Global, cell non-autonomous gene regulation drives individual lifespan among isogenic C. elegans

Across species, lifespan is highly variable among individuals within a population. Even genetically identica

Differential Microglial Responses Induced by N-a-Synuclein-Specific Effector T Cell Clones

Parkinson\u27s disease (PD) is a neurodegenerative movement disorder in which symptoms derive from deficits in dopamine neurotransmitter levels secondary to loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) associated with misfolding and accumulation of α−synuclein. Neuroinflammation via microglia and T effector cells (Teffs) contribute to dopaminergic neuronal cell death. Recognition of cytokine profiles of pro-inflammatory microglia is not well understood and serve as potential therapeutic targets to reduce neuroinflammation. Recent studies demonstrated a novel Th17.1 Teff clonotype increases neurotoxicity. The aim of this study was to demonstrate in vitro cytokine responses by BV-2 microglia induced by Th1, Th17, and Th17.1 clonotypes to assess neuroinflammation mechanisms in PD. Cytokine responses by BV-2 microglia co-cultured with activated Teff clonotypes were analyzed using a cytokine membrane array. Co-culture with Teffs led to significant increases in the majority of cytokine responses from BV-2 microglia compared to control. Cross group analysis relative expression demonstrated variation in cytokine profiles produced between microglia treated with different Teff clonotypes, especially with regard to IFNγ, MIG, MIP-1α, TIMP-1, RANTES, SDF-1, and IL-12 p40/p70. Ingenuity Pathway Analysis (IPA) of cytokines displaying significant relative expression levels for each Teff clonotype showed Th1- and Th17- treated BV-2 microglia demonstrated pathways related to cellular movement, hematological development and function, and immune trafficking while Th17.1-treated microglia upregulated pathways related to disorders of connective tissues, inflammation, and organismal injury. In conclusion, Th1, Th17, and Th17.1 Teffs treatment of BV-2 microglia led to upregulation of most pro-inflammatory cytokines and pathways. However, specific Teff clonotype culture with BV-2 microglia displayed different cytokine profile responses through varying relative expression profiles with significant differences related to IFNγ, MIG, MIP-1α, TIMP-1, RANTES, SDF-1, and IL12 p40/p70 delineating alternative inflammatory pathways. These results provide relevant targets for strategies to attenuate neuroinflammation and protect dopaminergic neurons in PD.https://digitalcommons.unmc.edu/emet_posters/1005/thumbnail.jp

Subjective estimates of uncertainty during gambling and impulsivity after subthalamic deep brain stimulation for Parkinson\u2019s disease

Subthalamic deep brain stimulation (DBS) for Parkinson\u2019s disease (PD) may modulate chronometric and instrumental aspects of choice behaviour, including motor inhibition, decisional slowing, and value sensitivity. However, it is not well known whether subthalamic DBS affects more complex aspects of decision-making, such as the influence of subjective estimates of uncertainty on choices. In this study, 38 participants with PD played a virtual casino prior to subthalamic DBS (whilst \u2018on\u2019 medication) and again, 3-months postoperatively (whilst \u2018on\u2019 stimulation). At the group level, there was a small but statistically significant decrease in impulsivity postoperatively, as quantified by the Barratt Impulsiveness Scale (BIS). The gambling behaviour of participants (bet increases, slot machine switches and double or nothing gambles) was associated with this self-reported measure of impulsivity. However, there was a large variance in outcome amongst participants, and we were interested in whether individual differences in subjective estimates of uncertainty (specifically, volatility) were related to differences in pre- and postoperative impulsivity. To examine these individual differences, we fit a computational model (the Hierarchical Gaussian Filter, HGF), to choices made during slot machine game play as well as a simpler reinforcement learning model based on the Rescorla-Wagner formalism. The HGF was superior in accounting for the behaviour of our participants, suggesting that participants incorporated beliefs about environmental uncertainty when updating their beliefs about gambling outcome and translating these beliefs into action. A specific aspect of subjective uncertainty, the participant\u2019s estimate of the tendency of the slot machine\u2019s winning probability to change (volatility), increased subsequent to DBS. Additionally, the decision temperature of the response model decreased post-operatively, implying greater stochasticity in the belief-to-choice mapping of participants. Model parameter estimates were significantly associated with impulsivity; specifically, increased uncertainty was related to increased postoperative impulsivity. Moreover, changes in these parameter estimates were significantly associated with the maximum post-operative change in impulsivity over a six month follow up period. Our findings suggest that impulsivity in PD patients may be influenced by subjective estimates of uncertainty (environmental volatility) and implicate a role for the subthalamic nucleus in the modulation of outcome certainty. Furthermore, our work outlines a possible approach to characterising those persons who become more impulsive after subthalamic DBS, an intervention in which non-motor outcomes can be highly variable