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    • A neuroinflammatory response typically occurs when signals i

    2018-11-07

    A neuroinflammatory response typically occurs when signals involving infection or irritation are evoked in the brain, or through vagal afferents, transport of cytokines into the Etoposide through the blood–brain-barrier (BBB), or infiltration of cytokines where the BBB is absent (Schoderboeck et al., 2009; Northrop and Yamamoto, 2012; reviewed by Schwarz and Bilbo, 2011). Microglia are resident immune cells in the brain and are known to play a major mediating role in neuroinflammation. Although the mechanism by which neuroinflammation causes etiology of behavioral and psychological disorders is not fully understood, the damaging effects of microglial and astrocyte activation on neuron function and circuitry are being elucidated. Under normal circumstances, resting microglia continuously survey the brain parenchyma (Nimmerjahn et al., 2005). Microglia become activated in response to various danger signals posed by neurons and/or astrocytes (Davalos et al., 2005) and have local protective effects via regulated release of cytokines and phagocytosis of cellular debris. Under conditions of serious injury, microglia become reactive, characterized by heightened release of inflammatory mediators. When reactive, microglia can be neurotoxic and damage otherwise healthy neurons (Banati and Graeber, 1994). For example, activated microglia release nitric oxide (NO) (Chao et al., 1992). While low levels of NO function as signaling molecules, high levels of this free radical can cause neuronal cytotoxicity (Uttara et al., 2009). Several studies have shown that excess production of free radicals such as NO contributed significantly to neuronal loss in schizophrenia, Parkinson\'s and Alzheimer\'s disease (Mahadik and Mukherjee, 1996; Christen, 2000; Beal, 2003), likely through excitotoxicity and apoptosis (Kehrer, 2000). These mechanisms may partially explain the etiology of psychopathologies that emerge after ELA. It is noteworthy that different insults may summate upon microglia and potentiate each other to worsen the outcome of the response (Luo and Chen, 2012). It is therefore plausible that ELA acts to sensitize microglia toward a lower threshold for a reactive state, leading to increased inflammatory cytokine levels and altered neurotransmission. Alternatively, activated microglia can express anti-inflammatory cytokines and play a role in tissue protection and repair. Neuroinflammatory influences on neurotransmission and morphology also rely largely on glial activity. Activated microglia may contribute to neuroplastic changes through synaptic remodeling, excitatory transmission, and phagocytosis of newborn neurons and cellular debris (reviewed by Kovacs, 2012). Monoamine transmission is also affected by neuroinflammation. In activated microglia, tryptophan is metabolized by indoleamine to the NMDA agonist quinolinic acid instead of serotonin (Steiner et al., 2011). Microglial activity has therefore been directly linked to depressive symptoms through a reduction in serotonin production (Muller, 2014). Importantly, neural-immune interactions begin during fetal development (Schwarz and Bilbo, 2011), and a growing landscape of data supports an active role for these interactions on the programming of lifelong function.
    The neuroinflammatory link between ELA and behavioral changes Pioneering work describing how ELA can alter immunological development was conducted in the 1980s in primates (Laudenslager et al., 1982, 1990; Coe et al., 1987, 1988, 1989). Since then, the growing appreciation for an immunological contribution to mental illness has led to a resurgence of interest in neuroimmune interactions. Tables 1 and 2 display studies over the past 15 years directly investigating the effect of ELA on later immune function in rodents (Table 1) and humans (Table 2). Despite stress paradigms, species/strain differences, and age differences, a pattern emerges suggesting ELA leads to increased pro-inflammatory responsivity in early adolescence or later. This heightened response is likely a consequence of the early response to ELA during and immediately following exposure.