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Paredes D.,USF Tampa | Paredes D.,Laboratory of Molecular Biology | Acosta S.,USF Tampa | Gemma C.,USF Tampa | Bickford P.C.,USF Tampa
Aging and Disease | Year: 2010

Tumor necrosis factor alpha (TNF-α) is a multifunctional proinflammatory cytokine, which is a critical inflammatory mediator involved in aging and neurodegenerative diseases of aging. Previous work has shown that diets enriched with antioxidants reduce levels of the cytokine TNF-α and improve classical eyeblink conditioning performance. Therefore we tested the hypothesis that the proinflamatory cytokine TNF-α may be a critical factor that modulates classical conditioning behavior. If increased levels of endogenous cerebellar TNF-α negatively affect performance on the eyeblink conditioning task in aged rats, then exogenous administration of TNF-α in young rats should result in an impaired acquisition and/or retention of eyeblink conditioning memory. On the other hand, the reduction or blockage of the age-related increase in cerebellar TNF-α levels in aged rats should result in an improvement in memory. Young (3 month old) F344 rats were pretreated with an intracerebellar injection of recombinant rat (rr)TNF-α or denatured (rr)TNF-α prior to eyeblink conditioning coupled to microdialysis. The results showed that young rats treated with rrTNF-α have a decreased rate of learning compared to the control group. Norepinephrine which has been shown to play a critical role in cerebellar learning tasks presented a shift on training day one of young rats resembling that observed in aged rats. In a second experiment aged (22 month old) F344 rats were pretreated with intracerebellar microinjection of anti-rat TNF-α three times a week for 4 weeks prior to eyeblink conditioning training couple to microdialysis. Aged rats showed a better performance in the conditioned responses when compared to controls. The release of norepinephrine in this group reached basal levels sooner than the control group but not as early as the young rats. The results of these experiments demonstrate a critical correlation between TNF-α and the rate of learning and the pattern of NE release during eyeblink conditioning. Source


Gemma C.,USF Tampa | Bachstetter A.D.,USF Tampa | Bachstetter A.D.,University of Kentucky | Bickford P.C.,USF Tampa
Aging and Disease | Year: 2010

Age-related changes in innate immune function and glial-neuronal communication are early and critical events in brain aging and neurodegenerative disease, and lead to a chronic increase in oxidative stress and inflammation, which initiates neuronal dysfunction and reduced synaptic plasticity, and ultimately disruption in learning and memory in the aged brain. Several lines of evidence suggest a correlation between adult neurogenesis and learning. It has been proposed that a decline in hippocampal neurogenesis contributes to a physiologic decline in brain function. Recently, new and important insights relating to the production of new neurons affecting hippocampal-dependent memory ability have been provided. A multitude of factors have been shown to regulate the production of new neurons in the adult hippocampus, many of which change as a result of aging. Yet, the potential importance of neurogenesis in some affective and cognitive behaviors, as well as endogenous tissue repair mechanisms, makes further investigation of neurogenic regulators warranted. We have recent evidence that key regulators of communication between neurons and microglia are disrupted in the aged brain and may be one of the factors that precedes and initiates the observed increase in chronic inflammatory state. In this review the role of dysfunction in these neuronal-glial communication regulators underlying age-related impairments in cognition and hippocampal neurogenesis will be discussed. An understanding of these mechanisms will lead to the development of preventive or protective therapies. Source


Kacanek D.,Harvard University | Kacanek D.,Center for Biostatistics in Research | Angelidou K.,Center for Biostatistics in Research | Williams P.L.,Harvard University | And 60 more authors.
AIDS | Year: 2015

Objectives: The relationship of specific psychiatric conditions to adherence has not been examined in longitudinal studies of youth with perinatal HIV infection (PHIV). We examined associations between psychiatric conditions and antiretroviral nonadherence over 2 years. Design: Longitudinal study in 294 PHIV youth, 6'17 years old, in the United States and Puerto Rico. Methods: We annually assessed three nonadherence outcomes: missed above 5% of doses in the past 3 days, missed a dose within the past month, and unsuppressed viral load (>400 copies/ml). We fit multivariable logistic models for nonadherence using Generalized Estimating Equations, and evaluated associations of psychiatric conditions (attention deficit hyperactivity disorder, disruptive behavior, depression, anxiety) at entry with incident nonadherence using multivariable logistic regression. Results: Nonadherence prevalence at study entry was 14% (3-day recall), 32% (past month nonadherence), and 38% (unsuppressed viral load), remaining similar over time. At entry, 38% met symptom cut-off criteria for at least one psychiatric condition. Greater odds of 3-day recall nonadherence were observed at week 96 for those with depression [adjusted odds ratio (aOR) 4.14, 95% confidence interval (CI) 1.11'15.42] or disruptive behavior (aOR 3.36, 95% CI 1.02'11.10], but not at entry. Those with vs. without attention deficit hyperactivity disorder had elevated odds of unsuppressed viral load at weeks 48 (aOR 2.46, 95% CI 1.27'4.78) and 96 (aOR 2.35, 95% CI 1.01'5.45), but not at entry. Among 232 youth adherent at entry, 16% reported incident 3-day recall nonadherence. Disruptive behavior conditions at entry were associated with incident 3- day recall nonadherence (aOR 3.01, 95% CI 1.24'7.31). Conclusion: In PHIV youth, comprehensive adherence interventions that address psychiatric conditions throughout the transition to adult care are needed. © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source

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