Chronic SSRI treatment reverses HIV-1 protein-mediated synaptodendritic damage

Denton, Adam R.; Mactutus, Charles F.; Lateef, Almeera U; Harrod, Steven B.; Booze, Rosemarie M.

doi:10.1007/s13365-021-00960-6

Cited by 7 publications

(3 citation statements)

References 77 publications

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“…One of the notable advantages of the HIV-1 Tg rat is its utility for investigating the debilitating neurocognitive impairments (e.g., Vigorito et al, 2007;Moran et al, 2014;Repunte Canonigo et al, 2014;McLaurin et al, 2019) and affective (e.g., Nemeth et al, 2014;Bertrand et al, 2018;Denton et al, 2021;McLaurin et al, 2021b) alterations associated with HIV-1. The HIV-1 Tg rat, developed by Reid et al (2001), constitutively expresses seven of the nine HIV-1 viral proteins (the gag and pol genes are deleted) under the control of the natural HIV-1 promoter.…”

Section: Discussionmentioning

confidence: 99%

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Synaptic Dysfunction Underlies Alterations in the Initiation of Goal-Directed Behaviors: Implications for Hiv-1 Associated Apathy

McLaurin

Cranston

et al. 2021

Preprint

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Individuals living with human immunodeficiency virus type 1 (HIV-1) exhibit an increased prevalence of neuropsychiatric comorbities (e.g., apathy) relative to their seronegative counterparts. Given the profound functional consequences associated with apathy, conceptualizing the multidimensional neuropsychiatric syndrome, and associated neural mechanisms, following chronic HIV-1 viral protein exposure remains a critical need. HIV-1 associated apathy was examined by quantifying goal-directed behaviors, indexed using voluntary wheel running, during the diurnal and nocturnal cycle. Apathetic behaviors in the HIV-1 Tg rat were characterized by a profound decrease in the number of running bouts during both the diurnal and nocturnal cycle, supporting a prominent deficit in the self-initiation of spontaneous behaviors. Additionally, HIV-1 Tg animals exhibited a decreased reinforcing efficacy of voluntary wheel running during the nocturnal cycle. Following the completion of voluntary wheel running, synaptic dysfunction in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) was examined as a potential neural mechanism underlying HIV-1 associated apathy. HIV-1 Tg animals displayed prominent synaptic dysfunction in MSNs of the NAc, characterized by decreased synaptic connectivity and a population shift towards an immature dendritic spine phenotype relative to control animals. Synaptic dysfunction accounted for 42.0% to 68.5% of the variance in the number of running bouts affording a key neural mechanism underlying the self-initiation of spontaneous behaviors. The establishment of a fundamental neural mechanism underlying apathy affords a key target for the development of novel therapeutics and cure strategies for affective alterations associated with HIV-1.

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Section: Discussionmentioning

confidence: 99%

“…Collectively, the decreased dopamine levels commonly observed in HIV-1 seropositive individuals (e.g., Kumar et al, 2009;Kumar et al, 2011) and biological systems utilized to model HAND (e.g., Jenuwein et al, 2004;Ferris et al, 2009;Denton et al, 2021) may result from and/or lead to alterations in dendritic spines (McLaurin et al, 2021a).…”

Section: Discussionmentioning

confidence: 99%

Synaptic Dysfunction Underlies Alterations in the Initiation of Goal-Directed Behaviors: Implications for Hiv-1 Associated Apathy

McLaurin

Cranston

et al. 2021

Preprint

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“…These include structural abnormalities in neurons/dendrites, such as reduced spine density and changes in synaptic proteins ( 21 – 23 ), disrupted frontostriatal circuitry ( 24 ), and glial abnormalities including microglial activation and micro/astrogliosis ( 20 , 21 , 25 ). Further, these mice and related neuroHIV rodent models also develop changes in learning/memory, motor activity, and motivated behaviors ( 24 , 26 – 30 ) relevant for cART-treated PLWH. As dopaminergic neurocircuitry is highly susceptible to disruption by HIV proteins, including HIV Tat ( 29 , 31 – 34 ), motivational alterations remain problematic neurobehavioral manifestations in cART-treated PLWH, including apathy ( 35 , 36 ) which parallels lack of motivation.…”

Section: Introductionmentioning

confidence: 99%

A helping HAND: therapeutic potential of MAGL inhibition against HIV-1-associated neuroinflammation

League,

Yadav-Samudrala,

Kolagani

et al. 2024

Front. Immunol.

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BackgroundHuman immunodeficiency virus (HIV) affects nearly 40 million people globally, with roughly 80% of all people living with HIV receiving antiretroviral therapy. Antiretroviral treatment suppresses viral load in peripheral tissues but does not effectively penetrate the blood-brain barrier. Thus, viral reservoirs persist in the central nervous system and continue to produce low levels of inflammatory factors and early viral proteins, including the transactivator of transcription (Tat). HIV Tat is known to contribute to chronic neuroinflammation and synaptodendritic damage, which is associated with the development of cognitive, motor, and/or mood problems, collectively known as HIV-associated neurocognitive disorders (HAND). Cannabinoid anti-inflammatory effects are well documented, but therapeutic utility of cannabis remains limited due to its psychotropic effects, including alterations within brain regions encoding reward processing and motivation, such as the nucleus accumbens. Alternatively, inhibiting monoacylglycerol lipase (MAGL) has demonstrated therapeutic potential through interactions with the endocannabinoid system.MethodsThe present study utilized a reward-related operant behavioral task to quantify motivated behavior in female Tat transgenic mice treated with vehicle or MAGL inhibitor MJN110 (1 mg/kg). Brain tissue was collected to assess dendritic injury and neuroinflammatory profiles, including dendritic microtubule-associated protein (MAP2ab) intensity, microglia density, microglia morphology, astrocyte density, astrocytic interleukin-1ß (IL-1ß) colocalization, and various lipid mediators.ResultsNo significant behavioral differences were observed; however, MJN110 protected against Tat-induced dendritic injury by significantly upregulating MAP2ab intensity in the nucleus accumbens and in the infralimbic cortex of Tat(+) mice. No or only minor effects were noted for Iba-1+ microglia density and/or microglia morphology. Further, Tat increased GFAP+ astrocyte density in the infralimbic cortex and GFAP+ astrocytic IL-1ß colocalization in the nucleus accumbens, with MJN110 significantly reducing these measures in Tat(+) subjects. Lastly, selected HETE-related inflammatory lipid mediators in the striatum were downregulated by chronic MJN110 treatment.ConclusionsThese findings demonstrate anti-inflammatory and neuroprotective properties of MJN110 without cannabimimetic behavioral effects and suggest a promising alternative to cannabis for managing neuroinflammation.

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Synaptic dysfunction is associated with alterations in the initiation of goal-directed behaviors: Implications for HIV-1-associated apathy

McLaurin¹,

Cranston²,

Li³

et al. 2022

Experimental Neurology

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Chronic SSRI treatment reverses HIV-1 protein-mediated synaptodendritic damage

Cited by 7 publications

References 77 publications

Synaptic Dysfunction Underlies Alterations in the Initiation of Goal-Directed Behaviors: Implications for Hiv-1 Associated Apathy

Synaptic Dysfunction Underlies Alterations in the Initiation of Goal-Directed Behaviors: Implications for Hiv-1 Associated Apathy

A helping HAND: therapeutic potential of MAGL inhibition against HIV-1-associated neuroinflammation

Synaptic dysfunction is associated with alterations in the initiation of goal-directed behaviors: Implications for HIV-1-associated apathy

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