Background-Clinical and epidemiologic evidence demonstrates sex differences in the prevalence and course of various psychiatric disorders. Understanding sex-specific brain differences in healthy individuals is a critical first step towards understanding sex-specific expression of psychiatric disorders. Here, we evaluate evidence on sex differences in brain structure, chemistry and function using imaging methodologies, including functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single photon emission computed tomography (SPECT) and structural magnetic resonance imaging (MRI) in mentally healthy individuals.
Neuroinflammation is associated with a broad spectrum of neurodegenerative and psychiatric diseases. The core process in neuroinflammation is activation of microglia, the innate immune cells of the brain. We measured the neuroinflammatory response produced by a systemic administration of the Escherichia coli lipopolysaccharide (LPS; also called endotoxin) in humans with the positron emission tomography (PET) radiotracer [ 11 C]PBR28, which binds to translocator protein, a molecular marker that is up-regulated by microglial activation. In addition, inflammatory cytokines in serum and sickness behavior profiles were measured before and after LPS administration to relate brain microglial activation with systemic inflammation and behavior. Eight healthy male subjects each had two 120-min [ 11 C]PBR28 PET scans in 1 d, before and after an LPS challenge. LPS (1.0 ng/kg, i.v.) was administered 180 min before the second [ 11 C]PBR28 scan. LPS administration significantly increased [ 11 C]PBR28 binding 30-60%, demonstrating microglial activation throughout the brain. This increase was accompanied by an increase in blood levels of inflammatory cytokines, vital sign changes, and sickness symptoms, well-established consequences of LPS administration. To our knowledge, this is the first demonstration in humans that a systemic LPS challenge induces robust increases in microglial activation in the brain. This imaging paradigm to measure brain microglial activation with [ 11 C]PBR28 PET provides an approach to test new medications in humans for their putative antiinflammatory effects.neuroinflammation | PBR28 | endotoxin | microglia | cytokines
Nicotine, the addictive chemical in tobacco smoke, initiates its actions in brain through nicotinic acetylcholine receptors (nAChRs). In particular, nAChRs containing  2 -subunits ( 2 *-nAChRs) the most prevalent subtype, mediate the reinforcing properties of nicotine. We hypothesized that abnormal numbers of  2 *-nAChRs during early abstinence contribute to the perpetuation of addiction to tobacco smoking. Using molecular imaging, specifically single-photon emission computed tomography with the nAChR agonist radiotracer ]5-IA uptake was significantly higher throughout the cerebral cortex (26 -36%) and in the striatum (27%) than in nonsmokers, suggesting higher  2 *-nAChR in recently abstinent smokers.  2 *-nAChR availability in recently abstinent smokers correlated with the days since last cigarette and the urge to smoke to relieve withdrawal symptoms but not the severity of nicotine dependence, severity of nicotine withdrawal, or the desire to smoke. Higher brain  2 *-nAChR during early abstinence indicates that, when smokers quit smoking, they do so in the face of a significant increase in the receptors normally activated by nicotine. Greater  2 *-nAChR availability during early abstinence may impact the ability of smokers to maintain abstinence.
Rates of alcohol use disorder (AUD) have increased in women by 84% over the past ten years relative to a 35% increase in men. This substantive increase in female drinking is alarming given that women experience greater alcohol-related health consequences compared to men. Stress is strongly associated with all phases of alcohol addiction, including drinking initiation, maintenance, and relapse for both women and men, but plays an especially critical role for women. The purpose of the present narrative review is to highlight what is known about sex differences in the relationship between stress and drinking. The critical role stress reactivity and negative affect play in initiating and maintaining alcohol use in women is addressed, and the available evidence for sex differences in drinking for negative reinforcement as it relates to brain stress systems is presented. This review discusses the critical structures and neurotransmitters that may underlie sex differences in stress-related alcohol use (e.g., prefrontal cortex, amygdala, norepinephrine, corticotropin releasing factor, and dynorphin), the involvement of sex and stress in alcohol-induced neurodegeneration, and the role of ovarian hormones in stress-related drinking. Finally, the potential avenues for the development of sex-appropriate pharmacological and behavioral treatments for AUD are identified. Overall, women are generally more likely to drink to regulate negative affect and stress reactivity. Sex differences in the onset and maintenance of alcohol use begin to develop during adolescence, coinciding with exposure to early life stress. These factors continue to affect alcohol use into adulthood, when reduced responsivity to stress, increased affect-related psychiatric comorbidities and alcohol-induced neurodegeneration contribute to chronic and problematic alcohol use, particularly for women. However, current research is limited regarding the examination of sex in the initiation and maintenance of alcohol use. Probing brain stress systems and associated brain regions is an important future direction for developing sex-appropriate treatments to address the role of stress in AUD.
Microglia play an essential role in many brain diseases. Microglia are activated by local tissue damage or inflammation, but systemic inflammation can also activate microglia. An important clinical question is whether the effects of systemic inflammation on microglia mediates the deleterious effects of systemic inflammation in diseases such as Alzheimer's dementia, multiple sclerosis, and stroke. Positron Emission Tomography (PET) imaging with ligands that bind to Translocator Protein (TSPO) can be used to detect activated microglia. The aim of this study was to evaluate whether the effect of systemic inflammation on microglia could be measured with PET imaging in nonhuman primates, using the TSPO ligand [11C]PBR28. Methods Six female baboons (Papio anubis) were scanned before and at 1 h and/or 4h and/or 22h after intravenous administration of E. coli lipopolysaccharide (LPS; 0.1 mg/kg), which induces systemic inflammation. Regional time-activity data from regions of interest (ROIs) were fitted to the two-tissue compartmental model, using the metabolite-corrected arterial plasma curve as input function. Total volume of distribution (VT) of [11C]PBR28 was used as a measure of total ligand binding. The primary outcome was change in VT from baseline. Serum levels of tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) were used to assess correlations between systemic inflammation and microglial activation. In one baboon, immunohistochemistry was used to identify cells expressing TSPO. Results LPS administration increased [11C]PBR28 binding (F(3,6)=5.1, p=.043) with a 29±16 % increase at 1h (n = 4) and a 62±34% increase at 4h (n = 3) post-LPS. There was a positive correlation between serum IL-1β and IL-6 levels and the increase in [11C]PBR28 binding. TSPO immunoreactivity occurred almost exclusively in microglia and rarely in astrocytes. Conclusion In the nonhuman-primate brain, LPS-induced systemic inflammation produces a robust increase in the level of TSPO that is readily detected with [11C]PBR28 PET. The effect of LPS on [11C]PBR28 binding is likely mediated by inflammatory cytokines. Activation of microglia may be a mechanism through which systemic inflammatory processes influence the course of diseases such as Alzheimer's, multiple sclerosis, and possibly depression.
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