Central HIV-1 Tat exposure elevates anxiety and fear conditioned responses of male mice concurrent with altered mu-opioid receptor-mediated G-protein activation and β-arrestin 2 activity in the forebrain

Hahn, Yun Kyung; Paris, Jason J.; Lichtman, Aron H.; Hauser, Kurt F.; Sim‐Selley, Laura J.; Selley, Dana E.; Knapp, Pamela E.

doi:10.1016/j.nbd.2016.01.014

Cited by 35 publications

(31 citation statements)

References 93 publications

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“…The analgesic properties of MOR activation are also reduced when there is an abundance of CCR5 ligands [ 80 ]. MOR function is also altered by Tat exposure, which lowers morphine efficacy through decreased G-protein activation [ 81 ]. Reduced MOR signaling would tend to increase the amounts of opiates used by HIV-infected individuals for effective analgesia or for illicit effects.…”

Section: Discussionmentioning

confidence: 99%

A central role for glial CCR5 in directing the neuropathological interactions of HIV-1 Tat and opiates

Kim

Hahn

Podhaizer

et al. 2018

J Neuroinflammation

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BackgroundThe collective cognitive and motor deficits known as HIV-associated neurocognitive disorders (HAND) remain high even among HIV+ individuals whose antiretroviral therapy is optimized. HAND is worsened in the context of opiate abuse. The mechanism of exacerbation remains unclear but likely involves chronic immune activation of glial cells resulting from persistent, low-level exposure to the virus and viral proteins. We tested whether signaling through C-C chemokine receptor type 5 (CCR5) contributes to neurotoxic interactions between HIV-1 transactivator of transcription (Tat) and opiates and explored potential mechanisms.MethodsNeuronal survival was tracked in neuronal and glial co-cultures over 72 h of treatment with HIV-1 Tat ± morphine using cells from CCR5-deficient and wild-type mice exposed to the CCR5 antagonist maraviroc or exogenously-added BDNF (analyzed by repeated measures ANOVA). Intracellular calcium changes in response to Tat ± morphine ± maraviroc were assessed by ratiometric Fura-2 imaging (analyzed by repeated measures ANOVA). Release of brain-derived neurotrophic factor (BDNF) and its precursor proBDNF from CCR5-deficient and wild-type glia was measured by ELISA (analyzed by two-way ANOVA). Levels of CCR5 and μ-opioid receptor (MOR) were measured by immunoblotting (analyzed by Student’s t test).ResultsHIV-1 Tat induces neurotoxicity, which is greatly exacerbated by morphine in wild-type cultures expressing CCR5. Loss of CCR5 from glia (but not neurons) eliminated neurotoxicity due to Tat and morphine interactions. Unexpectedly, when CCR5 was lost from glia, morphine appeared to entirely protect neurons from Tat-induced toxicity. Maraviroc pre-treatment similarly eliminated neurotoxicity and attenuated neuronal increases in [Ca2+]i caused by Tat ± morphine. proBDNF/BDNF ratios were increased in conditioned media from Tat ± morphine-treated wild-type glia compared to CCR5-deficient glia. Exogenous BDNF treatments mimicked the pro-survival effect of glial CCR5 deficiency against Tat ± morphine.ConclusionsOur results suggest a critical role for glial CCR5 in mediating neurotoxic effects of HIV-1 Tat and morphine interactions on neurons. A shift in the proBDNF/BDNF ratio that favors neurotrophic support may occur when glial CCR5 signaling is blocked. Some neuroprotection occurred only in the presence of morphine, suggesting that loss of CCR5 may fundamentally change signaling through the MOR in glia.

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Section: Discussionmentioning

confidence: 99%

A central role for glial CCR5 in directing the neuropathological interactions of HIV-1 Tat and opiates

Kim

Hahn

Podhaizer

et al. 2018

J Neuroinflammation

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“…The iTat mouse has been utilized to investigate some of these processes. Among the many reports utilizing the iTat model just within the last decade are studies addressing Tau processing (Kadri et al 2015), host cell cycle regulation (Fields et al 2015b), cell survival (Fan and He 2016b), differentiation (Perry et al 2010; Wheeler et al 2008; Yao et al 2012) and glial activation (Kiebala et al 2010), substance abuse (Fitting et al 2012, 2010; Hauser et al 2009; Mediouni et al 2015; Paris et al 2014a; Zou et al 2011), sex differences (Hahn et al 2015a, b), behavior (Hahn et al 2016; Paris et al 2014b, c, 2015), memory and learning (Carey et al 2012; Fitting et al 2013) and brain changes observed via imaging (Carey et al 2015, 2013). Table 1, while not comprehensive by any means, provides examples of the diversity of studies that have utilized the iTat mouse model.…”

Section: Use Of Itat Mice In Studies Of Tat Neurotoxicity and Its Molmentioning

confidence: 99%

Doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) as an HIV/neuroAIDS model

et al. 2017

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HIV-1 Tat is known to be neurotoxic and important for HIV/neuroAIDS pathogenesis. However, the overwhelming majority of the studies involved use of recombinant Tat protein. To understand the contributions of Tat protein to HIV/neuroAIDS and the underlying molecular mechanisms of HIV-1 Tat neurotoxicity in the context of a whole organism and independently of HIV-1 infection, a doxycycline-inducible astrocyte-specific HIV-1 Tat transgenic mouse (iTat) was created. Tat expression in the brains of iTat mice was determined to be in the range of 1-5 ng/ml and led to astrocytosis, loss of neuronal dendrites, and neuroinflammation. iTat mice have allowed us to define the direct effects of Tat on astrocytes and the molecular mechanisms of Tat-induced GFAP expression/astrocytosis, astrocyte-mediated Tat neurotoxicity, Tat-impaired neurogenesis, Tat-induced loss of neuronal integrity, and exosome-associated Tat release and uptake. In this review, we will provide an overview about the creation and characterization of this model and its utilities for our understanding of Tat neurotoxicity and the underlying molecular mechanisms.

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“…In the present model, Tat induction activates astrocytes (as well as bystander microglia) in the striatum ( Bruce-Keller et al, 2008 ; Fitting et al, 2010a ; Zou et al, 2011 ) and causes modest gliosis within 48 h following expression ( Bruce-Keller et al, 2008 ) that can be sustained for as long as 1 year ( Dickens et al, 2017 ). In preclinical rodent studies, CNS exposure to HIV-1 Tat induces behavioral impairments similar to HAND, including deficits in pre-attentive filter processing ( Fitting et al, 2006 ; Paris et al, 2015 ), emotionality ( Fu et al, 2011 ; Hahn et al, 2015 , 2016 ; Lawson et al, 2011 ; Paris et al, 2014 , 2016 ), motivation ( Kesby et al, 2018 ), and memory ( Carey et al, 2012 ; Fitting et al, 2013 ; Marks et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Chronic HIV-1 Tat exposure alters anterior cingulate cortico-basal ganglia-thalamocortical synaptic circuitry, associated behavioral control, and immune regulation in male mice

Nass

Hahn

McLane

et al. 2020

Brain, Behavior, & Immunity - Health

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HIV-1 selectively disrupts neuronal integrity within specific brain regions, reflecting differences in viral tropism and/or the regional differences in the vulnerability of distinct neuronal subpopulations within the CNS. Deficits in prefrontal cortex (PFC)-mediated executive function and the resultant loss of behavioral control are a particularly debilitating consequence of neuroHIV. To explore how HIV-1 disrupts executive function, we investigated the effects of 48 h, 2 and/or 8 weeks of HIV-1 Tat exposure on behavioral control, synaptic connectivity, and neuroimmune function in the anterior cingulate cortex (ACC) and associated cortico-basal ganglia (BG)-thalamocortical circuitry in adult, Tat transgenic male mice. HIV-1 Tat exposure increased novelty-exploration in response to novel food, flavor, and environmental stimuli, suggesting that Tat triggers increased novelty-exploration in situations of competing motivation (e.g., drive to feed or explore vs. fear of novel, brightly lit open areas). Furthermore, Tat induced adaptability in response to an environmental stressor and pre-attentive filtering deficits. The behavioral insufficiencies coincided with decreases in the inhibitory pre- and post-synaptic proteins, synaptotagmin 2 and gephyrin, respectively, in the ACC, and alterations in specific pro- and anti-inflammatory cytokines out of 23 assayed. The interaction of Tat exposure and the resultant time-dependent, selective alterations in CCL4, CXCL1, IL-12p40, and IL-17A levels in the PFC predicted significant decreases in adaptability. Tat decreased dendritic spine density and cortical VGLUT1 inputs, while increasing IL-1β, IL-6, CCL5, and CCL11 in the striatum. Alternatively, IL-1α, CCL5, and IL-13 were decreased in the mediodorsal thalamus despite the absence of synaptic changes. Thus, HIV-1 Tat appears to uniquely and systematically disrupt immune regulation and the inhibitory and excitatory synaptic balance throughout the ACC-BG-thalamocortical circuitry resulting in a loss of behavioral control.

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Central HIV-1 Tat exposure elevates anxiety and fear conditioned responses of male mice concurrent with altered mu-opioid receptor-mediated G-protein activation and β-arrestin 2 activity in the forebrain

Cited by 35 publications

References 93 publications

A central role for glial CCR5 in directing the neuropathological interactions of HIV-1 Tat and opiates

A central role for glial CCR5 in directing the neuropathological interactions of HIV-1 Tat and opiates

Doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) as an HIV/neuroAIDS model

Chronic HIV-1 Tat exposure alters anterior cingulate cortico-basal ganglia-thalamocortical synaptic circuitry, associated behavioral control, and immune regulation in male mice

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