Abstract
In the era of combined antiretroviral therapy, HIV-1 infected individuals are living longer lives; however, longevity is met with an increasing number of HIV-1 associated neurocognitive disorders (HAND) diagnoses. The transactivator of transcription (Tat) is known to mediate the neurotoxic effects in HAND by acting directly on neurons and also indirectly via its actions on glia. The Go/No-Go (GNG) task was used to examine HAND in the Tat transgenic mouse model. The GNG task involves subjects discriminating between two stimuli sets in order to determine whether or not to inhibit a previously trained response. Data reveal inhibitory control deficits in female Tat(+) mice (p = .048) and an upregulation of cannabinoid type 1 receptors (CB1R) in the infralimbic (IL) cortex in the same female Tat(+) group (p < .05). A significant negative correlation was noted between inhibitory control and IL CB1R expression (r = −.543, p = .045), with CB1R expression predicting 30% of the variance of inhibitory control (R2 = .295, p = .045). Furthermore, there was a significant increase in spontaneous excitatory postsynaptic current (sEPSC) frequencies in Tat(+) compared to Tat(−) mice (p = .008, across sexes). The increase in sEPSC frequency was significantly attenuated by bath application of PF3845, a fatty acid amide hydrolase (FAAH) enzyme inhibitor (p < .001). Overall, the GNG task is a viable measure to assess inhibitory control deficits in Tat transgenic mice and results suggest a potential therapeutic treatment for the observed deficits with drugs which modulate endocannabinoid enzyme activity.Graphical Results of the Go/No-Go operant conditioning task reveal inhibitory control deficits in female transgenic Tat(+) mice without significantly affecting males. The demonstrated inhibitory control deficits appear to be associated with an upregulation of cannabinoid type 1 receptors (CB1R) in the infralimbic (IL) cortex in the same female Tat(+) group.
Highlights
The World Health Organization estimates 36.7 million people are diagnosed with human immunodeficiency virus type 1 (HIV-1) worldwide, which has been considered a fatal diagnosis before antiretroviral treatments were established
Before combined antiretroviral therapy (cART), the later stages in the progression of HIV-1 infection were marked with HIV-1 associated dementia (HAD), but a newer, milder form of cognitive impairment has emerged during the post-cART era called HIV-1-associated neurocognitive disorders (HAND) (Ellis et al 2007)
A Pearson correlation demonstrated no significant correlation between PInhibition and cannabinoid type 1 receptors (CB1R) expression in the PL region (r = −.371, p = .191; Fig. 4a) but a significant negative correlation for the IL region (r = −.543, p = .045; Fig. 4b), indicating an association between inhibitory control deficits and an upregulation of CB1R expression in the IL of the medial PFC (mPFC)
Summary
The World Health Organization estimates 36.7 million people are diagnosed with human immunodeficiency virus type 1 (HIV-1) worldwide, which has been considered a fatal diagnosis before antiretroviral treatments were established. Symptoms that have been associated with HAND in the post-cART era include reduced mental acuity, and deficits in working memory, attention, and inhibitory control (Connolly et al 2014; Ernst et al 2003; Wang et al 2017) that are associated with cortical brain structures such as the prefrontal cortex (PFC) (Heaton et al 2011) It is unclear how HAND manifests and what molecular and cellular mechanisms are driving HAND, the severity of synaptic disruption and dendritic injury is correlated with the severity of expressed symptoms of HAND (Everall et al 1999; Masliah et al 1997). Tat can induce neurotoxicity through indirect mechanisms via its actions on microglia and astrocytes by stimulating the production of proinflammatory cytokines (Chen et al 1997), inducing TNF-α and IL-1 in monocytes and macrophages and a milieu of cytokines and chemokines in astrocytes, including IL-8, RANTES, MCP-1, and TNF-α (El-Hage et al 2005; Kutsch et al 2000)
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