Nicotine attenuates the effect of HIV-1 proteins on the neural circuits of working and contextual memories

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.

Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons

“…Collectively, our novel findings emphasize the therapeutic potential of combined long-term blockade of over-activated L-channel/NMDAR as a strategy to ameliorate and/or reduce HAND ( Figure 5 ). Future studies are needed to determine whether combined chronic L-channel/NMDAR blockade improves deficits in mPFC-related behavior, that have been reported in HIV-1 Tg rats (Nesil et al, 2015; Reid et al, 2016; Repunte-Canonigo et al, 2014). …”

Modulation Effect of HIV-1 Viral Proteins and Nicotine on Expression of the Immune-Related Genes in Brain of the HIV-1 Transgenic Rats

“…F344 and HIV-1Tg rats were injected subcutaneously ( s.c .) with either saline or nicotine once per day (0.4 mg/kg/day) for 27 d before tissue collection, a procedure commonly used to study pharmacological effects of nicotine in our and other groups (Gutala et al, 2006, Matta et al, 2007, Nesil et al, 2015). The concentration of nicotine was calculated as nicotine free base, pH 7.0, according to Matta et al (Matta et al, 2007) and based on our previous reported (Song et al, 2015, Nesil et al, 2015).…”

“…Like the peripheral immune system, the central nervous system (CNS) is also highly vulnerable to HIV-1 infection. The brain regions targeted by HIV-1 virus include the prefrontal cortex region (PFC), nucleus accumbens (NAc), and ventral tegmental area (VTA) (Midde et al, 2011, Nesil et al, 2015). Although combination anti-retroviral therapy (cART) leads to a temporary reversal of HIV dementia (Portegies, 1995, Gisslen et al, 1998, Gendelman et al, 1998), both HIV-associated neurocognitive disorders (HAND) and HIV-associated dementia (HAD) are resistant to cART and become more severe as the lifespan of HIV-1 infected patients is prolonged (McArthur et al, 2003).…”

Chronic Binge Alcohol Administration Dysregulates Hippocampal Genes Involved in Immunity and Neurogenesis in Simian Immunodeficiency Virus-Infected Macaques

“…A list of differentially expressed genes for CBA/SIV+ animals was generated by finding the top one percent of up-regulated genes and top one percent of down-regulated genes based on the frequency of fold-change values. This corresponded to the inclusion of genes that were increased or decreased 1.3 fold in CBA/SIV+ compared to SUC/SIV+, as used by other investigators [63,64]. The list of differentially expressed genes was further filtered by removing any genes for which there was overlap of their raw expression values between animals in the two groups.…”