIONS OF RATS AFTER CHRONIC 153 ALCOHOL INTOXICATION

The aim of this study was assess the effect of the heptral on the cognitive functions of female rats exposed to chronic alcohol intoxication (CAI). CAI was modeled with 6-month replacement of drinking water with a 10% solution of ethyl alcohol with sucrose (50 g/l). The "One-way step-down inhibitory (“passive”) avoidance test", "Extrapolation escape task test", "Novel object recognition test" and "Barnes maze test" were carried out at the age of 16 months. The experimental data obtained indicate that there is impairment in preservation of the memory track in female rats after CAI. Heptral neutralized cognitive impairment in animals exposed to prolonged alcohol abuse.

Methylmercury exposure during prenatal and postnatal neurodevelopment promotes oxidative stress associated with motor and cognitive damages in rats: an environmental-experimental toxicology study

The environmental contamination by methylmercury (MeHg) is a major concern for public health. The effects of MeHg in the central nervous system (CNS) of adult animals have been extensively investigated; however, little is known about the effects of MeHg exposure during intrauterine and lactation periods on motor and cognitive functions of adolescent rats. Therefore, this study aimed to investigate the effect of MeHg exposure during intrauterine life and lactation on both motor and cognitive functions of offspring rats. Ten female Wistar rats were exposed to 40 μg/kg/day of MeHg through cookie treats from the first day of pregnancy until the last day of breastfeeding. Both motor and cognitive functions of offspring male rats were assessed by open field, rotarod, and step-down inhibitory avoidance tests. Forty-one days after birth, the hippocampus and cerebellum were collected to determine total Hg content, antioxidant capacity against peroxyl radicals (ACAP), reduced glutathione (GSH) levels, lipid peroxidation (LPO), and nitrite levels. MeHg exposure during CNS development increased Hg levels in both hippocampal and cerebellar parenchymas, triggered oxidative stress throughout ACAP and GSH decrease, increased LPO and nitrite levels. These alterations resulted in reduced spontaneous and stimulated locomotion and short- and long-term memory deficits. Therefore, damages triggered by MeHg exposure during intrauterine life and lactation had detrimental effects on oxidative biochemistry and motor and cognitive functions of offspring rats.

Long-term increase in sensitivity to ketamine's behavioral effects in mice exposed to mild blast induced traumatic brain injury

Neurobehavioral deficits emerge in nearly 50% of patients following a mild traumatic brain injury (TBI) and may persist for months. Ketamine is used frequently as an anesthetic/analgesic and for management of persistent psychiatric complications. Although ketamine may produce beneficial effects in patients with a history of TBI, differential sensitivity to its impairing effects could make the therapeutic use of ketamine in TBI patients unsafe. This series of studies examined male C57BL/6 J mice exposed to a mild single blast overpressure (mbTBI) for indications of altered sensitivity to ketamine at varying times after injury. Dystaxia (altered gait), diminished sensorimotor gating (reduced prepulse inhibition) and impaired working memory (step-down inhibitory avoidance) were examined in mbTBI and sham animals 15 min following intraperitoneal injections of saline or R,S-ketamine hydrochloride, from day 7–16 post injury and again from day 35–43 post injury. Behavioral performance in the forced swim test and sucrose preference test were evaluated on day 28 and day 74 post injury respectively, 24 h following drug administration. Dynamic gait stability was compromised in mbTBI mice on day 7 and 35 post injury and further exacerbated following ketamine administration. On day 14 and 42 post injury, prepulse inhibition was robustly decreased by mbTBI, which ketamine further reduced. Ketamine-associated memory impairment was apparent selectively in mbTBI animals 1 h, 24 h and day 28 post shock (tested on day 15/16/43 post injury). Ketamine selectively reduced immobility scores in the FST in mbTBI animals (day 28) and reversed mbTBI induced decreases in sucrose consumption (Day 74). These results demonstrate increased sensitivity to ketamine in mice when tested for extended periods after TBI. The results suggest that ketamine may be effective for treating neuropsychiatric complications that emerge after TBI but urge caution when used in clinical practice for enhanced sensitivity to its side effects in this patient population.

A new arylsulfanyl-benzo-2,1,3-thiadiazoles derivative produces an anti-amnesic effect in mice by modulating acetylcholinesterase activity

The aim of the present study was investigate the binding affinity of 5-((4-methoxyphenyl)thio)benzo[c][1,2,5]thiadiazole (MTDZ) with acetylcholinesterase (AChE). We also evaluated the effect of MTDZ against scopolamine (SCO)-induced amnesia in mice and we looked at the toxicological potential of this compound in mice. The binding affinity of MTDZ with AChE was investigated by molecular docking analyses. For an experimental model, male Swiss mice were treated daily with MTDZ (10 mg/kg, intragastrically (i.g.)) or canola oil (10 ml/kg, i.g.), and induced, 30 min later, with injection of SCO (0.4 mg/kg, intraperitoneally (i.p.)) or saline (0.9%, 5 ml/kg, i.p.) daily. From day 1 to day 10, mice were submitted to the behavioral tasks (Barnes maze, open-field, object recognition and location, Y-maze and step-down inhibitory avoidance tasks), 30 min after induction with SCO. On the tenth day, the animals were euthanized and blood was collected for the analysis of biochemical markers (creatinine, aspartate (AST), and alanine (ALT) aminotransferase). MTDZ interacts with residues of the AChE active site. SCO caused amnesia in mice by changing behavioral tasks. MTDZ treatment attenuated the behavioral changes caused by SCO. In ex vivo assay, MTDZ also protected against the alteration of AChE activity, reactive species (RS) levels, thiobarbituric acid reative species (TBARS) levels, catalase (CAT) activity in tissues, as well as in transaminase activities of plasma caused by SCO in mice. In conclusion, MTDZ presented anti-amnesic action through modulation of the cholinergic system and provided protection from kidney and liver damage caused by SCO.

Protective Effects of Inosine on Memory Consolidation in a Rat Model of Scopolamine-Induced Cognitive Impairment: Involvement of Cholinergic Signaling, Redox Status, and Ion Pump Activities.

This study investigated the effects of inosine on memory acquisition and consolidation, cholinesterases activities, redox status and Na+, K+-ATPase activity in a rat model of scopolamine-induced cognitive impairment. Adult male rats were divided into four groups: control (saline), scopolamine (1mg/kg), scopolamine plus inosine (50mg/kg), and scopolamine plus inosine (100mg/kg). Inosine was pre-administered for 7days, intraperitoneally. On day 8, scopolamine was administered pre (memory acquisition protocol) or post training (memory consolidation protocol) on inhibitory avoidance tasks. The animals were subjected to the step-down inhibitory avoidance task 24hours after the training. Scopolamine induced impairment in the acquisition and consolidation phases; however, inosine was able to prevent only the impairment in memory consolidation. Also, scopolamine increased the activity of acetylcholinesterase and reduced the activity of Na+, K+-ATPase and the treatment with inosine protected against these alterations in consolidation protocol. In the animals treated with scopolamine, inosine improved the redox status by reducing the levels of reactive oxygen species and thiobarbituric acid reactive substances and restoring the activity of the antioxidant enzymes, superoxide dismutase and catalase. Our findings suggest that inosine may offer protection against scopolamine-induced memory consolidation impairment by modulating brain redox status, cholinergic signaling and ion pump activity. This compound may provide an interesting approach in pharmacotherapy and as a prophylactic against neurodegenerative mechanisms involved in Alzheimer's disease.

Inhibition of Piezo1/Ca2+/calpain signaling in the rat basal forebrain reverses sleep deprivation-induced fear memory impairments

In this study, we tested the hypothesis that the Piezo1/Ca2+/calpain pathway of the basal forebrain (BF) modulates impaired fear conditioning caused by sleep deprivation. Adult male Wistar rats were subjected to 6 h of total sleep deprivation using the gentle handling protocol. Step-down inhibitory avoidance tests revealed that sleep deprivation induced substantial short- and long-term fear memory impairment in rats, which was accompanied by increased Piezo1 protein expression (P < 0.01) and increased cleavage of full-length tropomyocin receptor kinase B (TrkB-FL) (P < 0.01) in the BF area. Microinjection of the Piezo1 activator Yoda1 into the BF mimicked these sleep deprivation-induced phenomena; TrkB-FL cleavage was increased (P < 0.01) and short- and long-term fear memory was impaired (both P < 0.01) by Yoda1. Inhibition of Piezo1 by GsMTx4 in the BF area reduced TrkB-FL degradation (P < 0.01) and partially reversed short- and long-term fear memory impairments in sleep-deprived rats (both P < 0.01). Inhibition of calpain activation, downstream of Piezo1 signaling, also improved short- and long-term fear memory impairments (P = 0.038, P = 0.011) and reduced TrkB degradation (P < 0.01) in sleep-deprived rats. Moreover, sleep deprivation induced a lower pain threshold than the rest control, which was partly reversed by microinjection of GsMTx4 or PD151746. Neither sleep deprivation nor the abovementioned drugs affected locomotion and sedation. Taken together, these results indicate that BF Piezo1/Ca2+/calpain signaling plays a role in sleep deprivation-induced TrkB signaling disruption and fear memory impairments in rats.

The neurotherapeutic role of a selenium-functionalized quinoline in hypothalamic obese rats.

Obesity is considered one of the major global health problems and increases the risk of several medical complications, such as diabetesand mental illnesses. The present study investigated the effect of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) on obesity parameters,behavioral and neurochemical alterations in hypothalamic obese rats. Male Wistar rats received subcutaneous neonatal injections of monosodiumglutamate (MSG, 4g/kg) or saline. After the Lee Index evaluation, rats were divided into groups and treated with 4-PSQ (5 mg/kg, intragastric route) orcanola oil once a day (post-natal days (PND) 60→76). Open-field, elevated plus-maze, forced swim task, object recognition/location memory, and stepdowninhibitory avoidance tasks were conducted from PND 66 to 74. On PND 76, rats were euthanized and epididymal fat, blood, cerebral cortex, andhippocampus were removed. Blood biochemical parameters and cortical/hippocampal acetylcholinesterase (AChE) and Na /K -ATPase activities wereassessed. MSG increased the Lee Index characterizing the chemically induced hypothalamic obesity model. 4-PSQ reversed the increases ofepididymal fat, blood glucose, and triglyceride levels caused by MSG exposure. 4-PSQ attenuated anxiety-like and depression-like behaviors induced byneonatal administrations of MSG. Memory deficits found in MSG-obese rats were reversed by treatment with 4-PSQ. Neurochemical alterations producedby MSG evidenced by stimulation ofNa+/K+-ATPase and AChE activities in the cerebral cortex and hippocampus of rats were normalized by 4-PSQtreatment. In brief, 4-PSQ therapy improved hypothalamic obesity-related parameters, as well as psychiatric symptoms, cognitive impairment,and neurochemical alterations found in obese rats.

Improved Spatial Memory And Neuroinflammatory Profile Changes in Aged Rats Submitted to Photobiomodulation Therapy.

Recent evidences have shown the therapeutic potential of transcranial photobiomodulation on traumatic brain injury and Alzheimer's disease. Despite the promising benefits in the brain, little is known about the laser's effects in the absence of pathological conditions. We submitted young (4months old) and aged (20months old) rats to transcranial low-level laser and evaluated their exploratory activity and habituation in open field, anxiety in elevated plus maze, spatial memory in Barnes maze, and aversive memory in a step-down inhibitory avoidance task. Additionally, the levels of a panel of inflammatory cytokines and chemokines were quantified in two different brain regions: the cerebral cortex and the hippocampus. Young and aged rats submitted to transcranial laser exhibited better cognitive performance in Barnes maze than did control rats. Transcranial laser therapy decreased cortical levels of GM-CSF, IL-10, MCP-1, LIX, and TNFα in young rats and IL-5 in aged rats. High levels of IL-6, IL-10, and TNF-alpha were found in the cerebral cortex of aged rats submitted to transcranial laser. In the hippocampus, a decrease in IP-10 and fractalkine levels was observed in the aged rats from the laser group when compared to the aged rats from the control group. Our data indicate that transcranial photobiomodulation improves spatial learning and memory and alters the neuroinflammatory profile of young and aged rats' brains.

Effect of a purine derivative containing selenium to improve memory decline and anxiety through modulation of the cholinergic system and Na+/K+-ATPase in an Alzheimer's disease model.

Alzheimer's disease (AD) is a worldwide problem, and there are currently no treatments that can stop this disease. To investigate the binding affinity of 6-((4-fluorophenyl) selanyl)-9H-purine (FSP) with acetylcholinesterase (AChE), to verify the effects of FSP in an AD model in mice and to evaluate the toxicological potential of this compound in mice. The binding affinity of FSP with AChE was investigated by molecular docking analyses. The AD model was induced by streptozotocin (STZ) in Swiss mice after FSP treatment (1mg/kg, intragastrically (i.g.)), 1st-10th day of the experimental protocol. Anxiety was evaluated in an elevated plus maze test, and memory impairment was evaluated in the Y-maze, object recognition and step-down inhibitory avoidance tasks. The cholinergic system was investigated based on by looking at expression and activity of AChE and expression of choline acetyltransferase (ChAT). We evaluated expression and activity of Na+/K+-ATPase. For toxicological analysis, animals received FSP (300mg/kg, i.g.) and aspartate aminotransferase, alanine aminotransferase activities were determined in plasma and δ-aminolevulinate dehydratase activity in brain and liver. FSP interacts with residues of the AChE active site. FSP mitigated the induction of anxiety and memory impairment caused by STZ. FSP protected cholinergic system dysfunction and reduction of activity and expression of Na+/K+-ATPase. FSP did not modify toxicological parameters evaluated and did not cause the death of mice. FSP protected against anxiety, learning and memory impairment with involvement of the cholinergic system and Na+/K+-ATPase in these actions.

GluN2B and GluN2A-containing NMDAR are differentially involved in extinction memory destabilization and restabilization during reconsolidation

Extinction memory destabilized by recall is restabilized through mTOR-dependent reconsolidation in the hippocampus, but the upstream pathways controlling these processes remain unknown. Hippocampal NMDARs drive local protein synthesis via mTOR signaling and may control active memory maintenance. We found that in adult male Wistar rats, intra dorsal-CA1 administration of the non-subunit selective NMDAR antagonist AP5 or of the GluN2A subunit-containing NMDAR antagonist TCN201 after step down inhibitory avoidance (SDIA) extinction memory recall impaired extinction memory retention and caused SDIA memory recovery. On the contrary, pre-recall administration of AP5 or of the GluN2B subunit-containing NMDAR antagonist RO25-6981 had no effect on extinction memory recall or retention per se but hindered the recovery of the avoidance response induced by post-recall intra-CA1 infusion of the mTOR inhibitor rapamycin. Our results indicate that GluN2B-containing NMDARs are necessary for extinction memory destabilization whereas GluN2A-containing NMDARs are involved in its restabilization, and suggest that pharmacological modulation of the relative activation state of these receptor subtypes around the moment of extinction memory recall may regulate the dominance of extinction memory over the original memory trace.

Valerian treatment during the postpartum period alters breast milk composition and impairs long-term memory in female rat offspring.

Maternal anxiety symptoms in the perinatal period might have long-term health effects on both the mother and the developing child. Valerian is a phytotherapeutic agent that is widely used for the treatment of anxiety. This study investigated the effects of valerian treatment in postpartum rats on maternal care, toxicity, and milk composition. Postnatal development, memory, and anxiety behavior in the offspring were also assessed. Postpartum Wistar rats received the valerian (500, 1000, or 2000 mg·kg-1·day-1) by oral gavage. Clinical and biochemical toxicity was evaluated with commercial kits. Maternal behavior was observed daily. Milk composition was analyzed by colorimetric methods. Physical and neuromotor tests were used to analyze postnatal development. Anxiolytic activity was assessed by the elevated plus maze, and memory was evaluated by the step-down inhibitory avoidance task. Maternal toxicity and care behavior were not altered by the treatment, while only the highest dose promoted a significant increase of lactose, and the doses 1000 and 2000 mg·kg-1·day-1 promoted a reduction of protein contents in milk. Postnatal development was similar in all offspring. Adult offspring did not display altered anxiety behavior, while long-term memory was impaired in the female adult offspring by maternal treatment with 1000 mg·kg-1·day-1. These results suggested that high doses of valerian had significant effects on important maternal milk components and can cause long-term alterations of offspring memory; thus, treatment with high doses of valerian is not safe for breastfeeding Wistar rat mothers.

Hippocampal Impairment Triggered by Long-Term Lead Exposure from Adolescence to Adulthood in Rats: Insights from Molecular to Functional Levels.

Lead (Pb) is an environmental and occupational neurotoxicant after long-term exposure. This study aimed to investigate the effects of systemic Pb exposure in rats from adolescence to adulthood, evaluating molecular, morphologic and functional aspects of hippocampus. For this, male Wistar rats were exposed to 50 mg/kg of Pb acetate or distilled water for 55 days by intragastric gavage. For the evaluation of short-term and long-term memories, object recognition and step-down inhibitory avoidance tests were performed. At the end of the behavioral tests, the animals were euthanized and the hippocampus dissected and processed to the evaluation of: Pb content levels in hippocampal parenchyma; Trolox equivalent antioxidant capacity (TEAC), glutathione (GSH) and malondialdehyde (MDA) levels as parameters of oxidative stress and antioxidant status; global proteomic profile and neuronal degeneration by anti-NeuN immunohistochemistry analysis. Our results show the increase of Pb levels in the hippocampus of adult rats exposed from adolescence, increased MDA and GSH levels, modulation of proteins related to neural structure and physiology and reduced density of neurons, hence a poor cognitive performance on short and long-term memories. Then, the long-term exposure to Pb in this period of life may impair several biologic organizational levels of the hippocampal structure associated with functional damages.