Abstract
BackgroundHuman immunodeficiency virus (HIV)-1-associated neurocognitive disorders (HAND) are characterized by synaptic damage and neuronal loss in the brain. Excessive glutamatergic transmission and loss of cholinergic neurons are the major indicators of HAND. Nicotine acts as a cholinergic channel modulator, and its cognitive-enhancing effect in neurodegenerative and cognitive disorders has been documented. However, it is unclear whether nicotine has any positive effect on memory and synaptic plasticity formation in HAND.MethodsWe investigated the effects of nicotine on synaptic plasticity and hippocampus–prefrontal cortex (PFC)–amygdala-dependent memory formation in the HIV-1 transgenic (Tg) and F344 control rats.ResultsChronic nicotine treatment (0.4 mg/kg nicotine, base, subcutaneously) significantly attenuated the cognitive deficits in the HIV-1Tg rats in both the spatial and contextual fear memories but impaired the contextual learning memory in the F344 rats. To determine the role of nicotine in the synaptic dysfunction caused by HIV-1 proteins, we analyzed the expression of key representative genes related to synaptic plasticity in the hippocampus, PFC, and amygdala of the HIV-1Tg and F344 rats using a custom-designed qRT-PCR array. The HIV-1 proteins significantly altered the glutamate receptor-mediated intracellular calcium cascade and its downstream signaling cascade in a brain region-specific manner. Further, chronic nicotine treatment reversed the effect of HIV-1 proteins on the expression of genes involved in synaptic plasticity in the three brain regions. The effects of nicotine differed significantly in the HIV-1Tg and F344 rats.ConclusionsOur findings indicate that nicotine can attenuate the effect of HIV viral proteins on cognitive function and produce a brain region- and strain-specific effect on the intracellular signaling cascades involved in synaptic plasticity and memory formation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0134-x) contains supplementary material, which is available to authorized users.
Highlights
Human immunodeficiency virus (HIV)-1 proteins penetrate the central nervous system (CNS) during the early stages of viral infection and induce progressive neuronal damages in the brain [1, 2]
We aimed to answer the following two interrelated questions: (1) does chronic nicotine treatment attenuate HIV-1-associated cognitive impairment? And (2) does nicotine show differential effects on intracellular signaling mechanisms underlying the synaptic plasticity formation of the HIV-1Tg rats in comparison to the F344 control animals? We addressed the first question by testing HIV-1Tg and F344 rats for spatial working memory in the Y-maze and for contextual fear memory in the passive avoidance test
Improvement of spatial working memory performance by chronic nicotine treatment in the HIV-1Tg and F344 rats To evaluate the effects of HIV viral proteins and nicotine on spatial working memory performance, spontaneous alternation behavior was tested in the nicotine-treated and saline control groups of both HIV-1Tg and F344 rats
Summary
Human immunodeficiency virus (HIV)-1 proteins penetrate the central nervous system (CNS) during the early stages of viral infection and induce progressive neuronal damages in the brain [1, 2]. HIV-1-associated neurocognitive disorders (HAND) are the major CNS complications of HIV-1 infection, with approximately 50 % of patients developing some degrees of cognitive impairment [3]. It has been reasoned that the high prevalence of smoking in HIV-1-infected patients is attributable to the compensatory effect of smoking on cognitive deficits [7]. Human immunodeficiency virus (HIV)-1-associated neurocognitive disorders (HAND) are characterized by synaptic damage and neuronal loss in the brain. Nicotine acts as a cholinergic channel modulator, and its cognitive-enhancing effect in neurodegenerative and cognitive disorders has been documented.
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