RESUMEN
Chromogranin A (CgA), a â¼ 49 kDa acidic secretory protein, is ubiquitously distributed in endocrine and neuroendocrine cells and neurons. As a propeptide, CgA is proteolytically cleaved to generate several peptides of biological importance, including pancreastatin (PST: hCgA250-301), Vasostatin 1 (VS1: hCgA1-76), and catestatin (CST: CgA 352-372). VS1 represents the most conserved fragment of CgA. A 20 amino acid domain within VS1 (CgA 47-66) exhibits potent antimicrobial and anti-inflammatory activities. Autism is known to be associated with inflammation. Therefore, we seek to test the hypothesis that VS1 modulates autism behaviors by reducing inflammation in the hippocampus. Treatment of C57BL/6 (B6) and BTBR (a mouse model of idiopathic autism) mice with VS1 revealed the following: BTBR mice showed a significant decrease in chamber time in the presence of a stranger or a novel object. Treatment with VS1 significantly increased chamber time in both cases, underscoring a crucial role for VS1 in improving behavioral deficits in BTBR mice. In contrast to chamber time, sniffing time in BTBR mice in the presence of a stranger was less compared to B6 control mice. VS1 did not improve this latter parameter. Surprisingly, sniffing time in BTBR mice in the presence of a novel object was comparable with B6 mice. Proinflammatory cytokines such as IL-6 and IL-1b, as well as other inflammatory markers, were elevated in BTBR mice, which were dramatically reduced after supplementation with VS1. Interestingly, even Beclin-1/p62, pAKT/AKT, and p-p70-S6K/p70-S6K ratios were notably reduced by VS1. We conclude that VS1 plays a crucial role in restoring autistic spectrum disorders (ASD) plausibly by attenuating neuroinflammation.
Asunto(s)
Trastorno Autístico , Cromogranina A , Modelos Animales de Enfermedad , Hipocampo , Enfermedades Neuroinflamatorias , Fragmentos de Péptidos , Animales , Masculino , Ratones , Trastorno Autístico/tratamiento farmacológico , Trastorno Autístico/metabolismo , Cromogranina A/farmacología , Cromogranina A/metabolismo , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Fragmentos de Péptidos/farmacologíaRESUMEN
Alzheimer's disease (AD) is an age-dependent incurable neurodegenerative disorder accompanied by neuroinflammation, amyloid accumulation, and memory impairment. It begins decades before the first clinical symptoms appear, and identifying early biomarkers is key for developing disease-modifying therapies. We show now in a mouse model of AD that before any amyloid deposition the brains of 1.5-month-old mice contain increased levels of pro-inflammatory cytokines IL-1ß and IL-6, decreased levels of nicotinic acetylcholine receptors (nAChRs) in the brain and brain mitochondria and increased amounts of α7 nAChR-bound Aß1-42, along with impaired episodic memory and increased risk of apoptosis. Both acute (1-week-long) and chronic (4-month-long) treatments with α7-selective agonist PNU282987, starting at 1.5 months of age, were well tolerated. The acute treatment did not affect the levels of soluble Aß1-42 but consistently upregulated the α7 nAChR expression, decreased the level of α7-Aß1-42 complexes, and improved episodic memory of 1.5-month-old mice. The chronic treatment, covering the disease development phase, strongly upregulated the expression of all abundant brain nAChRs, reduced both free and α7-coupled Aß1-42 within the brain, had anti-inflammatory and antiapoptotic effects, and potently upregulated cognition, thus identifying α7 nAChRs as both early biomarker and potent therapeutic target for fighting this devastating disease.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Encéfalo , Modelos Animales de Enfermedad , Receptor Nicotínico de Acetilcolina alfa 7 , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Ratones , Fragmentos de Péptidos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Compuestos Bicíclicos con Puentes/farmacología , Benzamidas/farmacología , Apoptosis/efectos de los fármacosRESUMEN
Schizophrenia is a complex neuropsychiatric disorder with positive, negative, and cognitive symptoms. In rats, sub-chronic administration of ketamine is used for the induction of schizophrenia model. Increased locomotor activity is one of the most important features of psychotic-like symptoms in rodents. On the other hand, risperidone is a potent antipsychotic medication that is approved for the treatment of schizophrenia and bipolar disorder. In the present research, we aimed to investigate the effect of sub-chronic treatment of ketamine on cognitive and behavioral functions, and brain-derived neurotrophic factor (BDNF) expression level in the prefrontal cortex. Also, we assessed the efficacy of risperidone on cognitive and behavioral impairments induced by ketamine. Possible sex differences were also measured. Ketamine was intraperitoneally injected at the dose of 30 mg/kg for five consecutive days. Risperidone was also intraperitoneally injected at the dose of 2 mg/kg. Novel object recognition memory, pain threshold, locomotor activity, rearing behavior, and BDNF level were evaluated. The results showed that ketamine injection for five consecutive days impaired the acquisition of long-term recognition memory and decreased BDNF level in the prefrontal cortex in both sexes. Also, it decreased pain threshold in females, increased rearing behavior in males, and induced hyperlocomotion with greater effect in females. On the other hand, risperidone restored or attenuated the effect of ketamine on all the behavioral effects and BDNF level. In conclusion, we suggested that there were sex differences in the effects of ketamine on pain perception, locomotion, and rearing behavior in a rat model of schizophrenia.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Modelos Animales de Enfermedad , Ketamina , Corteza Prefrontal , Risperidona , Esquizofrenia , Caracteres Sexuales , Animales , Ketamina/farmacología , Ketamina/administración & dosificación , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/inducido químicamente , Esquizofrenia/fisiopatología , Masculino , Femenino , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Risperidona/farmacología , Risperidona/administración & dosificación , Ratas , Antipsicóticos/farmacología , Antipsicóticos/administración & dosificación , Reconocimiento en Psicología/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Ratas Wistar , Conducta Animal/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Actividad Motora/efectos de los fármacosRESUMEN
Early-life glucocorticoid overexposure induces diverse neurodevelopmental outcomes regarding stress reactivity and cognition. Increased fructose consumption has also been associated with alterations in cognitive capacity and behavior. The present study investigated the effects of prenatal dexamethasone exposure on synaptic plasticity, locomotion, anxiety, and recognition memory in adult male Wistar rat offspring, and whether these effects are potentiated by postnatal fructose consumption. Pregnant female rats were treated with dexamethasone during late gestation and male offspring were supplemented with a moderate dose of fructose. Recognition memory, locomotion, and anxiety-like behavior were assessed using a novel object recognition test, open-field test, and elevated plus maze, respectively. Hippocampal synaptic plasticity was estimated by the levels of growth-associated protein 43 (GAP-43), synaptophysin, postsynaptic density protein 95, calcium/calmodulin-dependent kinase IIα, and their activating phosphorylations. Additionally, protein levels of the glucocorticoid receptor (GR) and its transcriptionally active phosphorylated form were evaluated. Prenatal dexamethasone treatment induced an anxiolytic-like effect, stimulation of exploratory behavior, and novelty preference associated with an increase in GR and GAP-43 protein levels in the hippocampus. Fructose overconsumption after weaning did not modify the effects of prenatal glucocorticoid exposure. Applied prenatal dexamethasone treatment may induce changes in reactions to novel situations in male Wistar rats.
RESUMEN
Rodents use their whisker system to discriminate surface texture. Whisker-based texture discrimination tasks are often used to investigate the mechanisms encoding tactile sensation. One such task is the textured Novel Object Recognition Test (tNORT). It takes advantage of a tendency of rodents to explore novel objects more than familiar ones and assesses the sensitivity of whiskers in discriminating different textures of objects. It requires little training of the animals and the equipment involved is a simple arena with typically two objects placed inside. The success of the test relies on rodents spending sufficient time exploring these objects. Animals may lose interests in such tasks when performed repetitively within a limited time frame. However, such repeated tests may be crucial when establishing a sensitivity threshold of the whisker system. Here we present an adapted rodent tNORT protocol designed to maintain sustained interest in the objects even with repeated testing. We constructed complex objects from three simple-shaped objects. Different textures were provided by sandpapers of varying grit sizes. To minimise olfactory clues, we used the sandy and the laminar side of the same sandpaper as the familiar and novel textures assigned at random. We subsequently conducted repeated tNORTs on eight rats in order to identify a critical threshold of the sandpaper grit size below which rats would be unable to discriminate the sandy from the laminar side. With an inter-test-interval of seven days and after five tNORTs, the protocol enabled us to successfully identify the threshold. We suggest that the proposed tNORT is a useful tool for investigating the sensitivity threshold of the whisker system of rodent, and for testing the effectiveness of an intervention by comparing sensitivity threshold pre- and post-intervention.
Asunto(s)
Reconocimiento en Psicología , Percepción del Tacto , Vibrisas , Animales , Vibrisas/fisiología , Reconocimiento en Psicología/fisiología , Ratas , Percepción del Tacto/fisiología , Masculino , Conducta Exploratoria/fisiología , Discriminación en Psicología/fisiología , Tacto/fisiología , Umbral Sensorial/fisiologíaRESUMEN
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays key roles in neuronal protection and synaptic plasticity. Changes in BDNF are associated with various pathological conditions, including methamphetamine (meth) addiction, although the effects of meth on BDNF expression are not always consistent. We have previously demonstrated region-specific effects of a chronic meth regime on BDNF methylation and expression in the rat brain. This study aims to determine the effect of chronic meth administration on the expression of BDNF protein using immunohistochemistry in the rat frontal cortex and hippocampus. Novel object recognition (NOR) as a measure of cognitive function was also determined. Male Sprague Dawley rats were administered a chronic escalating dose (0.1-4 mg/kg over 14 days) (ED) of meth or vehicle; a subgroup of animals receiving meth were also given an acute "binge" (4x6mg) dose on the final day before NOR testing. The results showed that hippocampal CA1 BDNF protein was significantly increased by 72 % above control values in the ED-binge rats, while other hippocampal regions and frontal cortex were not significantly affected. Meth-administered animals also demonstrated deficits in NOR after 24 h delay. No significant effect of the additional binge dose on BDNF protein or NOR findings was apparent. This finding is consistent with our previous results of reduced DNA methylation and increased expression of the BDNF gene in this region. The hippocampal BDNF increase may reflect an initial increase in a protective factor produced in response to elevated glutamate release resulting in neurodegenerative excitotoxicity.
Asunto(s)
Trastornos Relacionados con Anfetaminas , Factor Neurotrófico Derivado del Encéfalo , Metanfetamina , Ratas Sprague-Dawley , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Metanfetamina/toxicidad , Metanfetamina/administración & dosificación , Metanfetamina/farmacología , Masculino , Trastornos Relacionados con Anfetaminas/metabolismo , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/toxicidad , Estimulantes del Sistema Nervioso Central/farmacología , Ratas , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Lóbulo Frontal/metabolismo , Lóbulo Frontal/efectos de los fármacos , Modelos Animales de Enfermedad , Reconocimiento en Psicología/efectos de los fármacosRESUMEN
Nicotine has been shown to enhance object recognition memory in the novel object recognition (NOR) test by activating excitatory neurons in the medial prefrontal cortex (mPFC). However, the exact neuronal mechanisms underlying the nicotine-induced activation of mPFC neurons and the resultant memory enhancement remain poorly understood. To address this issue, we performed brain-slice electrophysiology and the NOR test in male C57BL/6J mice. Whole-cell patch-clamp recordings from layer V pyramidal neurons in the mPFC revealed that nicotine augments the summation of evoked excitatory postsynaptic potentials (eEPSPs) and that this effect was suppressed by N-[3,5-Bis(trifluoromethyl)phenyl]-N'-[2,4-dibromo-6-(2H-tetrazol-5-yl)phenyl]urea (NS5806), a voltage-dependent potassium (Kv) 4.3 channel activator. In line with these findings, intra-mPFC infusion of NS5806 suppressed systemically administered nicotine-induced memory enhancement in the NOR test. Additionally, miRNA-mediated knockdown of Kv4.3 channels in mPFC pyramidal neurons enhanced object recognition memory. Furthermore, inhibition of A-type Kv channels by intra-mPFC infusion of 4-aminopyridine was found to enhance object recognition memory, while this effect was abrogated by prior intra-mPFC NS5806 infusion. These results suggest that nicotine augments the summation of eEPSPs via the inhibition of Kv4.3 channels in mPFC layer V pyramidal neurons, resulting in the enhancement of object recognition memory.
Asunto(s)
Ratones Endogámicos C57BL , Nicotina , Corteza Prefrontal , Reconocimiento en Psicología , Animales , Masculino , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiología , Corteza Prefrontal/metabolismo , Nicotina/farmacología , Ratones , Reconocimiento en Psicología/efectos de los fármacos , Canales de Potasio Shal/metabolismo , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Memoria/efectos de los fármacos , Potenciales Postsinápticos Excitadores/efectos de los fármacosRESUMEN
BACKGROUND: Elevated brain levels of kynurenic acid (KYNA), a metabolite in the kynurenine pathway, are associated with cognitive dysfunctions, which are nowadays often considered as fundamental characteristics of several psychopathologies; however, the role of KYNA in mental illnesses, such as schizophrenia, is not fully elucidated. This study aimed to assess KYNA levels in the prefrontal cortex (PFC) of rats prenatally treated with methylazoxymethanol (MAM) acetate, i.e., a well-validated neurodevelopmental animal model of schizophrenia. The effects of an early pharmacological modulation of the endogenous cannabinoid system were also evaluated. METHODS: Pregnant Sprague-Dawley rats were treated with MAM (22 mg/kg, ip) or its vehicle at gestational day 17. Male offspring were treated with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day, ip) or with the typical antipsychotic haloperidol (0.6 mg/kg/day, ip) from postnatal day (PND) 19 to PND39. The locomotor activity and cognitive performance were assessed in the novel object recognition test and the open field test in adulthood. KYNA levels in the PFC of prenatally MAM-treated rats were also assessed. RESULTS: A significant cognitive impairment was observed in prenatally MAM-treated rats (p < 0.01), which was associated with enhanced PFC KYNA levels (p < 0.05). The peripubertal AM251, but not haloperidol, treatment ameliorated the cognitive deficit (p < 0.05), by normalizing the PFC KYNA content in MAM rats. CONCLUSIONS: The present findings suggest that the cognitive deficit observed in MAM rats may be related to enhanced PFC KYNA levels which could be, in turn, mediated by the activation of cannabinoid CB1 receptor. These results further support the modulation of brain KYNA levels as a potential therapeutic strategy to ameliorate the cognitive dysfunctions in schizophrenia.
Asunto(s)
Ácido Quinurénico , Acetato de Metilazoximetanol , Corteza Prefrontal , Efectos Tardíos de la Exposición Prenatal , Ratas Sprague-Dawley , Esquizofrenia , Animales , Corteza Prefrontal/metabolismo , Corteza Prefrontal/efectos de los fármacos , Embarazo , Femenino , Efectos Tardíos de la Exposición Prenatal/metabolismo , Ácido Quinurénico/metabolismo , Ratas , Masculino , Esquizofrenia/metabolismo , Esquizofrenia/tratamiento farmacológico , Acetato de Metilazoximetanol/análogos & derivados , Haloperidol/farmacología , Piperidinas/farmacología , Modelos Animales de Enfermedad , Antipsicóticos/farmacología , Pirazoles/farmacología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Receptor Cannabinoide CB1/metabolismoRESUMEN
This study examined the influence of genetic background on cognitive performance in a selectively bred high nicotine-preferring (NP) rat line. Using the novel object recognition (NOR), novel location recognition (NLR), and Morris water maze (MWM) tests, we evaluated object memory, spatial memory, and spatial navigation in nicotine-naive NP rats compared to controls. Our results demonstrate that in the NOR test, both male and female NP rats spent more time exploring the novel object (higher discrimination index) compared to sex-matched controls. In the NLR, the discrimination index differed significantly from zero chance (no preference) in both NP males and females but not in controls, indicating enhanced spatial memory in the NP line. During MWM acquisition, the NP groups and control males took a shorter path to reach the platform compared to control females. On the probe trial, the distance traveled in the target quadrant was longer for NP males and females compared to their respective controls, suggesting enhanced spatial navigation and learning in the NP rats. The interesting preference for novel objects and locations displayed by NP rats may indicate a potential novelty-seeking phenotype in this line. These results highlight the complex interplay between genetic factors, cognitive function, and nicotine preference.
RESUMEN
Background: There is growing evidence that the treatment of several mental disorders can potentially benefit from activation of delta-opioid receptors. In the future, delta-agonists with a safe pharmacological profile can be used for the treatment of mood disorders in pregnant women. However, the data on prenatal exposure to delta-opioid agonists are missing. The present study is aimed to test the hypothesis that the activation of delta-opioid receptors during gravidity has positive effects on the behaviour accompanied by changes in glutamate and monoamine neurotransmission. Methods: Gestating Wistar rats were chronically treated with a selective delta-agonist SNC80 or vehicle. Adult male and female offspring underwent novel object recognition (for the assessment of cognition) and open field (for the assessment of anxiety and habituation) tests, followed by in vivo electrophysiological examination of the activity of hippocampal glutamate and midbrain serotonin (5-HT) and dopamine neurons. Results: We found that the maternal treatment with SNC80 did not affect the offspring's anxiety, habituation, and 5-HT neuronal firing activity. Female offspring of SNC80-treated dams exhibited improved novelty recognition associated with decreased firing rate and burst activity of glutamate and dopamine neurons. Conclusion: Maternal treatment with delta-opioid agonists during gestation may have a pro-cognitive effect on offspring without any negative effects on anxiety and habituation. The putative pro-cognitive effect might be mediated via mechanism(s) involving the firing activity of hippocampal glutamate and mesolimbic dopamine neurons.
RESUMEN
BACKGROUND: Anxiety is an adaptive response to potentially threatening conditions. Excessive and uncontrolled anxiety responses become nonadaptive and cause anxiety disorders. To better understand the anxiety-modulating effects of Mg sulfate, behavioral test batteries in the assessment of anxiety and learning and memory functions were performed simultaneously over a time period. This study also examines the effects of Mg sulfate compared to diazepam, an anxiolytic drug with amnestic effects on anxiety-like behavior, as well as possible oxidative-nitrosative stress and hippocampal changes in male rats exposed to predator odor. METHODS: Young adult Sprague-Dawley male rats were used. The rats were assessed using a comprehensive neurobehavioral test battery consisting of novel object recognition, open field, and successive alleys tasks. Anxiety was induced by cat odor, and diazepam and Mg were used as study drugs. Of the frontal cortex and hippocampus, the state of total oxidant and antioxidant and NO levels and histological examination of hippocampal CA1, CA2, CA3, and DG regions were performed. RESULTS: Diazepam- and Mg-treated rats showed an improvement in anxiety-related behavior to predator odors. Furthermore, Mg treatment alleviated some of the increasing oxidative stress in the frontal cortex and hippocampus of rats, while diazepam treatment in particular enhanced hippocampal oxidant and antioxidant activity. In addition, brain NO increase induced by animal odor exposure or diazepam treatment was ameliorated by Mg administration. CONCLUSIONS: Overall, our work suggests that Mg had a partial anxiolytic effect on anxiety-like behaviors, although not as much as diazepam, and this effect varied depending on the dose. Mg treatment might counteract increased oxidative stress and elevated NO levels in the brain.
Asunto(s)
Ansiolíticos , Ansiedad , Diazepam , Modelos Animales de Enfermedad , Sulfato de Magnesio , Ratas Sprague-Dawley , Animales , Masculino , Ansiedad/tratamiento farmacológico , Diazepam/farmacología , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Sulfato de Magnesio/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Memoria/efectos de los fármacos , Óxido Nítrico/metabolismo , OdorantesRESUMEN
The two tests most widely used in nonhuman primates to assess the neurobiology of recognition memory produce conflicting results. Preferential viewing tests (e.g., visual paired comparison) produce robust impairments following hippocampal lesions, whereas matching tests (e.g., delayed nonmatching-to-sample) often show complete sparing. Here, we review the data, the proposed explanations for this discrepancy, and then critically evaluate those explanations. The most likely explanation is that preferential viewing tests are not a process-pure assessment of recognition memory, but also test elements of novelty-seeking, habituation, and motivation. These confounds likely explain the conflicting results. Thus, we propose that memory researchers should prefer explicit matching tests and readers interested in the neural substrates of recognition memory should give explicit matching tests greater interpretive weight.
Asunto(s)
Reconocimiento en Psicología , Animales , Humanos , Hipocampo/fisiología , Pruebas Neuropsicológicas , Reconocimiento en Psicología/fisiologíaRESUMEN
The beneficial effects of increasing histamine levels on memory have acquired special interest due to their applicability to psychiatric conditions that cause memory impairments. In addition, by employing drug repurposing approaches, it was demonstrated that dihydroergotamine (DHE), an FDA drug approved to treat migraines, inhibits Histamine N Methyl Transferase (HNMT), the enzyme responsible for the inactivation of histamine in the brain. For this reason, in the present work, the effect of DHE on histamine levels in the hippocampus and its effects on memory was evaluated, employing the scopolamine-induced amnesia model, the Novel Object Recognition (NOR) paradigm, and the Morris Water Maze (MWM). Furthermore, the role of histamine 1 receptor (H1R) and histamine 2 receptor (H2R) antagonists in the improvement in memory produced by DHE in the scopolamine-induced amnesia model was evaluated. Results showed that the rats that received DHE (10 mg/kg, i.p.) showed increased histamine levels in the hippocampus after 1 h of administration but not after 5 h. In behavioral assays, it was shown that DHE (1 mg/kg, i.p.) administered 20 min before the training reversed the memory impairment produced by the administration of scopolamine (2 mg/kg, i.p.) immediately after the training in the NOR paradigm and MWM. Additionally, the effects in memory produced by DHE were blocked by pre-treatment with pyrilamine (20 mg/kg, i.p.) administered 30 min before the training in the NOR paradigm and MWM. These findings allow us to demonstrate that DHE improves memory in a scopolamine-induced amnesia model through increasing histamine levels at the hippocampus due to its activity as an HNMT inhibitor.
Asunto(s)
Dihidroergotamina , Escopolamina , Animales , Ratas , Histamina , Amnesia/inducido químicamente , Amnesia/tratamiento farmacológico , Encéfalo , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Antagonistas de los Receptores H2 de la HistaminaRESUMEN
In recent years, there has been a surge in interest in investigating the mechanisms underlying memory consolidation. However, our understanding of the behavioural tagging (BT) model and its establishment in diverse brain regions remains limited. This study elucidates the contributions of the anterior cingulate cortex (ACC) and hippocampus in the formation of long-term memory (LTM) employing behaviour tagging as a model for studying the underlying mechanism of LTM formation in rats. Existing knowledge highlights a protein synthesis-dependent phase as imperative for LTM. Brain-derived neurotrophic factor (BDNF) stands as a pivotal plasticity-related protein (PRP) in mediating molecular alterations crucial for long-term synaptic plasticity and memory consolidation. Our study offers evidence suggesting that tropomyosin receptor kinase B (TrkB), the receptor of BDNF, may act as a combined "behavioural tag/PRP". Interfering with the expression of these molecules resulted in impaired LTM after 24 h. Furthermore, augmenting BDNF expression led to an elevation in Arc protein levels in both the ACC and hippocampus regions. Introducing novelty around weak inhibitory avoidance (IA) training resulted in heightened step-down latencies and expression of these molecules, respectively. We also demonstrate that the increase in Arc expression relies on BDNF synthesis, which is vital for the memory consolidation process. Additionally, inhibiting BDNF using an anti-BDNF function-blocking antibody impacted Arc expression in both the ACC and hippocampus regions, disrupting the transformations from labile to robust memory. These findings mark the initial identification of a "behavioural tag/PRP" combination and underscore the involvement of the TrkB-BDNF-Arc cascade in the behavioural tagging model of learning and memory.
RESUMEN
HIV-1-associated neurocognitive disorders (HAND) are a major comorbidity of HIV-1 infection, marked by impairment of executive function varying in severity. HAND affects nearly half of people living with HIV (PLWH), with mild forms predominating since the use of anti-retroviral therapies (ART). The HIV-1 transactivator of transcription (Tat) protein is found in the cerebrospinal fluid of patients adherent to ART, and its administration or expression in animals causes cognitive symptoms. Studies of Tat interaction with the N-methyl-D-aspartate receptor (NMDAR) suggest that glutamate toxicity contributes to Tat-induced impairments. To identify changes in regional glutamatergic circuitry underlying cognitive impairment, we injected recombinant Tat86 or saline to medial prefrontal cortex (mPFC) of male Sprague-Dawley rats. Rats were assessed with behavioral tasks that involve intact functioning of mPFC including the novel object recognition (NOR), spatial object recognition (SOR), and temporal order (TO) tasks at 1 and 2 postoperative weeks. Following testing, mPFC tissue was collected and analyzed by RT-PCR. Results showed Tat86 in mPFC-induced impairment in SOR, and upregulation of Grin1 and Grin2a transcripts. To further understand the mechanism of Tat toxicity, we assessed the effects of full-length Tat101 on gene expression in mPFC by RNA sequencing. The results of RNAseq suggest that glutamatergic effects of Tat86 are maintained with Tat101, as Grin2a was upregulated in Tat101-injected tissue, among other differentially expressed genes. Spatial learning and memory impairment and Grin2a upregulation suggest that exposure to Tat protein drives adaptation in mPFC, altering the function of circuitry supporting spatial learning and memory.
RESUMEN
BACKGROUND: The recreational drug ±3,4-methylenedioxymethamphetamine (MDMA; also known as "ecstasy") has unusual subjective prosocial and empathogenic effects, and has exhibited potential as an adjunct to psychotherapy in recent years. However, there has been some concern regarding possible neuropsychiatric symptoms, such as cognitive impairment and dependence, emerging after abstinence. Therefore, this study aimed to evaluate the mechanism underlying cognitive impairment during MDMA withdrawal. To achieve this, we focused on the arachidonic acid cascade, which is related to addiction to some abusive drugs. METHODS: A novel object recognition task was used to investigate cognitive function in mice. Furthermore, we quantified prostaglandin E2 during MDMA withdrawal. RESULTS: The recognition index significantly decreased during withdrawal after repeated administration of MDMA (10mg/kg, i.p., once daily for 7 days), but not following co-administration of diclofenac (10mg/kg, i.p.), a cyclooxygenase inhibitor. On day 1, following repeated MDMA treatment, prostaglandin E2 content significantly increased in the hippocampus but not in the prefrontal cortex and striatum. CONCLUSIONS: Our findings indicate that activation of the arachidonic acid cascade at least in the hippocampus is likely involved in the development of recognition memory impairment during MDMA withdrawal. Therefore, co-use of cyclooxygenase inhibitors with MDMA may reduce concerns regarding MDMA-induced impairment of recognition memory.
Asunto(s)
N-Metil-3,4-metilenodioxianfetamina , Ratones , Animales , N-Metil-3,4-metilenodioxianfetamina/efectos adversos , Ácido Araquidónico/farmacología , Cognición , Hipocampo , Prostaglandinas/farmacologíaRESUMEN
BACKGROUND: Muscarinic or 5-HT1A receptors are crucial in learning and memory processes, and their expression is evident in the brain areas involved in cognition. The administration of the activators of these receptors prevents the development of cognitive dysfunctions in animal models of schizophrenia induced by MK-801 (N-methyl-d-aspartate receptor antagonist) administration. GABAergic dysfunction is considered as one of the most important causes of MK-801-induced spatial learning deficits. METHODS: Novel object recognition (NOR) and Morris water maze (MWM) tests were used to study the anti-amnestic effect of the biased 5-HT1A receptor agonist (F15599) alone or in combinations with VU0357017 (M1 receptor allosteric agonist), VU0152100 (M4 receptor positive allosteric modulator), and VU0238429 (M5 receptor positive allosteric modulator) on MK-801-induced dysfunctions. The compounds were administered for 5 consecutive days. Animals tested with the MWM underwent 5-day training. Western blotting was used to study the expressions of 5-HT1A receptors and the level of GAD65 in the frontal cortices (FCs) and hippocampi of the animals. RESULTS: F15599 prevented the amnestic effect induced by MK-801 in the MWM at a dose of 0.1 mg/kg. The co-administration of the compound with muscarinic receptors activators had no synergistic effect. The additive effect of the combinations was evident in the prevention of declarative memory dysfunctions investigated in NOR. The administration of MK-801 impaired 5-HT1A expression in the hippocampi and decreased GAD65 levels in both the FCs and hippocampi. The administration of muscarinic ligands prevented these MK-801-induced deficits only in the hippocampi of MWM-trained animals. No effects of the compounds were observed in untrained mice. CONCLUSION: Our results indicate that F15599 prevents schizophrenia-related spatial learning deficits in the MWM; however, the activity of the compound is not intensified with muscarinic receptors activators. In contrast, the combined administration of the ligands is effective in the NOR model of declarative memory. The muscarinic receptors activators reversed MK-801-induced 5-HT1A and GAD65 dysfunctions in the hippocampi of MWM-trained mice, but not in untrained mice.
Asunto(s)
Maleato de Dizocilpina , Serotonina , Ratones , Animales , Maleato de Dizocilpina/farmacología , Receptores Muscarínicos , Encéfalo , Colinérgicos/farmacología , Receptor de Serotonina 5-HT1ARESUMEN
The role of endothelial nitric oxide synthase (eNOS) in the regulation of a variety of biological processes is well established, and its dysfunction contributes to brain pathologies, including schizophrenia or Alzheimer's disease (AD). Positive allosteric modulators (PAMs) of metabotropic glutamate (mGlu) receptors were shown to be effective procognitive compounds, but little is known about their impact on eNOS expression and stability. Here, we investigated the influence of the acute and chronic administration of LY487379 or CDPPB (mGlu2 and mGlu5 PAMs), on eNOS expression in the mouse brain and the effect of the joint administration of the ligands with nitric oxide (NO) releasers, spermineNONOate or DETANONOate, in different combinations of doses, on MK-801- or scopolamine-induced amnesia in the novel object recognition (NOR) test. Our results indicate that both compounds provoked eNOS monomer formation, and CDPPB at a dose of 5 mg/kg exaggerated the effect of MK-801 or scopolamine. The coadministration of spermineNONOate or DETANONOate enhanced the antiamnesic effect of CDPPB or LY487379. The best activity was observed for ineffective or moderate dose combinations. The results indicate that treatment with mGluR2 and mGluR5 PAMs may be burdened with the risk of promoting eNOS uncoupling through the induction of dimer dissociation. Administration of the lowest possible doses of the compounds with NO⢠donors, which themselves have procognitive efficacy, may be proposed for the treatment of schizophrenia or AD.
Asunto(s)
Benzamidas , Disfunción Cognitiva , Maleato de Dizocilpina , Compuestos Nitrosos , Pirazoles , Piridinas , Sulfonamidas , Ratones , Animales , Maleato de Dizocilpina/farmacología , Óxido Nítrico/farmacología , Escopolamina/farmacología , Óxido Nítrico Sintasa de Tipo III , Disfunción Cognitiva/tratamiento farmacológico , Encéfalo , Regulación AlostéricaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Centella asiatica (L.) Urban, is a medicinal herb with rich history of traditional use in Indian subcontinent. This herb has been valued for its diverse range of medicinal properties including memory booster, and also as a folk treatment for skin diseases, wound healing and mild diuretic. AIM OF STUDY: Aging is a gradual and continuous process of natural decay in the biological systems, including the brain. This work aims to evaluate the effectiveness of ethanolic extract of Centella asiatica (CAE) on age-associated cognitive impairments in rats, as well as the underlying mechanism. MATERIAL AND METHODS: Rats were allocated into five distinct groups of 5 animals each: Young rats (3 months old rats), middle-aged (m-aged) rats (13-14 months old), and the remaining three groups were comprised of m-aged rats treated with different concentrations of CAE, viz., 150, 300, and 450 mg/kg b. w., orally for 42 days. Y-maze, open field, novel object recognition, and elevated plus maze tests were used to assess animal behavior. The malondialdehyde (MDA), superoxide dismutase (SOD), and acetylcholinesterase (AChE) assays; and H&E staining were done in the rat brain to assess the biochemical and structural changes. CAE was also subjected to HPLC analysis, in vitro antioxidant and anti-cholinergic activity. The active compounds of CAE were docked with AChE and BuChE in molecular docking study. RESULTS: The results showed that CAE treatment improves behavioral performance; attenuates the age-associated increase in MDA content, SOD, and AChE activity; and reduces neuronal loss. In vitro study showed that CAE has concentration-dependent antioxidant and anti-AChE activity. Furthermore, the presence of Asiatic acid and Madecassic acid in CAE and their good binding with cholinergic enzymes (in silico) also suggest the anticholinergic effect of CAE. CONCLUSION: The findings of the current study show that the anticholinergic and antioxidant effects of CAE are attributable to the presence of Asiatic acid and Madecassic acid, which not only provide neuroprotection against age-associated cognitive decline but also reverse it.
Asunto(s)
Antioxidantes , Centella , Triterpenos Pentacíclicos , Triterpenos , Ratas , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Antioxidantes/metabolismo , Función Ejecutiva , Acetilcolinesterasa/metabolismo , Centella/química , Simulación del Acoplamiento Molecular , Estrés Oxidativo , Antagonistas Colinérgicos/farmacología , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Superóxido Dismutasa/metabolismoRESUMEN
Long-term use of anabolic androgenic steroids (AAS) in supratherapeutic doses is associated with severe adverse effects, including physical, mental, and behavioral alterations. When used for recreational purposes several AAS are often combined, and in scientific studies of the physiological impact of AAS either a single compound or a cocktail of several steroids is often used. Because of this, steroid-specific effects have been difficult to define and are not fully elucidated. The present study used male Wistar rats to evaluate potential somatic and behavioral effects of three different AAS; the decanoate esters of nandrolone, testosterone, and trenbolone. The rats were exposed to 15 mg/kg of nandrolone decanoate, testosterone decanoate, or trenbolone decanoate every third day for 24 days. Body weight gain and organ weights (thymus, liver, kidney, testis, and heart) were measured together with the corticosterone plasma levels. Behavioral effects were studied in the novel object recognition-test (NOR-test) and the multivariate concentric square field-test (MCSF-test). The results conclude that nandrolone decanoate, but neither testosterone decanoate nor trenbolone decanoate, caused impaired recognition memory in the NOR-test, indicating an altered cognitive function. The behavioral profile and stress hormone level of the rats were not affected by the AAS treatments. Furthermore, the study revealed diverse AAS-induced somatic effects i.e., reduced body weight development and changes in organ weights. Of the three AAS included in the study, nandrolone decanoate was identified to cause the most prominent impact on the male rat, as it affected body weight development, the weights of multiple organs, and caused an impaired memory function.