Authors: Reed JL, D'Ambrosio E, Marenco S, Ursini G, Zheutlin AB, Blasi G, Spencer BE, Romano R, Hochheiser J, Reifman A, Sturm J, Berman KF, Bertolino A, Weinberger DR, Callicott JH.
Journal: PLoS One. 2018 Apr 10;13(4):e0195189. doi: 10.1371/journal.pone.0195189.
Brain phenotypes showing environmental influence may help clarify unexplained associations between urban exposure and psychiatric risk. Heritable prefrontal fMRI activation during working memory (WM) is such a phenotype. We hypothesized that urban upbringing (childhood urbanicity) would alter this phenotype and interact with dopamine genes that regulate prefrontal function during WM. Further, dopamine has been hypothesized to mediate urban-associated factors like social stress. WM-related prefrontal function was tested for main effects of urbanicity, main effects of three dopamine genes-catechol-O-methyltransferase (COMT), dopamine receptor D1 (DRD1), and dopamine receptor D2 (DRD2)-and, importantly, dopamine gene-by-urbanicity interactions. For COMT, three independent human samples were recruited (total n = 487). We also studied 253 subjects genotyped for DRD1 and DRD2. 3T fMRI activation during the N-back WM task was the dependent variable, while childhood urbanicity, dopamine genotype, and urbanicity-dopamine interactions were independent variables. Main effects of dopamine genes and of urbanicity were found. Individuals raised in an urban environment showed altered prefrontal activation relative to those raised in rural or town settings. For each gene, dopamine genotype-by-urbanicity interactions were shown in prefrontal cortex-COMT replicated twice in two independent samples. An urban childhood upbringing altered prefrontal function and interacted with each gene to alter genotype-phenotype relationships. Gene-environment interactions between multiple dopamine genes and urban upbringing suggest that neural effects of developmental environmental exposure could mediate, at least partially, increased risk for psychiatric illness in urban environments via dopamine genes expressed into adulthood.
Authors: Lozoya OA, Martinez-Reyes I, Wang T, Grenet D, Bushel P, Li J, Chandel N, Woychik RP, Santos JH
Journal: PLoS Biol. 2018 Apr 18;16(4):e2005707. doi: 10.1371/journal.pbio.2005707. [Epub ahead of print]
Mitochondrial function affects many aspects of cellular physiology, and, most recently, its role in epigenetics has been reported. Mechanistically, how mitochondrial function alters DNA methylation patterns in the nucleus remains ill defined. Using a cell culture model of induced mitochondrial DNA (mtDNA) depletion, in this study we show that progressive mitochondrial dysfunction leads to an early transcriptional and metabolic program centered on the metabolism of various amino acids, including those involved in the methionine cycle. We find that this program also increases DNA methylation, which occurs primarily in the genes that are differentially expressed. Maintenance of mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation in the context of mtDNA loss rescues methionine salvage and polyamine synthesis and prevents changes in DNA methylation and gene expression but does not affect serine/folate metabolism or transsulfuration. This work provides a novel mechanistic link between mitochondrial function and epigenetic regulation of gene expression that involves polyamine and methionine metabolism responding to changes in the tricarboxylic acid (TCA) cycle. Given the implications of these findings, future studies across different physiological contexts and in vivo are warranted.
Authors: Diaz-Ruiz A, Lanasa M, Garcia J, Mora H, Fan F, Martin-Montalvo A, Di Francesco A, Calvo-Rubio M, Salvador-Pascual A, Aon MA, Fishbein KW, Pearson KJ, Villalba JM, Navas P, Bernier M, de Cabo R
Journal: Aging Cell. 2018 Apr 28:e12767. doi: 10.1111/acel.12767. [Epub ahead of print]
Calorie restriction (CR) is one of the most robust means to improve health and survival in model organisms. CR imposes a metabolic program that leads to increased stress resistance and delayed onset of chronic diseases, including cancer. In rodents, CR induces the upregulation of two NADH-dehydrogenases, namely NAD(P)H:quinone oxidoreductase 1 (Nqo1) and cytochrome b5 reductase 3 (Cyb5r3), which provide electrons for energy metabolism. It has been proposed that this upregulation may be responsible for some of the beneficial effects of CR, and defects in their activity are linked to aging and several age-associated diseases. However, it is unclear whether changes in metabolic homeostasis solely through upregulation of these NADH-dehydrogenases have a positive impact on health and survival. We generated a mouse that overexpresses both metabolic enzymes leading to phenotypes that resemble aspects of CR including a modest increase in lifespan, greater physical performance, a decrease in chronic inflammation, and, importantly, protection against carcinogenesis, one of the main hallmarks of CR. Furthermore, these animals showed an enhancement of metabolic flexibility and a significant upregulation of the NAD+/sirtuin pathway. The results highlight the importance of these NAD+ producers for the promotion of health and extended lifespan.
Authors: Mischkowski D, Palacios-Barrios EE, Banker L, Dildine TC, Atlas LY
Journal: Pain. 2018 Apr;159(4):699-711. doi: 10.1097/j.pain.0000000000001132.
Nociception reliably elicits an autonomic nervous system (ANS) response. Because pain and ANS circuitry interact on multiple spinal, subcortical, and cortical levels, it remains unclear whether autonomic responses are simply a reflexive product of noxious stimulation regardless of how stimulation is consciously perceived or whether the experience of pain mediates ANS responses to noxious stimulation. To test these alternative predictions, we examined the relative contribution of noxious stimulation and individual pain experience to ANS responses in healthy volunteers who underwent 1 or 2 pain assessment tasks. Participants received 8 seconds of thermal stimulation of varied temperatures and judged pain intensity on every trial. Skin conductance responses and pupil dilation responses to stimulation served as measures of the heat-evoked autonomic response. We used multilevel modelling to examine trial-by-trial relationships between heat, pain, and ANS response. Although both pain and noxious heat stimulation predicted skin conductance response and pupil dilation response in separate analyses, the individual pain experience statistically mediated effects of noxious heat on both outcomes. Furthermore, moderated mediation revealed that evidence for this process was stronger when stimulation was perceived as painful compared with when stimulation was perceived as nonpainful. These findings suggest that pain appraisal regulates the heat-evoked autonomic response to noxious stimulation, documenting the flexibility of the autonomic pain response to adjust to perceived or actual changes in environmental affordances above and beyond nociceptive input.
Authors: Ward Y, Lake R, Faraji F, Sperger J, Martin P, Gilliard C, Ku KP, Rodems T, Niles D, Tillman H, Yin J, Hunter K, Sowalsky AG, Lang J, Kelly K
Journal: Cell Rep. 2018 Apr 17;23(3):808-822. doi: 10.1016/j.celrep.2018.03.092.
Tumor cells initiate platelet activation leading to the secretion of bioactive molecules, which promote metastasis. Platelet receptors on tumors have not been well-characterized, resulting in a critical gap in knowledge concerning platelet-promoted metastasis. We identify a direct interaction between platelets and tumor CD97 that stimulates rapid bidirectional signaling. CD97, an adhesion G protein-coupled receptor (GPCR), is an overexpressed tumor antigen in several cancer types. Purified CD97 extracellular domain or tumor cell-associated CD97 stimulated platelet activation. CD97-initiated platelet activation led to granule secretion, including the release of ATP, a mediator of endothelial junction disruption. Lysophosphatidic acid (LPA) derived from platelets induced tumor invasiveness via proximal CD97-LPAR heterodimer signaling, coupling coincident tumor cell migration and vascular permeability to promote transendothelial migration. Consistent with this, CD97 was necessary for tumor cell-induced vascular permeability in vivo and metastasis formation in preclinical models. These findings support targeted blockade of tumor CD97 as an approach to ameliorate metastatic spread.
Authors: Anttila JE, Albert K, Wires ES, Mätlik K, Loram L, Watkins L, Rice KC, Wang Y, Harvey BK, Airavaara M
Journal: eNeuro. 2018 Apr 16;ENEURO.0395-17.2018.
Ischemic stroke is the leading cause of disability, and effective therapeutic strategies are needed to promote incomplete recovery. Neuroinflammation plays a significant role in stroke pathophysiology, and there is limited understanding how it affects recovery. The aim of the study was to characterize the spatiotemporal expression profile of microglial activation and to study whether dampening microglial/macrophage activation post-stroke facilitates the recovery. For dampening microglial/macrophage activation we chose intranasal administration of naloxone, a drug that is already in clinical use for opioid overdose and is known to decrease microglia/macrophage activation. We characterized the temporal progression of microglia/macrophage activation following cortical ischemic injury in rat and found the peak activation in cortex 7 days post-stroke. Unexpectedly, there was a chronic expression of phagocytic cells in the thalamus associated with neuronal loss. (+)-Naloxone, an enantiomer that reduces microglial activation without antagonizing opioid receptors, was administered intranasally starting 1 day post-stroke and continuing for 7 days. (+)-Naloxone treatment decreased microglia/macrophage activation in the striatum and thalamus, promoted behavioral recovery during the 14-day monitoring period, and reduced neuronal death in the lesioned cortex and ipsilateral thalamus. Our results are the first to show that post-stroke intranasal (+)-naloxone administration promotes short-term functional recovery and reduces microglia/macrophage activation. Therefore, (+)-naloxone is a promising drug for the treatment of ischemic stroke and further studies should be conducted.
Authors: Chia CW, Shardell M, Gravenstein KS, Carlson OD, Simonsick EM, Ferrucci L, Egan JM
Journal: Diabetes Obes Metab. 2018 Apr 23. doi: 10.1111/dom.13328. [Epub ahead of print]
Low-calorie sweeteners (LCS) are widely used for weight control despite limited evidence of their effectiveness and studies linking LCS consumption with incident obesity. We tested the hypothesis that regular LCS consumption is associated with higher post-prandial glucose-dependent insulinotropic polypeptide (GIP) secretion, which has been linked to obesity. We used data from Baltimore Longitudinal Study of Aging participants who had completed a diet diary, had at least one visit with an oral glucose tolerance test (OGTT), and had no diabetes. Of 232 participants, 166 contributed one, 39 contributed two, and 27 contributed three visits; and 96 (41%) reported using LCS. Plasma OGTT samples were analyzed for glucose, insulin and GIP. Fasting glucose, insulin or GIP were no different between LCS users and non-users. The association of LCS use with 2-hr OGTT responses after adjustment for covariates were non-significant for glucose (P=0.98) and insulin (P=0.18), but significant for greater increase in GIP in users (P=0.037). Regular consumption of LCS is associated with greater increases in GIP secretion following food intake, which may potentially lead to weight gain through lipogenic properties of GIP.
Authors: Lee NJ, Ha SK, Sati P, Absinta M, Luciano NJ, Lefeuvre JA, Schindler MK, Leibovitch EC, Ryu JK, Petersen MA, Silva AC, Jacobson S, Akassoglou K, Reich DS
Journal: Brain. 2018 Apr 20. doi: 10.1093/brain/awy082. [Epub ahead of print]
Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Although it has been extensively studied, the proximate trigger of the immune response remains uncertain. Experimental autoimmune encephalomyelitis in the common marmoset recapitulates many radiological and pathological features of focal multiple sclerosis lesions in the cerebral white matter, unlike traditional experimental autoimmune encephalomyelitis in rodents. This provides an opportunity to investigate how lesions form as well as the relative timing of factors involved in lesion pathogenesis, especially during early stages of the disease. We used MRI to track experimental autoimmune encephalomyelitis lesions in vivo to determine their age, stage of development, and location, and we assessed the corresponding histopathology post-mortem. We focused on the plasma protein fibrinogen-a marker for blood-brain barrier leakage that has also been linked to a pathogenic role in inflammatory demyelinating lesion development. We show that fibrinogen has a specific spatiotemporal deposition pattern, apparently deriving from the central vein in early experimental autoimmune encephalomyelitis lesions <6 weeks old, and preceding both demyelination and visible gadolinium enhancement on MRI. Thus, fibrinogen leakage is one of the earliest detectable events in lesion pathogenesis. In slightly older lesions, fibrinogen is found inside microglia/macrophages, suggesting rapid phagocytosis. Quantification demonstrates positive correlation of fibrinogen deposition with accumulation of inflammatory cells, including microglia/macrophages and T cells. The peak of fibrinogen deposition coincides with the onset of demyelination and axonal loss. In samples from chronic multiple sclerosis cases, fibrinogen was found at the edge of chronic active lesions, which have ongoing demyelination and inflammation, but not in inactive lesions, suggesting that fibrinogen may play a role in sustained inflammation even in the chronic setting. In summary, our data support the notion that fibrinogen is a key player in the early pathogenesis, as well as sustained inflammation, of inflammatory demyelinating lesions.
Authors: LeBlanc KH, London TD, Szczot I, Bocarsly ME, Friend DM, Nguyen KP, Mengesha MM, Rubinstein M, Alvarez VA, Kravitz AV
Journal: Mol Psychiatry. 2018 Apr 25. doi: 10.1038/s41380-018-0051-3. [Epub ahead of print]
The dorsal striatum has been linked to decision-making under conflict, but the mechanism by which striatal neurons contribute to approach-avoidance conflicts remains unclear. We hypothesized that striatopallidal dopamine D2 receptor (D2R)-expressing neurons promote avoidance, and tested this hypothesis in two exploratory approach-avoidance conflict paradigms in mice: the elevated zero maze and open field. Genetic elimination of D2Rs on striatopallidal neurons (iMSNs), but not other neural populations, increased avoidance of the open areas in both tasks, in a manner that was dissociable from global changes in movement. Population calcium activity of dorsomedial iMSNs was disrupted in mice lacking D2Rs on iMSNs, suggesting that disrupted output of iMSNs contributes to heightened avoidance behavior. Consistently, artificial disruption of iMSN output with optogenetic stimulation heightened avoidance of open areas of these tasks, while inhibition of iMSN output reduced avoidance. We conclude that dorsomedial striatal iMSNs control approach-avoidance conflicts in exploratory tasks, and highlight this neural population as a potential target for reducing avoidance in anxiety disorders.
Authors: Saint-Maurice PF, Troiano RP, Berrigan D, Kraus WE, Matthews CE
Journal: J Am Heart Assoc. 2018 Apr 2;7(7). pii: e008815. doi: 10.1161/JAHA.118.008815.
BACKGROUND: It is unclear whether the greater benefits of moderate-to-vigorous physical activity (PA) over light PA are attributed to the higher-intensity PA or simply the greater volume of PA accumulated per unit time for moderate-to-vigorous PA. We examined this question using estimates of the volume of light and moderate-to-vigorous PA in relation to all-cause mortality.
METHODS AND RESULTS: We used National Health and Nutrition Examination Survey 2003-2006 accelerometer records in adults (≥40 years; n=4840) and mortality data collected through 2011 (n=700 deaths). We estimated intensity-specific PA volume using activitycounts (AC) accumulated in light (100-759 AC/min), moderate-to-vigorous PA (≥760 AC/min), and total PA (≥100 AC/min). We examined quartiles of each exposure using Cox proportional hazard models (hazard ratios [95% confidence interval) adjusted for demographic and behavioral risk factors, health status, and body mass index. Mortality risk was less across increasing quartiles of light PA volume (AC×1000) when compared with the least quartile (AC ≤61.8); the least risk occurred in the upper quartile of light PA, AC >98.5 (hazard ratios=0.69, 95% confidence interval: 0.47, 1.00, P trend ≤0.05). The benefits for mortality risk were greater across quartiles of moderate-to-vigorous PA and reached a hazard ratio of 0.28 (95% confidence interval: 0.17, 0.46, P trend ≤0.05) for AC >187.9, when compared with the referent group (AC ≤50.8). Results examining various combinations of light and moderate-to-vigorous intensity-specific volumes demonstrated the strong influence of total activity on mortality risk.
CONCLUSIONS: In this population, increasing light PA was associated with less mortality, but at an approximately equal volume of PA, moderate-to-vigorous PA appeared to have greater benefits.