HIV-1 Transgenic Female Rat: Synaptodendritic Alterations of Medium Spiny Neurons in the Nucleus Accumbens

Roscoe, Robert F.; Mactutus, Charles F.; Booze, Rosemarie M.

doi:10.1007/s11481-014-9555-z

Cited by 58 publications

(92 citation statements)

References 70 publications

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“…Hippocampus is also noted to be a region of high Tat mRNA expression in the GT-tg bigenic mouse model [7], potentially contributing to the present behavioral observation. Given recent demonstrations of Tat's sublethal effects to reduce spine density on medium spiny neurons in hippocampus [44] and similar HIV-1-related effects in nucleus accumbens [45], the involvement of the greater limbic/extralimbic circuit for other tasks that involve attentional processing presents as an important target for future investigations.…”

Section: Discussionmentioning

confidence: 99%

Exposure to HIV-1 Tat in brain impairs sensorimotor gating and activates microglia in limbic and extralimbic brain regions of male mice

Paris

Singh

Carey

et al. 2015

Behavioural Brain Research

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Human immunodeficiency virus (HIV) infection is associated with mood disorders and behavioral disinhibition. Impairments in sensorimotor gating and associated neurocognitive disorders are reported, but the HIV-proteins and mechanisms involved are not known. The regulatory HIV-1 protein, Tat, is neurotoxic and its expression in animal models increases anxiety-like behavior concurrent with neuroinflammation and structural changes in limbic and extra-limbic brain regions. We hypothesized that conditional expression of HIV-1 Tat1–86 in the GT-tg bigenic mouse model would impair sensorimotor gating and increase microglial reactivity in limbic and extralimbic brain regions. Conditional Tat induction via doxycycline (Dox) treatment (0–125 mg/kg, i.p., for 1–14 days) significantly potentiated the acoustic startle reflex (ASR) of GT-tg mice and impaired prepulse inhibition (PPI) of this response in a dose-dependent manner when Dox (100 mg/kg) was administered for brief (1 day) or prolonged (daily for 7 days) intervals. A greater proportion of active/reactive Iba1-labeled microglia was seen in the anterior cingulate cortex (ACC), dentate gyrus, and nucleus accumbens core when Tat protein was induced under either brief or prolonged expression conditions. Other subregions of the medial prefrontal cortex, amygdala, hippocampal formation, ventral tegmental area, and ventral pallidum also displayed Tat-induced microglial activation, but only the activation observed in the ACC recapitulated the pattern of ASR and PPI behaviors. Tat exposure also increased frontal cortex GFAP. Pretreatment with indomethacin attenuated the behavioral effects of brief (but not prolonged) Tat-exposure. Overall, exposure to HIV-1 Tat protein induced sensorimotor deficits associated with acute and persistent neuroinflammation in limbic/extralimbic brain regions.

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Section: Discussionmentioning

confidence: 99%

Exposure to HIV-1 Tat in brain impairs sensorimotor gating and activates microglia in limbic and extralimbic brain regions of male mice

Paris

Singh

Carey

et al. 2015

Behavioural Brain Research

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“…Synaptic alterations in pyramidal cells of the hippocampus [221], as well as decreased spine density in medium spiny neurons [222], have also been reported in mice conditionally expressing the HIV-1 Tat protein in astrocytes. Similarly, we have recently reported that HIV-1 Tg rats have altered dendritic spines in the nucleus accumbens medium spiny neurons [159]. The HIV-1 Tg rats had a reduction of longer spines and an increase in shorter, less projected spines, indicating a population shift to a more immature spine phenotype as a consequence of constitutive, low-level, exposure to HIV-1 proteins.…”

Section: Treatment Possibilitiesmentioning

confidence: 53%

“…Although HIV-1 Tg animals have light to moderate cataracts, our studies using light levels of 22 lux (dim) and 100 lux (bright) found similar visual abilities of HIV-1 Tg rats and controls to detect light cues [158, 159]. Thus, the ability of the HIV-1 Tg rats to respond to brief dim visual cues in small behavioral testing chambers is intact.…”

Section: Specific Targets Of the Viral Proteins Tat And Gp120 Inmentioning

confidence: 75%

“…The developmental effects of HIV-1, and its impact on the DA system, have been addressed by our group with the use of the HIV-1 transgenic (Tg) rat [108, 109, 157–159]. With the exception of a Gag-Pol deletion, which renders them noninfectious, the HIV genome is intact in the HIV-1 Tg rat [160].…”

Section: Specific Targets Of the Viral Proteins Tat And Gp120 Inmentioning

confidence: 99%

“…Adult female HIV-1 Tg rats display similar growth rates as controls [109, 161], show normal estrous cyclicity [159], and reveal no body weight loss through 11 months of age [109]. Notably, the health status of our HIV-1 Tg animals would not have been anticipated from the original description of the HIV-1 Tg rat [160].…”

Section: Specific Targets Of the Viral Proteins Tat And Gp120 Inmentioning

confidence: 99%

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HIV-1 Proteins, Tat and gp120, Target the Developing Dopamine System

Fitting¹,

Booze

Mactutus³

2015

CHR

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In 2014, 3.2 million children (< 15 years of age) were estimated to be living with HIV and AIDS worldwide, with the 240,000 newly infected children in the past year, i.e., another child infected approximately every two minutes [1]. The primary mode of HIV infection is through mother-to-child transmission (MTCT), occurring either in utero, intrapartum, or during breastfeeding. The effects of HIV-1 on the central nervous system (CNS) are putatively accepted to be mediated, in part, via viral proteins, such as Tat and gp120. The current review focuses on the targets of HIV-1 proteins during the development of the dopamine (DA) system, which appears to be specifically susceptible in HIV-1-infected children. Collectively, the data suggest that the DA system is a clinically relevant target in chronic HIV-1 infection, is one of the major targets in pediatric HIV-1 CNS infection, and may be specifically susceptible during development. The present review discusses the development of the DA system, follows the possible targets of the HIV-1 proteins during the development of the DA system, and suggests potential therapeutic approaches. By coupling our growing understanding of the development of the CNS with the pronounced age-related differences in disease progression, new light may be shed on the neurological and neurocognitive deficits that follow HIV-1 infection.

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Neuropathogenic role of astrocyte‐derived extracellular vesicles in HIV‐associated neurocognitive disorders

Chemparathy,

Ray,

Ochs

et al. 2024

J of Extracellular Vesicle

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Our previous findings demonstrated that astrocytic HIF‐1α plays a major role in HIV‐1 Tat‐mediated amyloidosis which can lead to Alzheimer's‐like pathology‐a comorbidity of HIV‐Associated Neurocognitive Disorders (HAND). These amyloids can be shuttled in extracellular vesicles, and we sought to assess whether HIV‐1 Tat stimulated astrocyte‐derived EVs (ADEVs) containing the toxic amyloids could result in neuronal injury in vitro and in vivo. We thus hypothesized that blocking HIF‐1α could likely mitigate HIV‐1 Tat‐ADEV‐mediated neuronal injury. Rat hippocampal neurons when exposed to HIV‐1 Tat‐ADEVs carrying the toxic amyloids exhibited amyloid accumulation and synaptodendritic injury, leading to functional loss as evidenced by alterations in miniature excitatory post synaptic currents. The silencing of astrocytic HIF‐1α not only reduced the biogenesis of ADEVs, as well as amyloid cargos, but also ameliorated neuronal synaptodegeneration. Next, we determined the effect of HIV‐1 Tat‐ADEVs carrying amyloids in the hippocampus of naive mice brains. Naive mice receiving the HIV‐1 Tat‐ADEVs, exhibited behavioural changes, and Alzheimer's ’s‐like pathology accompanied by synaptodegeneration. This impairment(s) was not observed in mice injected with HIF‐1α silenced ADEVs. This is the first report demonstrating the role of amyloid‐carrying ADEVs in mediating synaptodegeneration leading to behavioural changes associated with HAND and highlights the protective role of HIF‐1α.

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HIV-1 Transgenic Female Rat: Synaptodendritic Alterations of Medium Spiny Neurons in the Nucleus Accumbens

Cited by 58 publications

References 70 publications

Exposure to HIV-1 Tat in brain impairs sensorimotor gating and activates microglia in limbic and extralimbic brain regions of male mice

Exposure to HIV-1 Tat in brain impairs sensorimotor gating and activates microglia in limbic and extralimbic brain regions of male mice

HIV-1 Proteins, Tat and gp120, Target the Developing Dopamine System

Neuropathogenic role of astrocyte‐derived extracellular vesicles in HIV‐associated neurocognitive disorders

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