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![FIG URE 4 HIV-1 Tat expression decreases TH immunoreactivity in the SNc but not VTA. (a) Bar graph shows the density of TH1 neurons in the rostral SNc of wild type and GT-tg bigenic animals. Absolute counting values were put in relation to the measured area of the ROI. n 5 8-20 sections from 4 to 5 animals. Data is shown as mean 1 SEM, *p < .05, **p < .01, ***p < .001, one-way ANOVA followed by post hoc Tukey HSD test, all groups relative to WT-Saline. (b) Similar to absolute counting values, stereological assessment of the SNc reveals significant reduction in TH immunoreactivity in GT-tg bigenic animals as compared with WT controls. SNc defined as the first two sections (40 mm thick slices, every other slice, representing the first 120 mm) of the SNc displaying TH immunoreactivity. n 5 4-5 animals. (c and d) TH immunoreactivity in the VTA is unaffected by 7-day Tat induction in both counting (n 5 8-20 sections from 4 to 5 animals per group) and stereological assessment (n 5 4-5 animals per group). (e) Representative images of the SNc (top) and VTA (bottom) in WT-Saline, GTSaline, and GT-Dox conditions. Note the significant reduction of TH1 SNc neurons in the GT-tg bigenic animals while TH immunoreactivity in the VTA remains unaffected. Scale bar is 200 mm [Color figure can be viewed at wileyonlinelibrary.com]](profile/Habibeh-Khoshbouei/publication/324998798/figure/fig2/AS:650489054117891@1532100084673/FIG-URE-4-HIV-1-Tat-expression-decreases-TH-immunoreactivity-in-the-SNc-but-not-VTA-a.png)
FIG URE 4 HIV-1 Tat expression decreases TH immunoreactivity in the SNc but not VTA. (a) Bar graph shows the density of TH1 neurons in the rostral SNc of wild type and GT-tg bigenic animals. Absolute counting values were put in relation to the measured area of the ROI. n 5 8-20 sections from 4 to 5 animals. Data is shown as mean 1 SEM, *p < .05, **p < .01, ***p < .001, one-way ANOVA followed by post hoc Tukey HSD test, all groups relative to WT-Saline. (b) Similar to absolute counting values, stereological assessment of the SNc reveals significant reduction in TH immunoreactivity in GT-tg bigenic animals as compared with WT controls. SNc defined as the first two sections (40 mm thick slices, every other slice, representing the first 120 mm) of the SNc displaying TH immunoreactivity. n 5 4-5 animals. (c and d) TH immunoreactivity in the VTA is unaffected by 7-day Tat induction in both counting (n 5 8-20 sections from 4 to 5 animals per group) and stereological assessment (n 5 4-5 animals per group). (e) Representative images of the SNc (top) and VTA (bottom) in WT-Saline, GTSaline, and GT-Dox conditions. Note the significant reduction of TH1 SNc neurons in the GT-tg bigenic animals while TH immunoreactivity in the VTA remains unaffected. Scale bar is 200 mm [Color figure can be viewed at wileyonlinelibrary.com]
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The transactivator of transcription protein, HIV‐1 Tat, is linked to neuroAIDS, where degeneration of dopamine neurons occurs. Using a mouse model expressing GFAP‐driven Tat protein under doxycycline (Dox) regulation, we investigated microglial‐neuronal interactions in the rostral substantia nigra pars compacta (SNc). Immunohistochemistry for micro...
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PurposeTo study the feasibility of the in vivo [18F]-DPA-714 TSPO positron emission tomography (PET) to detect glial activation in a rat model of progressive parkinsonism induced by viral-mediated overexpression of A53T mutated human α-synuclein (hα-syn) in the substantia nigra pars compacta (SNpc).Methods
We conducted a cross-sectional study in a...
Citations
... Inducing Tat expression is also sufficient to drive the reinstatement of cocaine CPP (refs. 14,15) following extinction, suggesting that HIV-1 proteins can act to alter cocaine-related behavior, potentially through inflammatory effects or effects on the dopamine transporter 17 . Notably, HIV-1 Tg rats show blunted cocaine preference and a failure to escalate selfadministration 18 , suggesting that there may be species or expression pattern specific differences in the effects of these proteins. ...
Substance use disorders (SUDs) are highly comorbid with HIV infection, necessitating an understanding of the interactive effects of drug exposure and HIV. The relationship between HIV infection and cocaine use disorder is likely bidirectional, with cocaine use directly impacting immune function while HIV infection alters addiction-related behavior. To better characterize the neurobehavioral and immune consequences of HIV infection and cocaine exposure, this study utilizes a humanized mouse model to investigate the outcomes of HIV-1 infection on cocaine-related behaviors in a conditioned place preference (CPP) model, and the interactive effects of cocaine and HIV infection on peripheral and central nervous system inflammation. HIV infection selectively impairs cocaine CPP extinction without effecting reinstatement or cocaine seeking under conflict. Behavioral alterations are accompanied by immune changes in HIV infected mice, including increased prefrontal cortex astrocyte immunoreactivity and brain-region specific effects on microglia number and reactivity. Peripheral immune system changes are observed in human cytokines, including HIV-induced reductions in human TNFα, and cocaine and HIV interactions on GM-CSF levels. Together these data provide new insights into the unique neurobehavioral outcomes of HIV infection and cocaine exposure and how they interact to effect immune responses.
... Intra-striatal injections of Tat alone tend to result in slight, non-significant, reductions in striatal dopamine concentrations in rats after 1 week exposure, though in combination with methamphetamine, Tat can synergistically reduce striatal dopamine levels and evoke its overflow in ex vivo slices (Cass et al., 2003;Maragos et al., 2002). By contrast, Tat selectively decreases tyrosine hydroxylase (TH) expression and neuronal firing rates without increasing neuronal death in the substantia nigra pars compacta (SNpc), but not in the VTA after 7 days induction in a similar murine Tat model with a greater tat gene copy number (Kim et al., 2003) than our Tat mice (discussed below), suggesting SNpc neurons are functionally vulnerable and a likely target of Tat-dependent alterations in dopamine release or metabolism (Miller et al., 2018). ...
... The reasons for the discrepancy are uncertain, but may relate to gene dosing. The transgenic mouse line used by Miller et al. (2018) expresses 3-7 copies of the tat gene (see Kim et al., 2003), whereas the mice used in the current study only express a single copy of the tat transgene and typically display a slower onset and less severe pathology (Dickens et al., 2017;Nass et al., 2020). Alternatively, we speculate that certain aspects of innate immune responsiveness become tolerant to Tat exposure in a time-dependent manner (Hermes et al., 2020;Nass et al., 2023), though the reasons why specific innate immune responses become tolerant are not well understood (see Divangahi et al., 2021). ...
... Results in open field were obtained from n = 93 mice (9-15 per group) and results in light dark box were obtained from n = 72 mice (9 per group). Data are presented as the mean ± SEM; θ p < 0.05 versus 2 weeks Tat and saline exposure.Analysis of early postmortem changes from male PWH revealed that while HIV alone lowers numbers of substantia nigra neurons assessed stereologically, co-morbid intravenous drug use can cause a significant additional loss of nigral neurons(Reyes et al., 1991).Although previous studies in another HIV-1 Tat transgenic model show decreased TH immunoreactivity following 7 days of Tat induction in SNpc neurons suggesting Tat directly inhibits the rate limiting enzyme for dopamine synthesis(Miller et al., 2018), decreases in the ...
Despite the advent of combination anti‐retroviral therapy (cART), nearly half of people infected with HIV treated with cART still exhibit HIV‐associated neurocognitive disorders (HAND). HAND can be worsened by co‐morbid opioid use disorder. The basal ganglia are particularly vulnerable to HIV‐1 and exhibit higher viral loads and more severe pathology, which can be exacerbated by co‐exposure to opioids. Evidence suggests that dopaminergic neurotransmission is disrupted by HIV exposure, however, little is known about whether co‐exposure to opioids may alter neurotransmitter levels in the striatum and if this in turn influences behavior. Therefore, we assayed motor, anxiety‐like, novelty‐seeking, exploratory, and social behaviors, and levels of monoamines and their metabolites following 2 weeks and 2 months of Tat and/or morphine exposure in transgenic mice. Morphine decreased dopamine levels, but significantly elevated norepinephrine, the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the serotonin metabolite 5‐hydroxyindoleacetic acid, which typically correlated with increased locomotor behavior. The combination of Tat and morphine altered dopamine, DOPAC, and HVA concentrations differently depending on the neurotransmitter/metabolite and duration of exposure but did not affect the numbers of tyrosine hydroxylase‐positive neurons in the mesencephalon. Tat exposure increased the latency to interact with novel conspecifics, but not other novel objects, suggesting the viral protein inhibits exploratory behavior initiation in a context‐dependent manner. By contrast, and consistent with prior findings that opioid misuse can increase novelty‐seeking behavior, morphine exposure increased the time spent exploring a novel environment. Finally, Tat and morphine interacted to affect locomotor activity in a time‐dependent manner, while grip strength and rotarod performance were unaffected. Together, our results provide novel insight into the unique effects of HIV‐1 Tat and morphine on monoamine neurochemistry that may underlie their divergent effects on motor and exploratory behavior.
... Intra-striatal injections of Tat alone tend to result in slight, non-significant, reductions in striatal dopamine concentrations in rats after 1 week exposure, though in combination with methamphetamine, Tat can synergistically reduce striatal dopamine levels and evoke its overflow in ex vivo slices (Cass et al., 2003;Maragos et al., 2002). By contrast, Tat selectively decreases tyrosine hydroxylase (TH) expression and neuronal firing rates without increasing neuronal death in the substantia nigra pars compacta (SNpc), but not in the VTA after 7 days induction in a similar murine Tat model with a greater tat gene copy number (Kim et al., 2003) than our Tat mice (discussed below), suggesting SNpc neurons are functionally vulnerable and a likely target of Tat-dependent alterations in dopamine release or metabolism (Miller et al., 2018). ...
... The reasons for the discrepancy are uncertain, but may relate to gene dosing. The transgenic mouse line used by Miller et al. (2018) expresses 3-7 copies of the tat gene (see Kim et al., 2003), whereas the mice used in the current study only express a single copy of the tat transgene and typically display a slower onset and less severe pathology (Dickens et al., 2017;Nass et al., 2020). Alternatively, we speculate that certain aspects of innate immune responsiveness become tolerant to Tat exposure in a time-dependent manner (Hermes et al., 2020;Nass et al., 2023), though the reasons why specific innate immune responses become tolerant are not well understood (see Divangahi et al., 2021). ...
... Results in open field were obtained from n = 93 mice (9-15 per group) and results in light dark box were obtained from n = 72 mice (9 per group). Data are presented as the mean ± SEM; θ p < 0.05 versus 2 weeks Tat and saline exposure.Analysis of early postmortem changes from male PWH revealed that while HIV alone lowers numbers of substantia nigra neurons assessed stereologically, co-morbid intravenous drug use can cause a significant additional loss of nigral neurons(Reyes et al., 1991).Although previous studies in another HIV-1 Tat transgenic model show decreased TH immunoreactivity following 7 days of Tat induction in SNpc neurons suggesting Tat directly inhibits the rate limiting enzyme for dopamine synthesis(Miller et al., 2018), decreases in the ...
Opioid overdose deaths have dramatically increased by 781% from 1999 to 2021. In the setting of HIV, opioid drug abuse exacerbates neurotoxic effects of HIV in the brain, as opioids enhance viral replication, promote neuronal dysfunction and injury, and dysregulate an already compromised inflammatory response. Despite the rise in fentanyl abuse and the close association between opioid abuse and HIV infection, the interactive comorbidity between fentanyl abuse and HIV has yet to be examined in vivo. The HIV-1 Tat-transgenic mouse model was used to understand the interactive effects between fentanyl and HIV. Tat is an essential protein produced during HIV that drives the transcription of new virions and exerts neurotoxic effects within the brain. The Tat-transgenic mouse model uses a glial fibrillary acidic protein (GFAP)-driven tetracycline promoter which limits Tat production to the brain and this model is well used for examining mechanisms related to neuroHIV. After 7 days of fentanyl exposure, brains were harvested. Tight junction proteins, the vascular cell adhesion molecule, and platelet-derived growth factor receptor-β were measured to examine the integrity of the blood brain barrier. The immune response was assessed using a mouse-specific multiplex chemokine assay. For the first time in vivo, we demonstrate that fentanyl by itself can severely disrupt the blood-brain barrier and dysregulate the immune response. In addition, we reveal associations between inflammatory markers and tight junction proteins at the blood-brain barrier.
... In addition to cocaine effects on HIV outcomes, cocaine-related behaviors are dysregulated in HIV rodent models. A majority of the work has employed transgenic models to investigate outcomes in a cocaine conditioned place preference (CPP) paradigm which assesses the al., 2015) following extinction, suggesting that HIV-1 proteins can act to alter cocaine-related behavior, potentially through in ammatory effects or effects on the dopamine transporter (Miller et al., 2018). ...
Substance use disorders (SUDs) are highly comorbid with HIV infection, necessitating an understanding of the interactive effects of drug exposure and HIV. The relationship between HIV infection and cocaine use disorder is likely bidirectional, with cocaine use directly impacting immune function while HIV infection alters addiction-related behavior. To better characterize the neurobehavioral and immune consequences of HIV infection and cocaine exposure, this study utilized a humanized mouse model to investigate the outcomes of HIV-1 infection on cocaine-related behaviors in a conditioned place preference (CPP) model, and the interactive effects of cocaine and HIV infection on peripheral and central nervous system inflammation. HIV infection selectively impaired cocaine CPP extinction without effecting reinstatement or cocaine seeking under conflict were observed. Behavioral alterations were accompanied by immune changes in HIV infected mice, including increased prefrontal cortex astrocyte immunoreactivity and brain-region specific effects on microglia number and reactivity. Peripheral immune system changes were observed in both mouse and human cytokines, including HIV-induced reductions in mouse IL-1α and G-CSF and human TNFα, and cocaine induced alterations in mouse GM-CSF. Together these data provide new insights into the unique neurobehavioral outcomes of HIV infection and cocaine exposure and how they interact to effect immune responses.
... In HIV-1 Tat transgenic (Tg) mice, Tat expression potentiates cocaine CPP Mediouni et al., 2015a;Zhu et al., 2022). Inducing Tat expression is also sufficient to drive the reinstatement of cocaine CPP Mediouni et al., 2015) following extinction, suggesting that HIV-1 proteins can act to alter cocaine-related behavior, potentially through inflammatory effects or effects on the dopamine transporter (Miller et al., 2018). Notably, HIV-1 Tg rats show blunted cocaine preference and a failure to escalate self-administration (Bertrand et al., 2018), suggesting that there may be species or expression pattern specific differences in the effects of these proteins. ...
Substance use disorders (SUDs) are highly comorbid with HIV infection, necessitating an understanding of the interactive effects of drug exposure and HIV. The relationship between progressive HIV infection and cocaine use disorder is likely bidirectional, with cocaine use having direct effects on immune function while HIV infection can alter addiction-related behavior. To better characterized the neurobehavioral and immune consequences of HIV infection and cocaine exposure, this study utilized a humanized mouse model to investigate the outcomes of progressive HIV infection on cocaine-related behaviors in a cocaine conditioned place preference (CPP) model, and the interactive effects of cocaine and HIV infection on peripheral and central nervous system inflammation. HIV infection did not impact the formation of a cocaine CPP, but did result in resistance to extinction of the CPP. No effects of HIV on yohimbine-primed reinstatement or cocaine seeking under conflict were observed. These behavioral alterations were accompanied by immune changes in HIV infected mice, including increased prefrontal cortex astrocyte immunoreactivity and brain-region specific effects on microglia number and reactivity. Peripheral immune system changes were observed in both mouse and human markers. Among other targets, this included HIV-induced reductions in mouse IL-1α and G-CSF and human TNFα, and cocaine-induced alterations in human TNFα, and mouse GM-CSF such that cocaine exposure increases both cytokines only in the absence of HIV infection. Together these data provide new insights into the unique neurobehavioral processes underlying HIV infection and cocaine use disorders, and further how they interact to effect immune responses.
... One possibility relates to the relative immaturity of MSNs at 48 h, which is discussed further below. Alternatively, reductions in tyrosine hydroxylase in the substantia nigra pars compacta suggest Tat induces a hypodopaminergic state (Miller et al. 2018). Tat-dependent dopamine deficiencies and pathophysiologic effects on MSNs could trigger a differential response among MSN subtypes. ...
... The coordinated pattern of enhanced D2 MSN excitation and reduced D1 MSN excitation along with early-onset pathology in D2 MSNs observed at 2 weeks in the Tat transgenic mice parallels patterns seen in models of Parkinson's disease and is consistent with lowered dopamine (Albin et al. 1989;Day et al. 2006;DeLong 1990;Neely et al. 2007;Suárez et al. 2014). Preclinical evidence indicates that Tat is highly toxic to dopaminergic neurons (Gaskill et al. 2017;Miller et al. 2018;Nath et al. 2000;Nolan and Gaskill 2019;Zauli et al. 2000) and may alter striatal dopamine receptor expression (Kesby et al. 2017) and disrupt dopamine transporter function (Aksenova et al. 2006;Aksenov et al. 2008;Quizon et al. 2016;Zhu et al. 2018) all effects that would eventually contribute to a hypodopaminergic state. Clinical evidence suggests that PWH are extremely sensitive to anti-psychotics that reduce dopamine levels and show improvement when dopamine is restored therapeutically (Berger and Nath 1997;Berger and Arendt 2000;Hriso et al. 1991;Nath et al. 2000;Obermann et al. 2009). ...
The striatum is especially vulnerable to HIV-1 infection, with medium spiny neurons (MSNs) exhibiting marked synaptodendritic damage that can be exacerbated by opioid use disorder. Despite known structural defects in MSNs co-exposed to HIV-1 Tat and opioids, the pathophysiological sequelae of sustained HIV-1 exposure and acute comorbid effects of opioids on dopamine D1 and D2 receptor-expressing (D1 and D2) MSNs are unknown. To address this question, Drd1-tdTomato- or Drd2-eGFP-expressing reporter and conditional HIV-1 Tat transgenic mice were interbred. MSNs in ex vivo slices from male mice were assessed by whole-cell patch-clamp electrophysiology and filled with biocytin to explore the functional and structural effects of progressive Tat and acute morphine exposure. Although the excitability of both D1 and D2 MSNs increased following 48 h of Tat exposure, D1 MSN firing rates decreased below control (Tat−) levels following 2 weeks and 1 month of Tat exposure but returned to control levels after 2 months. D2 neurons continued to display Tat-dependent increases in excitability at 2 weeks, but also returned to control levels following 1 and 2 months of Tat induction. Acute morphine exposure increased D1 MSN excitability irrespective of the duration of Tat exposure, while D2 MSNs were variably affected. That D1 and D2 MSN excitability would return to control levels was unexpected since both subpopulations displayed significant synaptodendritic degeneration and pathologic phospho-tau-Thr205 accumulation following 2 months of Tat induction. Thus, despite frank morphologic damage, D1 and D2 MSNs uniquely adapt to sustained Tat and acute morphine insults.
... First, dopaminergic neurons have a large axonal projection area, which may span different brain regions [57,58]. Second, it is a common observation in multiple neurodegeneration diseases that TH may lose immunoreactivity without a concomitant loss of dopamine neurons [59,60]. Next, the dopamine transporter (DAT), which reuptakes presynaptic dopamine neurons at the synapse, is detectable only in about half of the ventral tegmental neurons [61]. ...
Background
Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are common age-related neurodegenerative diseases comprising Lewy body spectrum disorders associated with cortical and subcortical Lewy body pathology. Over 30% of PD patients develop PD dementia (PDD), which describes dementia arising in the context of established idiopathic PD. Furthermore, Lewy bodies frequently accompany the amyloid plaque and neurofibrillary tangle pathology of Alzheimer’s disease (AD), where they are observed in the amygdala of approximately 60% of sporadic and familial AD. While PDD and DLB share similar pathological substrates, they differ in the temporal onset of motor and cognitive symptoms; however, protein markers to distinguish them are still lacking.
Methods
Here, we systematically studied a series of AD and PD pathogenesis markers, as well as mitochondria, mitophagy, and neuroinflammation-related indicators, in the substantia nigra (SN), temporal cortex (TC), and caudate and putamen (CP) regions of human post-mortem brain samples from individuals with PDD and DLB and condition-matched controls.
Results
We found that p-APPT668 (TC), α-synuclein (CP), and LC3II (CP) are all increased while the tyrosine hydroxylase (TH) (CP) is decreased in both PDD and DLB compared to control. Also, the levels of Aβ42 and DD2R, IBA1, and p-LRRK2S935 are all elevated in PDD compared to control. Interestingly, protein levels of p-TauS199/202 in CP and DD2R, DRP1, and VPS35 in TC are all increased in PDD compared to DLB.
Conclusions
Together, our comprehensive and systematic study identified a set of signature proteins that will help to understand the pathology and etiology of PDD and DLB at the molecular level.
... High doses of METH promote microglial activation (Thomas et al., 2004;Fantegrossi et al., 2008). Surprisingly, microglial activation can occur before the onset of pathology (LaVoie et al., 2004), reinforcing the notion of their sensitivity to homeostatic disturbances, such as neuronal loss (Miller et al., 2018). Similarly, in METH users, microglia are involved in METH-induced wakefulness (Wisor et al., 2011). ...
Methamphetamine (METH) is a potent psychostimulant that increases extracellular monoamines such as dopamine and norepinephrine and affects multiple tissue and cell types. The reinforcing properties of METH underlie its significant abuse potential and dysregulation of peripheral immunity and central nervous system functions. Together, the constellation of METH's effects on cellular targets and regulatory processes have shown to lead to immune suppression and neurodegeneration in METH addicts and animal models of METH exposure. Here we extensively review many of the cell types and mechanisms of METH-induced dysregulation of the central nervous system and peripheral immune system. Significance Statement Emerging research has begun to show that methamphetamine not only regulates dopaminergic neuronal activity, it also affects non-neuronal brain cells, such as microglia and astrocytes as well immunological cells of the periphery. The bi-directional communication between dopaminergic neurons in the CNS and peripheral immune cells becomes dysregulated by a constellation of dysfunctional neuronal and cell types revealing multiple targets that must be considered at the interface between basic and clinical neuroscience.
... First, alterations in the relationship between microglia and DA system function have been observed following induction of the HIV-1 viral protein, Tat [338]. Specifically, Tat simultaneously decreased the number of microglia (i.e., Iba1 immunoreactive cells) and the number of dopamine neurons (i.e., tyrosine hydroxylase positive neurons) in the substantia nigra pars compacta, while an impact of HIV-1 Tat induction was not observed in the VTA [338]. ...
... First, alterations in the relationship between microglia and DA system function have been observed following induction of the HIV-1 viral protein, Tat [338]. Specifically, Tat simultaneously decreased the number of microglia (i.e., Iba1 immunoreactive cells) and the number of dopamine neurons (i.e., tyrosine hydroxylase positive neurons) in the substantia nigra pars compacta, while an impact of HIV-1 Tat induction was not observed in the VTA [338]. Second, microglial activation and/or dysfunction may underlie HIV-1-associated synaptic dysfunction. ...
Individuals living with human immunodeficiency virus type 1 (HIV-1) are often plagued by debilitating neurocognitive impairments and affective alterations;the pathophysiology underlying these deficits likely includes dopaminergic system dysfunction. The present review utilized four interrelated aims to critically examine the evidence for dopaminergic alterations following HIV-1 viral protein exposure. First, basal dopamine (DA) values are dependent upon both brain region andexperimental approach (i.e., high-performance liquid chromatography, microdialysis or fast-scan cyclic voltammetry). Second, neurochemical measurements overwhelmingly support decreased DA concentrations following chronic HIV-1 viral protein exposure. Neurocognitive impairments, including alterations in pre-attentive processes and attention, as well as apathetic behaviors, provide an additional line of evidence for dopaminergic deficits in HIV-1. Third, to date, there is no compelling evidence that combination antiretroviral therapy (cART), the primary treatment regimen for HIV-1 seropositive individuals, has any direct pharmacological action on the dopaminergic system. Fourth, the infection of microglia by HIV-1 viral proteins may mechanistically underlie the dopamine deficit observed following chronic HIV-1 viral protein exposure. An inclusive and critical evaluation of the literature, therefore, supports the fundamental conclusion that long-term HIV-1 viral protein exposure leads to a decreased dopaminergic state, which continues to persist despite the advent of cART. Thus, effective treatment of HIV-1-associated apathy/depression and neurocognitive impairments must focus on strategies for rectifying decreases in dopamine function.
... The total number of sections for stereological analyses from each hemisphere was 12. To account for~10% tissue shrinkage in the z-plane, the mean section thickness for (Banuelos et al., 2013;Miller et al., 2018). TH positive neurons were included if the cytoplasm of the cell was clearly labeled and contained an unstained nucleus. ...
During aging humans lose midbrain dopamine neurons, but not all dopamine regions exhibit vulnerability to neurodegeneration. Microglia maintain tissue homeostasis and neuronal support, but microglia become senescent and likely lose some of their functional abilities. Since aging is the greatest risk factor for Parkinson's disease, we hypothesized that aging‐related changes in microglia and neurons occur in the vulnerable substantia nigra pars compacta (SNc) but not the ventral tegmental area (VTA). We conducted stereological analyses to enumerate microglia and dopaminergic neurons in the SNc and VTA of 1‐, 6‐, 9‐, 18‐, and 24‐month‐old C57BL/J6 mice using sections double‐stained with tyrosine hydroxylase (TH) and Iba1. Both brain regions show an increase in microglia with aging, whereas numbers of TH+ cells show no significant change after 9 months of age in SNc and 6 months in VTA. Morphometric analyses reveal reduced microglial complexity and projection area while cell body size increases with aging. Contact sites between microglia and dopaminergic neurons in both regions increase with aging, suggesting increased microglial support/surveillance of dopamine neurons. To assess neurotrophin expression in dopaminergic neurons, BDNF and TH mRNA were quantified. Results show that the ratio of BDNF to TH decreases in the SNc, but not the VTA. Gait analysis indicates subtle, aging‐dependent changes in gait indices. In conclusion, increases in microglial cell number, ratio of microglia to dopamine neurons, and contact sites suggest that innate biological mechanisms compensate for the aging‐dependent decline in microglia morphological complexity (senescence) to ensure continued neuronal support in the SNc and VTA. Microglia in SNc and VTA do not exhibit regionally specialized morphology. There is an age‐dependent increase in microglia with reduced structural complexity (senescence). Interactions between microglia and dopamine neurons are intensified with aging.
