Biology subjects

Minassian, A.

Publications and source records attributed to Minassian, A..

5 recordsLinked to original sources

bioRxiv2025

Chronic nicotine treatment enhanced cognition and reduced neuroinflammation in the gp120 transgenic mouse model of neuroHIV

RationaleAntiretroviral development has improved the longevity of people with HIV (PWH), but many experience impaired cognition potentially due to neuroinflammation. PWH smoke cigarettes at higher rates than the general population, possibly for self-medication given cognitive-enhancing and anti-inflammatory properties of nicotine, the primary psychoactive ingredient cigarette smoke. We hypothesized that chronic nicotine would improve cognition in a mouse model of HIV, gp120 transgenic (Tg) mice, and reduce neuroinflammation. MethodsMale and female gp120-Tg mice (n=64) and littermate controls (n=67) were operantly trained then tested for effortful motivation in the progressive ratio breakpoint task (PRBT). Mice were counter-balanced into three groups for saline or nicotine minipump implantation (0, 14 or 40 mg/kg/day) then retested 25 days later in the PRBT, probabilistic reversal learning task (PRLT - reinforcement learning and cognitive flexibility), and Iowa Gambling Task (IGT - risk-based decision-making), with a subset tested for neuroinflammation (Iba-1 levels). ResultsGp120-Tg mice exhibited worse PRLT performance, attenuated by nicotine. Furthermore, nicotine selectively optimized their response strategies in the PRLT and IGT, increasing loss sensitivity, shifting animals towards "safer" responses. No motivation effects were observed. Nicotine also reduced Iba-1 expression, suggesting that its cognitive-enhancing effects may relate to reduced neuroinflammation. ConclusionGp120-Tg mice exhibited deficits in the PRLT, which are attenuated by chronic nicotine. Furthermore, nicotine improved reinforcement learning and risky decision-making supporting its therapeutic potential for cognitive deficits in PWH, possibly via reducing neuroinflammation. With potential negative consequences of long-term nicotine use, future studies should determine its mechanism of action to develop more targeted therapeutics.

neuroscience↗

bioRxiv2024

Acute nicotine vapor normalizes sensorimotor gating and reduces locomotor activity deficits in HIV-1 transgenic rats

RationaleDespite improved life expectancy of people with HIV (PWH), HIV-associated neurocognitive impairment (NCI) persists, alongside deficits in sensorimotor gating and neuroinflammation. PWH exhibit high smoking rates, possibly due to neuroprotective, anti-inflammatory, and cognitive-enhancing effects of nicotine, suggesting potential self-medication. ObjectivesHere, we tested the effects of acute nicotine vapor exposure on translatable measures of sensorimotor gating and exploratory behavior in the HIV-1 transgenic (HIV-1Tg) rat model of HIV. MethodsMale and female HIV-1Tg and F344 control rats (n=57) were exposed to acute nicotine or vehicle vapor. Sensorimotor gating was assessed using prepulse inhibition (PPI) of the acoustic startle response, and exploratory behavior was evaluated using the behavioral pattern monitor (BPM). ResultsVehicle-treated HIV-1Tg rats exhibited PPI deficits at low prepulse intensities compared to F344 controls, as seen previously. No PPI deficits were observed in nicotine-treated HIV-1Tg rats, however. HIV-1Tg rats were hypoactive in the BPM relative to controls, whilst nicotine vapor increased activity and exploratory behavior across genotypes. Cotinine analyses confirmed comparable levels of the primary metabolite of nicotine across genotypes. ConclusionsPrevious findings of PPI deficits in HIV-1Tg rats were replicated and, importantly, attenuated by acute nicotine vapor. Evidence for similar cotinine levels suggest a nicotine-specific effect in HIV-1Tg rats. HIV-1Tg rats had reduced exploratory behavior compared to controls, attenuated by acute nicotine vapor. Therefore, acute nicotine may be beneficial for remediating sensorimotor and locomotor activity deficits in PWH. Future studies should determine the long-term effects of nicotine vapor on similar HIV/NCI-relevant behaviors.

neuroscience↗

bioRxiv2021

MicroPET evidence for a hypersensitive neuroinflammatory profile of gp120 mouse model of HIV

Despite increased survivability for people living with HIV (PLWH), HIV-related cognitive and behavioral abnormalities persist. Determining the biological mechanism(s) underlying these abnormalities is critical to minimize the long-term impact of HIV. Human positron emission tomography (PET) studies reveal that PLWH exhibit higher neuroinflammation, which may contribute to cognitive and behavioral problems. PLWH are hypersensitive to environmental insults that drive elevated inflammatory profiles. Gp120 is an envelope glycoprotein exposed on the surface of the HIV envelope which enables HIV virus entry into a cell and contributes to HIV-related neurotoxicity. Gp120 overexpression in mice enables delineating its impact, including on neuroinflammation. In vivo evidence for gp120 transgenic (Tg) mice exhibiting neuroinflammation has yet to be determined. Here, we conducted microPET imaging in male gp120 Tg and wildtype mice, using the radiotracer [(18)F]FEPPA which binds to the translocator protein expressed by activated microglial and serves as a marker of neuroinflammation. Imaging was performed at baseline and 24 hours after treatment with lipopolysaccharide (LPS; 5 mg/kg), endotoxin that triggers an immune response. Gp120 Tg mice exhibited elevated [(18F)]FEPPA in response to LPS vs. wildtype mice throughout the brain including dorsal and ventral striata, hypothalamus, and hippocampus, but not prefrontal cortex. Gp120 Tg mice are hypersensitive to environmental inflammatory insults, consistent with PLWH, measurable in vivo. It remains to-be-determined whether this heightened sensitivity is connected to the behavioral abnormalities of these mice or is sensitive to antiretroviral or other treatments.

neuroscience↗

bioRxiv2020

Both HIV Infection and Conditional Tat Expression Decrease Prepulse Inhibition with Further Impairment by Methamphetamine History in Humans

HIV infection and methamphetamine (METH) use are highly comorbid and represent a significant public health problem. Both conditions are known to negatively impact a variety of brain functions. One brain function that may be affected by HIV and METH use is sensorimotor gating, an automatic, pre-conscious filtering of sensory information that is thought to contribute to higher order cognitive processes. Sensorimotor gating is often measured using prepulse inhibition (PPI), a paradigm that can be conducted in both humans and animals, thereby enabling cross-species translational studies. While previous studies suggest HIV and METH may individually impair PPI, little research has been conducted on the effects of combined HIV and METH on PPI. The goal of this cross-species study was to determine the effects of METH on PPI in the inducible Tat (iTat) mouse model of HIV and in people with HIV. PPI was measured in the iTat mouse model before, during, and after chronic METH treatment and after Tat induction. Chronic METH treatment decreased PPI in male but not female mice. PPI normalized with cessation of METH. Inducing Tat expression decreased PPI in male but not in female mice. No interactions between chronic METH treatment and Tat expression were observed in mice. In humans, HIV was associated with decreased PPI in both men and women. Furthermore, PPI was lowest in people with HIV who also had a history of METH dependence. Overall, these results suggest HIV and METH may additively impair early information processing in humans, potentially affecting downstream cognitive function. HIGHLIGHTSO_LIHIV decreased PPI in men and women C_LIO_LIPPI was most decreased in people with HIV and a history of METH dependence C_LIO_LIChronic METH treatment decreased PPI in male but not female mice C_LIO_LITat expression decreased PPI in male but not female mice C_LIO_LIChronic METH treatment and Tat expression did not interact to affect PPI in mice C_LI

neuroscience↗

bioRxiv2020

Sustained attention and vigilance deficits associated with HIV and a history of methamphetamine dependence

BackgroundHuman immunodeficiency virus (HIV)-associated neurocognitive disorders persist in the era of antiretroviral therapy (ART). One factor that is elevated among persons with HIV (PWH) and independently associated with neurocognitive impairment is methamphetamine dependence (METH+). Such dependence may further increase cognitive impairment among PWH, by delaying HIV diagnosis (and thus, ART initiation), which has been posited to account for persistent cognitive impairment among PWH, despite subsequent treatment-related viral load suppression (VLS; [≤]50 copies of the virus per milliliter in plasma or cerebrospinal fluid). This study examined the independent and combined (additive versus synergistic) effects of HIV and history of METH+ on the sustained attention and vigilance cognitive domain, while controlling for VLS. MethodsParticipants included 205 (median age=44 years; 77% males; HIV-/METH- n=67; HIV+/METH - n=49; HIV-/METH+ n=36; HIV+/METH+ n=53) individuals enrolled in the Translational Methamphetamine AIDS Research Center, who completed Conners and the 5- Choice continuous performance tests (CPTs). ResultsMETH+ participants exhibited deficits in sustained attention and vigilance; however, these effects were not significant after excluding participants who had a positive urine toxicology screen for methamphetamine. Controlling for VLS, PWH did not have worse sustained attention and vigilance, but consistently displayed slower reaction times across blocks, relative to HIV-participants. There was no HIV x METH interaction on sustained attention and vigilance. ConclusionsRecent methamphetamine use among METH+ people and detectable viral loads are detrimental to sustained attention and vigilance. These findings highlight the need for prompt diagnosis of HIV and initiation of ART, and METH use interventions.

neuroscience↗