RESUMEN
The World Health Organization's epidemiological data from 2016 revealed that while 57% of the global population aged 15 years or older had abstained from drinking alcohol in the previous year, more than half of the population in the Americas, Europe, and Western Pacific consumed alcohol. The spectrum of alcohol use behavior is broad: low-risk use (sensible and in moderation), at-risk use (e.g., binge drinking), harmful use (misuse) and dependence (alcoholism; addiction; alcohol use disorder). The at-risk use and misuse of alcohol is associated with the transition to dependence, as well as many damaging health outcomes and preventable causes of premature death. Recent conceptualizations of alcohol dependence posit that the subjective experience of pain may be a significant contributing factor in the transition across the spectrum of alcohol use behavior. This narrative review summarizes the effects of alcohol at all levels of the pain system. The pain system includes nociceptors as sensory indicators of potentially dangerous stimuli and tissue damage (nociception), spinal circuits mediating defensive reflexes, and most importantly, the supraspinal circuits mediating nocifensive behaviors and the perception of pain. Although the functional importance of pain is to protect from injury and further or future damage, chronic pain may emerge despite the recovery from, and absence of, biological damage (i.e., in the absence of nociception). Like other biological perceptual systems, pain is a construction contingent on sensory information and a history of individual experiences (i.e., learning and memory). Neuroadaptations and brain plasticity underlying learning and memory and other basic physiological functions can also result in pathological conditions such as chronic pain and addiction. Moreover, the negative affective/emotional aspect of pain perception provides embodied and motivational components that may play a substantial role in the transition from alcohol use to dependence.
RESUMEN
Lesbian, gay, bisexual, transgender, queer/questioning and other sexual and gender diverse (LGBTQ+) persons frequently lack access to mental health service organizations (MHOs) and therapists who are competent with LGBTQ+ clients. Existing continuing education programmes to better equip therapists to work with LGBTQ+ clients are often not widely accessible or skills focused, evaluated for effectiveness and inclusive of MHO administrators who can address the organizational climate needed for therapist effectiveness. A virtual, face-to-face, multi-level (administrators and therapists) and multi-strategy (technical assistance, workshop and clinical consultations) LGBTQ+ cultural competence training-the Sexual and Gender Diversity Learning Community (SGDLC)-was tested in a pilot randomized controlled trial. Ten organizations were randomly assigned to the intervention (SGDLC plus free online videos) or control (free online videos only) group. Pretest/posttest Organization LGBTQ+ Climate Surveys (n = 10 MHOs) and pretest/posttest Therapist LGBTQ+ Competence Self-Assessments (n = 48 therapists) were administered. Results showed that at pretest, average ratings across organization LGBTQ+ climate survey items were low; twice as many items improved on average in the intervention (10/18 items) than control (5/18 items) group organizations. At pretest, therapist average scores (range 0-1) were highest for knowledge (0.88), followed by affirmative attitudes (0.81), practice self-efficacy (0.81), affirmative practices (0.75) and commitment to continued learning (0.69). Pretest/posttest change scores were higher for the intervention relative to the control group regarding therapist self-reported affirmative attitudes (cumulative ordinal ratio [OR] = 3.29; 95% confidence interval [CI] = 1.73, 6.26), practice self-efficacy (OR = 5.28, 95% CI = 2.00, 13.93) and affirmative practices (OR = 3.12, 95% CI = 1.18, 8.25). Average therapist and administrator satisfaction scores were high for the SGDLC. These findings suggest the SGDLC training can affect organizational- and therapist-level changes that may benefit LGBTQ+ clients.
RESUMEN
Objectives: Interferon Regulatory Factors (IRFs) regulate transcription of type-I interferons (IFNs) and IFN-stimulated genes. We previously reported that IFN-regulatory factor 7 (IRF7) is significantly upregulated in the brain of HIV-1 transgenic (HIV-1Tg) rats compared to F344 control rats in a region dependent manner [Li MD, Cao J, Wang S, Wang J, Sarkar S, Vigorito M, et al. Transcriptome sequencing of gene expression in the brain of the HIV-1 transgenic rat. PLoS One 2013]. The RNA deep-sequencing data were deposited in the NCBI SRA database with Gene Expression Omnibus (GEO) number GSE47474. Our current study utilized QIAGEN CLC Genomics Workbench and Ingenuity Pathway Analysis (IPA) to identify molecular pathways underlying the involvement of IRF7 in the HIV antiviral response. Methods: The differential RNA expression data between HIV-1Tg and F344 rats as well as HAND+ and HIV+ cognitively normal patients was collected from GSE47474 and GSE152416, respectively. The "Core Expression Data Analysis" function identified the significant canonical pathways in the datasets with or without IRF7 and its 455 associated molecules. Results: It was found that IRF7 and its 455 associated molecules altered the expression of pathways involving neurotransmission, neuronal survival, and immune function. Conclusions: This in-silico study reveals that IRF7 is involved in the promotion of macrophage activity, neuronal differentiation, the modulation of the Th-1/Th-2 ratio, and the suppression of HIV-1 translation. Furthermore, we demonstrate that bioinformatics tools such as IPA can be employed to simulate the complete knockout of a target molecule such as IRF7 to study its involvement in biological pathways.
RESUMEN
The human digestive tract contains a diverse and abundant microbiota that is important for health. Excessive alcohol use can disrupt the balance of these microbes (known as dysbiosis), leading to elevated blood endotoxin levels and systemic inflammation. Using QIAGEN Ingenuity Pathway Analysis (IPA) bioinformatics tool, we have confirmed that peripheral endotoxin (lipopolysaccharide) mediates various cytokines to enhance the neuroinflammation signaling pathway. The literature has identified alcohol-mediated neuroinflammation as a possible risk factor for the onset and progression of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), and psychiatric disorders such as addiction to alcohol and other drugs. In this review, we discuss alcohol-use-induced dysbiosis in the gut and other body parts as a causal factor in the progression of Central Nervous System (CNS) diseases including neurodegenerative disease and possibly alcohol use disorder.
Asunto(s)
Enfermedades Neurodegenerativas , Humanos , Enfermedades Neurodegenerativas/inducido químicamente , Sistema Nervioso CentralRESUMEN
HIV-Associated Dementia (HAD) is a significant comorbidity that many HIV-patients face. Our study utilized QIAGEN Ingenuity Pathway Analysis (IPA) to identify and analyze molecular profiles and pathways underlying nicotine's impact on HAD pathology. The Qiagen Knowledge Base (QKB) defines HAD as "Dementia associated with acquired immunodeficiency syndrome (disorder)." Although much remains unknown about HAD pathology, the curated research findings from the QKB shows 5 upregulated molecules that are associated with HAD + : CCL2 (Chemokine (C-C motif) ligand 2), L-glutamic acid, GLS (Glutaminase), POLG (DNA polymerase subunit gamma), and POLB (DNA polymerase subunit beta). The current study focused on these 5 HAD pathology molecules as the phenotype of interest. The Pathway Explorer tool of IPA was used to connect nicotine-associated molecules with the 5 HAD associated molecules (HAD pathology molecules) by connecting 29 overlapping molecules (including transcription regulators, cytokines, kinases, and other enzymes/proteins). The Molecule-Activity-Predictor (MAP) tool predicted nicotine-induced activation of the HAD pathology molecules indicating the exacerbation of HAD. However, alternative pathways with more holistic representations of molecular relationships revealed the potential of nicotine as a neuroprotective treatment. It was found that concurrent with nicotine treatment the individual inactivation of several of the intermediary molecules in the holistic pathways caused the downregulation of the HAD pathology molecules. These findings reveal that nicotine may have therapeutic properties for HAD when given alongside specific inhibitory drugs for one or more of the identified intermediary molecules.
Asunto(s)
Complejo SIDA Demencia , Nicotina , Humanos , Nicotina/farmacología , Nicotina/metabolismo , ADN Polimerasa Dirigida por ADNRESUMEN
Binge drinking affects the onset and progression of human immunodeficiency virus (HIV)-associated neurological disorders. The HIV-1 transgenic (HIV-1Tg) rat was created with a gag- and pol-deleted HIV-1 viral genome to mimic HIV-infected patients receiving combination anti-retroviral therapy (cART). Docosahexaenoic acid (DHA) is a marine compound that modulates inflammatory responses. Using HIV-1Tg rats subjected to binge exposure to ethanol (EtOH), this study examined whether DHA could reduce the detrimental neurological effects of EtOH and HIV proteins. Young adult male HIV-1Tg and F344 control rats received 4 mL/kg/day saline as a control (Saline group), 20 mg/kg/day DHA (DHA group), 4.8 g/kg/day 52% w/v EtOH (EtOH group), or 4.8 g/kg/day 52% w/v EtOH and 20 mg/kg/d DHA (DHA + EtOH group) by gavage for 5 weeks (n = 6 per group). EtOH was administrated on days 5, 6, and 7 of each week. Locomotor activity (LMA) was assessed using open field tests before and 45, 90, 135, and 180 min after each treatment. Repeated binge EtOH exposure gradually decreased LMA measured before daily treatments in HIV-1Tg and F344 rats, an effect that was reversed by DHA only in the HIV-1Tg rats. Decreased LMA of rats after treatment and under the influence of EtOH was less pronounced, and the reversal effect of DHA did not reach statistical significance. The plasma endotoxin level was significantly higher in HIV-1Tg rats than in F344 rats. IL-6 and IL-18 expression in the striatum was significantly higher in the HIV-1Tg EtOH group than in the F344 EtOH group. DHA significantly decreased the high levels of IL-6, IL-18, and NF-κB expression observed in the HIV-1Tg EtOH group. DHA appears to ameliorate inflammation and consequently lessen the reductions in LMA produced by the combination of EtOH and HIV-1 viral proteins.
Asunto(s)
Consumo Excesivo de Bebidas Alcohólicas/tratamiento farmacológico , Cuerpo Estriado/efectos de los fármacos , Ácidos Docosahexaenoicos/farmacología , Infecciones por VIH/tratamiento farmacológico , Locomoción/efectos de los fármacos , Animales , Consumo Excesivo de Bebidas Alcohólicas/fisiopatología , Consumo Excesivo de Bebidas Alcohólicas/virología , Cuerpo Estriado/química , Cuerpo Estriado/metabolismo , Cuerpo Estriado/virología , Modelos Animales de Enfermedad , Endotoxinas/sangre , Expresión Génica , Infecciones por VIH/fisiopatología , Infecciones por VIH/virología , VIH-1/genética , Interleucina-18/sangre , Interleucina-18/genética , Interleucina-18/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Locomoción/fisiología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , FN-kappa B/sangre , FN-kappa B/genética , FN-kappa B/metabolismo , Ratas , Ratas Endogámicas F344 , Ratas TransgénicasRESUMEN
Despite the ability of current combination anti-retroviral therapy (cART) to limit the progression of HIV-1 to AIDS, HIV-positive individuals continue to experience neuroHIV in the form of HIV-associated neurological disorders (HAND), which can range from subtle to substantial neurocognitive impairment. NeuroHIV may also influence substance use, abuse, and dependence in HIV-positive individuals. Because of the nature of the virus, variables such as mental health co-morbidities make it difficult to study the interaction between HIV and substance abuse in human populations. Several rodent models have been developed in an attempt to study the transmission and pathogenesis of the HIV-1 virus. The HIV-1 transgenic (HIV-1Tg) rat is a reliable model of neuroHIV because it mimics the condition of HIV-infected patients on cART. Research using this model supports the hypothesis that the presence of HIV-1 viral proteins in the central nervous system increases the sensitivity and susceptibility of HIV-positive individuals to substance abuse.
Asunto(s)
Complejo SIDA Demencia/psicología , Infecciones por VIH/psicología , Animales , Modelos Animales de Enfermedad , VIH-1 , Ratones , Ratas , Ratas TransgénicasRESUMEN
Persons infected with HIV-1 often develop neurologic disorders despite receiving highly active anti-retroviral therapy. Although the underlying mechanism is largely undetermined, our previous RNA-seq-based study showed that the expression of many genes was altered in the central nervous system (CNS) of HIV-1 transgenic (HIV-1Tg) rats. Because nicotine, a natural agonist of nicotinic acetylcholine receptors, exhibits a neuroprotective effect, we presently tested the hypothesis that nicotine restores the expression of altered genes in the CNS of HIV-1Tg rats. Adult male HIV-1Tg and F344 control strain rats were injected with either nicotine (0.25 mg/kg) or saline subcutaneously twice a day for 17 days. Gene expression in the prefrontal cortex (PFC), dorsal hippocampus (HIP), and dorsal striatum (STR) was evaluated using the RNA deep sequencing technique. We found that about 20% of the altered genes in the HIV-1Tg rat were affected by nicotine in each brain region, with the expression of most restored. Analysis of the restored genes showed distinct pathways corrected by nicotine in different brain regions of HIV-1Tg rats. Specifically, the two most significantly restored pathways were Wnt/ß-catenin signaling and ephrin B signaling in the PFC, cAMP-responsive element-binding protein (CREB) signaling and glutathione metabolism pathway in the HIP, and tricarboxylic acid (TCA) cycle and calcium signaling in the STR. Together, our findings indicate that cholinergic modulators such as nicotine have beneficial effects on HIV-1-induced neurologic deficits.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , VIH-1/genética , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Animales , Secuenciación de Nucleótidos de Alto Rendimiento , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Ratas Transgénicas , Análisis de Secuencia de ARN , Proteínas Virales/genética , beta Catenina/genéticaRESUMEN
The noninfectious HIV-1 transgenic (HIV-1Tg) rat was developed as a model of AIDs-related pathology and immune dysfunction by manipulation of a noninfectious HIV-1(gag-pol) virus with a deleted 3-kb SphI-MscI fragment containing the 3' -region of gag and the 5' region of pol into F344 rats. Our previous studies revealed significant behavioral differences between HIV-1Tg and F344 control rats in their performance in the Morris water maze and responses to psychostimulants. However, the molecular mechanisms underlying these behavioral differences remain largely unknown. The primary goal of this study was to identify differentially expressed genes and enriched pathways affected by the gag-pol-deleted HIV-1 genome. Using RNA deep sequencing, we sequenced RNA transcripts in the prefrontal cortex, hippocampus, and striatum of HIV-1Tg and F344 rats. A total of 72 RNA samples were analyzed (i.e., 12 animals per group × 2 strains × 3 brain regions). Following deep-sequencing analysis of 50-bp paired-end reads of RNA-Seq, we used Bowtie/Tophat/Cufflinks suites to align these reads into transcripts based on the Rn4 rat reference genome and to measure the relative abundance of each transcript. Statistical analyses on each brain region in the two strains revealed that immune response- and neurotransmission-related pathways were altered in the HIV-1Tg rats, with brain region differences. Other neuronal survival-related pathways, including those encoding myelin proteins, growth factors, and translation regulators, were altered in the HIV-1Tg rats in a brain region-dependent manner. This study is the first deep-sequencing analysis of RNA transcripts associated the HIV-1Tg rat. Considering the functions of the pathways and brain regions examined in this study, our findings of abnormal gene expression patterns in HIV-1Tg rats suggest mechanisms underlying the deficits in learning and memory and vulnerability to drug addiction and other psychiatric disorders observed in HIV-positive patients.
Asunto(s)
Encéfalo/metabolismo , Perfilación de la Expresión Génica , VIH-1/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Transcriptoma , Animales , Biología Computacional/métodos , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Masculino , Anotación de Secuencia Molecular , Ratas , Ratas Transgénicas , Reproducibilidad de los Resultados , Transducción de Señal , Transcripción GenéticaRESUMEN
The HIV-1 transgenic (HIV-1Tg) rat shows a deficit in learning to locate a submerged platform in a multiple-trial water maze task compared to transgenic littermate and F344 control rats (Vigorito et al., J.Neuroimmune Pharmacol 2:319-328, 2007; Lashomb et al., J.Neurovirol 15:14-24, 2009). Nicotine is known to have neuroprotective effects possibly by minimizing cytotoxic effects of glutamate or by modulating a cholinergic anti-inflammatory pathway. Nicotine also improves performance in a variety of learning tasks by enhancing attention and short-term memory (STM). The purpose of this study was to determine if the learning deficit in HIV-1Tg is ameliorated by repeated nicotine treatment independent of its effects on STM. HIV-1Tg and F344 rats were treated (subcutaneous) with nicotine (0.25 mg/kg/injection) or saline twice daily and tested in a single-trial-per-day procedure which precludes the impact of STM on the acquisition of the spatial learning task. HIV-1Tg rats showed a deficit in the acquisition of the task and in the long-term retention for the platform location in a probe test. Nicotine did not ameliorate the deficit in HIV-1Tg rats and slightly worsened performance during acquisition. Analysis of individual differences in performance during the probe test suggested that nicotine improved performance in some F344 rats but not in HIV-1Tg rats. These results indicate that a deficit in the consolidation of long-term memory contributes to the acquisition deficit of HIV1-Tg rats. The results, however, do not provide any evidence of the amelioration of the learning deficit observed in this behavioral model at least with the nicotine dose tested.
Asunto(s)
Complejo SIDA Demencia/psicología , VIH-1/genética , Aprendizaje por Laberinto/efectos de los fármacos , Memoria a Largo Plazo/efectos de los fármacos , Nicotina/farmacología , Retención en Psicología/efectos de los fármacos , Complejo SIDA Demencia/genética , Complejo SIDA Demencia/fisiopatología , Animales , Modelos Animales de Enfermedad , Esquema de Medicación , Efecto Fundador , Inyecciones Subcutáneas , Masculino , Ratas , Ratas Endogámicas F344 , Ratas TransgénicasRESUMEN
The prevalence of morphine addiction in HIV-1 infected persons is higher than the healthy population. The mu-opioid receptor (MOR) which mediates the actions of morphine is shown to be up-regulated in the HIV-1 transgenic (HIV-1Tg) rat. In this study, we used the conditioned place preference (CPP) test to investigate if HIV-1Tg rats are more sensitive to the addictive properties of morphine compared to F344 control animals. Morphine-CPP was successfully established in the HIV-1Tg and F344 rats at the dose of 3.5 mg/kg. Interestingly, the animals that had morphine paired with one side of the two-chamber CPP apparatus (the white chamber) failed to show any decline in preference for the morphine-paired chamber after 17 to 20 days of extinction testing. An analysis of the change in preference that occurs within a session as a result of the habituation of exploratory behaviour suggested that morphine enhanced a natural preference for the white chamber. We suggest that the morphine CPP procedure may sometimes result in a behavioural plasticity that does not conform to the predictive learning model of classical conditioning and may reflect a form of associative learning known as evaluative conditioning. The animals that had morphine paired with the other chamber (the black chamber) showed extinction. Moreover greater resistance to extinction was observed in the HIV-1Tg rats. Following extinction the HIV-1Tg and F344 groups were each divided into two groups. One group was tested for reinstatement following a 1 mg/kg and 3.5 mg/kg morphine prime on 2 consecutive days, respectively. The second group was tested for reinstatement after exposure to foot shock. Reinstatement with drug-prime or with the foot shock stressor was not observed.
RESUMEN
We recently reported that six consecutive days of treatment with a moderate dose of methamphetamine (METH) induced greater behavioral sensitization in adult HIV-1 transgenic (HIV-1 Tg) rats than in adult Fischer 344/NHsd (F344) non-transgenic, wild-type control animals. In the present study, we evaluated the effects of a moderate dose of METH on the brains of adolescent versus adult HIV-1 Tg male rats using both behavioral (METH-induced, stereotypic head movement) and physiological (rectal body temperature) parameters. We found that both the acute and behavior-sensitizing effects of METH were greater in HIV-1 Tg rats compared with controls and also in adolescent rats compared with adult animals, regardless of HIV-1 status. We determined that acute hyperthermic effects of METH as well as tolerance to METH-induced hyperthermia were greater in HIV-1 Tg rats than in controls. Taken together, these results suggest that both the neuroadaptations seen in HIV infection and the immaturity of the adolescent brain are associated with increased sensitivity to the psychoactive and behavior-sensitizing properties of METH. Thus, HIV-infected individuals and adolescents may be more vulnerable to the development of METH abuse and dependence than non-infected individuals and adults.
Asunto(s)
Trastornos Relacionados con Anfetaminas/complicaciones , Conducta Animal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Infecciones por VIH/complicaciones , Metanfetamina/farmacología , Factores de Edad , Trastornos Relacionados con Anfetaminas/fisiopatología , Trastornos Relacionados con Anfetaminas/virología , Animales , VIH-1 , Masculino , Ratas , Ratas Endogámicas F344 , Ratas TransgénicasRESUMEN
HIV-1 viral replication is limited in patients given highly active anti-retroviral therapy (HAART); however, HIV-1 viral proteins are still present. We demonstrate that the developing HIV-1Tg rat, which expresses all of the HIV-1 viral genes except the gag-pol replication genes, maintains lower body weight compared with the F344 control rat. Although HIV-1Tg rats eat and drink less than the control animals, they are not anorexic and show no evidence of anhedonia. At 19 months (mo) of age, HIV-1Tg rats begin to show clinical signs of wasting that progress to death. Using real-time RT-PCR, we compared the expression of the HIV viral proteins Tat, gp120, nef, and vif, in the HIV-1Tg rats at 2-3 mo of age with those at 10-11 mo of age. RNA levels of viral protein in the spleens of younger rats were significantly greater than those in the older rats (P<0.01). Conversely, viral protein mRNA levels in the spinal cord, cerebellum, and striatum were significantly greater in the older rats than in the younger animals (P<0.01). In the prefrontal cortex, Tat and nef expression was significantly greater at 2-3 mo of age than at 10-11 mo of age (P<0.05). These findings indicate that there may be age-dependent differential expression of various HIV viral proteins, with a switch from peripheral immune organs to the CNS, even when the animals are still pre-symptomatic. Our study also demonstrates that this non-infectious rat can be a useful model simulating HIV-1 infected individuals that are on HAART.
Asunto(s)
Envejecimiento/fisiología , Terapia Antirretroviral Altamente Activa , Infecciones por VIH/genética , VIH-1/genética , Proteínas Virales/biosíntesis , Animales , Sistema Nervioso Central/virología , Modelos Animales de Enfermedad , Expresión Génica , Perfilación de la Expresión Génica , Masculino , ARN Mensajero/análisis , ARN Viral/análisis , Ratas , Ratas Transgénicas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Bazo/virología , Proteínas Virales/genéticaRESUMEN
Methamphetamine (METH) addiction is prevalent among individuals with HIV infection. We hypothesize that HIV-positive individuals are more prone to METH use and to the development of METH dependence. To test this hypothesis, we examined the effects of METH (daily intraperitoneal injection 2.5 mg/kg for 6 days) on rearing and head movement in 12-13-week-old male HIV-1 transgenic (HIV-1Tg) rats compared to F344 control rats as an indicator of behavioral sensitization, also representing neural adaptation underlying drug dependence and addiction. Body and brain weights were also recorded. The involvement of the dopaminergic system was investigated by examining dopamine receptors 1 (D1R) and 2 (D2R) and dopamine transporter (DAT) expression in the striatum and prefrontal cortex. METH increased rearing number and duration in both F344 and HIV-1Tg rats. Rearing number was attenuated over time, whereas rearing duration remained constant. METH also induced a progressive increase in stereotypical head movement in both F344 and HIV-1Tg rats, but it was greater in the HIV-1Tg rats than in the F344 animals. The brain to body weight ratio was significantly lower in METH-treated HIV-1Tg rats compared to F344 controls. There was no significant difference in striatal D1R, D2R, or DAT messenger RNA in HIV-1Tg and F344 rats. However, D1R expression was greater in the prefrontal cortex of HIV-1Tg rats than F344 rats and was attenuated by METH. Our results indicate that METH-induced behavioral sensitization is greater in the presence of HIV infection and suggest that D1R expression in the prefrontal cortex may play a role in METH addiction in HIV-positive individuals.
Asunto(s)
Trastornos Relacionados con Anfetaminas/genética , Conducta Animal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Infecciones por VIH/psicología , VIH-1/genética , Metanfetamina/farmacología , Trastornos Relacionados con Anfetaminas/psicología , Animales , Animales Modificados Genéticamente , Fármacos Anti-VIH/uso terapéutico , Peso Corporal/efectos de los fármacos , Encéfalo/patología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Proteínas de Fusión gag-pol/genética , Infecciones por VIH/genética , Movimientos de la Cabeza/efectos de los fármacos , Masculino , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Endogámicas F344 , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Human immunodeficiency virus (HIV)-associated dementia (HAD) encompasses a spectrum of cognitive and motor deficits resulting from the progression of central nervous system abnormalities caused by the HIV-1 virus. With the advent of highly active antiretroviral therapy (HAART), these deficits have become milder, but more prevalent as the population of HIV-positive individuals ages. Mild impairment in cognition has also been identified in asymptomatic HIV-1 patients. The noninfectious HIV-1 transgenic (Tg) rat recently developed to study the pathogenesis of acquired immunodeficiency syndrome (AIDS) may also be useful for the study of the early and chronic effects of HIV-1 on learning and cognition. In a previous study, we demonstrated that HIV-1Tg rats show a deficit in learning how to swim to a hidden platform in a modified water maze task compared to normal and transgenic controls. In the present study, we replicate this result and demonstrate that HIV-1Tg rats also show a significant deficit in reversal learning and new strategy learning. These results indicate that the HIV-1Tg rat is a promising model in which to study the neuropathogenic mechanisms that can cause cognitive deficits in patients with HAD as well as asymptomatic HIV-positive individuals.
Asunto(s)
Infecciones por VIH/psicología , VIH-1 , Discapacidades para el Aprendizaje/psicología , Discapacidades para el Aprendizaje/virología , Aprendizaje , Conducta Espacial , Complejo SIDA Demencia/fisiopatología , Complejo SIDA Demencia/psicología , Animales , Cognición , Modelos Animales de Enfermedad , Infecciones por VIH/fisiopatología , Discapacidades para el Aprendizaje/fisiopatología , Ratas , Ratas TransgénicasRESUMEN
HIV-1 infection of the central nervous system impairs neural, cognitive, and behavioral functioning in patients despite antiretroviral therapy. However, studying mechanisms underlying HIV-1-related neurological and cognitive dysfunction has been limited without an adequate animal model. A novel, noninfectious HIV-1 transgenic (HIV-1Tg) rat model was recently created that expresses an HIV-1 provirus with a deletion of functional gag and pol genes. This HIV-1Tg rat reportedly develops clinical manifestations of human HIV disease and thus appears to mimic the persistent infection that results from the presence of HIV viral proteins in the host. We evaluated the HIV-1Tg rat model using the Morris water maze, a popular paradigm for testing learning and memory deficits in rodents. Because of congenital cataracts in HIV-1Tg rats, however, the traditional use of visual navigational cues in this paradigm were precluded. We first designed a modified Morris water maze and demonstrated that neurologically intact rats can effectively learn the water maze in the absence of visual cues and in the presence of non-visual navigation cues. We then tested HIV-1Tg rats in this modified Morris water maze. These HIV-1Tg rats showed a deficit in learning how to swim to the location of the hidden platform but did not show a deficit in their memory of the general location of the hidden platform. These results suggest that the noninfectious HIV-1Tg rat can be a valid model for the behavioral studies of HIV-related neurological dysfunction.
Asunto(s)
VIH-1/genética , Aprendizaje por Laberinto/fisiología , Memoria/fisiología , Conducta Espacial/fisiología , Animales , Animales Modificados Genéticamente , Reacción de Fuga/fisiología , Aprendizaje/fisiología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
For the past 35 years, learning theorists have been providing models that depend on mental representations, even in their most simple, deterministic, and mechanistic approaches. Hence, cognitive involvement (typically thought of as expectancy) is assumed for most instances of classical and operant conditioning, with current theoretical differences concerning the level of cognition that is involved (e.g., simple association vs. rule learning), rather than its presence. Nevertheless, many psychologists not in the mainstream of learning theory continue to think of cognitive and conditioning theories as rival families of hypotheses. In this article, the data pertaining to the role of higher-order cognition in conditioning is reviewed, and a theoretical synthesis is proposed that provides a role for both automatic and cognitively mediated processes.