Adolescent stress sensitizes the adult neuroimmune transcriptome and leads to sex-specific microglial and behavioral phenotypes

Bekhbat, Mandakh; Mukhara, Deepika; Dozmorov, Mikhail G.; Stansfield, John C.; Benusa, Savannah D.; Hyer, Molly M.; Rowson, Sydney A.; Kelly, Sean D.; Qin, Zhaohui S.; Dupree, Jeffrey L.; Tharp, Gregory K.; Tansey, Malú G.; Neigh, Gretchen N.

doi:10.1038/s41386-021-00970-2

Cited by 23 publications

(12 citation statements)

References 92 publications

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“…Our results implicate microglia as an initiating factor in promoting early neuronal AD pathology. Previous work from our laboratory and others has implicated microglia as key mediators in response to binge alcohol ( Walter and Crews, 2017 ; Bekhbat et al, 2021 ). These results suggest that microglia may be persistently “primed” by inflammatory insults earlier in life, which could play a crucial role in the pathogenesis of AD ( Li et al, 2018 ).…”

Section: Discussionmentioning

confidence: 94%

“…AIE persistently increased proinflammatory microglial markers in the female hippocampus. Other environmental insults during adolescence can also promote priming, such as chronic stress, which increases microglia responsive to LPS in adulthood ( Bekhbat et al, 2021 ). However, it remains unclear if glial changes during adolescence create a unique developmental period with heightened vulnerability to immune stimuli than other developmental periods.…”

Section: Discussionmentioning

confidence: 99%

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Adolescent Binge Alcohol Enhances Early Alzheimer’s Disease Pathology in Adulthood Through Proinflammatory Neuroimmune Activation

et al. 2022

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Epidemiological studies suggest that heavy alcohol use early in life is associated with increased risk for Alzheimer’s disease (AD). However, mechanisms connecting AD with alcohol use have not been identified. Both heavy alcohol use and AD feature increased proinflammatory signaling. Therefore, we hypothesized that adolescent binge ethanol would increase AD molecular and behavioral pathology in adulthood through proinflammatory signaling. The 3xTg-AD mouse model (APPSwe, tauP301, Psen1tm1Mpm) which features amyloid (Aβ) and tau pathology beginning at 6–12 months underwent adolescent intermittent ethanol (AIE, 5 g/kg/d, i.g., P25-55) with assessment of AD pathologic mediators at P200. A second group of mice received AIE +/− minocycline (30 mg/kg/d, IP) followed by behavioral testing in adulthood. Behavioral testing and age of testing included: locomotor activity and exploration (27–28 weeks), novel object recognition (NORT, 28-30 weeks), 3-chamber sociability and social memory (29–31 weeks), prepulse inhibition (PPI, 30–32 weeks), Morris Water Maze with reversal (MWM, 31–35 weeks), and Piezo sleep monitoring (35–37 weeks). We found that AIE increased levels of neurotoxic Aβ1–42 in adult female hippocampus as well as intraneuronal Aβ1–42 in amygdala and entorhinal cortex. Phosphorylated tau at residue Thr181 (p-tau-181) was also increased in female hippocampus by AIE. Several proinflammatory genes were persistently increased by AIE in the female hippocampus, including IL-1β, MCP-1, IL-6, and IFNα. Expression of these genes was strongly correlated with the levels of Aβ1–42 and p-tau-181 in hippocampus. AIE caused persistent decreases in locomotor activity (open-field and NORT habituation) and increased anxiety-like behavior (thigmotaxis) while reducing memory retention. Treatment with the anti-inflammatory compound minocycline during AIE blocked persistent increases in Aβ1–42 in amygdala and p-tau-181 in hippocampus, and prevented AIE-induced thigmotaxis and memory loss. Together, these data find that adolescent binge ethanol enhances AD molecular and behavioral pathology in adulthood through proinflammatory signaling. Blockade of proinflammatory signaling during ethanol exposure prevents ethanol-induced effects on pathologic accumulation of AD-associated proteins and persistent behavior changes relevant to human AD.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Adolescent Binge Alcohol Enhances Early Alzheimer’s Disease Pathology in Adulthood Through Proinflammatory Neuroimmune Activation

et al. 2022

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“…For instance, increases in microglia (particularly in the activated state) are reported in many of the brain areas that are significantly impacted by chronic stress, including the PFC and HIPP, although timing and sex modulate these responses 51 – 53 . Notably, recent work has demonstrated that exposure to chronic stress during adolescence (noted earlier in this review as a stress-sensitive period of exposure to glucocorticoids) can lead to significant changes in the neuroimmune transcriptome, likely marking a significant shift of developmental trajectories 54 . The role of the immune system as both a responder and modulator of the stress response is a major area of new research and certainly represents another important nexus between brain and periphery in the response to chronic stress.…”

Section: Chronic Stress and Inflammationmentioning

confidence: 89%

Brain–body responses to chronic stress: a brief review

Roberts¹,

Karatsoreos²

2021

Fac Rev

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In order to survive and thrive, organisms must adapt to constantly changing environmental pressures. When there are significant shifts in the environment, the brain and body engage a set of physiological and behavioral countermeasures collectively known as the “stress response”. These responses, which include changes at the cellular, systems, and organismal level, are geared toward protecting homeostasis and adapting physiological operating parameters so as to enable the organism to overcome short-term challenges. It is the shift of these well-organized acute responses to dysregulated chronic responses that leads to pathologies. In a sense, the protective measures become destructive, causing the myriad health problems that are associated with chronic stress. To further complicate the situation, these challenges need not be purely physical in nature. Indeed, psychosocial stressors such as ruminating about challenges at work, resource insecurity, and unstable social environments can engage the very same emergency threat systems and eventually lead to the same types of pathologies that sometimes are described as “burnout” in humans. This short review focuses on very recent empirical work exploring the effects of chronic stress on key brain circuits, metabolism and metabolic function, and immune function.

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“…Moreover, given the extensive poly(I:C) exposure that rats in Experiments 1 and 3 had, results may reflect the differential effects of neuroimmune priming between males and females. It is well-established that exposure to stressors can potentiate subsequent neuroimmune and microglial responses to immune challenges (Frank et al, 2011;Johnson et al, 2004;Johnson et al, 2003;Munhoz et al, 2006;Wohleb et al, 2011), and several studies identified that while both males and females are affected by priming of the neuroimmune response, the locus of that effect differs (Bekhbat et al, 2019;Bekhbat et al, 2021;Fonken et al, 2018;Gildawie et al, 2020). Priming of microglia (Melbourne et al, 2021;Walter et al, 2017) and specifically TLR responses (Crews and Vetreno, 2018) are thought to play an important role in AUD, thus a history of immune activation, whether through stress, pathogen exposure, or sterile central neuroimmune activation, may contribute to the onset and/or sustaining of AUD.…”

Section: Discussionmentioning

confidence: 99%

Increased alcohol self-administration following repeated Toll-like receptor 3 agonist treatment in male and female rats

Lovelock¹,

Randall

Voorhies³

et al. 2021

Preprint

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Toll-like receptor (TLR) signaling may play an important role in the neuroimmune system’s involvement in the development and maintenance of alcohol use disorder. In the present study we administered TLR3 agonist poly(I:C) in male and female Long-Evans rats to determine whether TLR3 agonism can increase alcohol consumption in a daily 15% alcohol operant self-administration paradigm. We found few effects when poly(I:C) was given every-other-day at 0.3 or 1.0 mg/kg, however when instead 1.0 mg/kg was given on consecutive days alcohol intake increased in the days following injections specifically in females. Furthermore, in a second experiment we found that this effect only emerged when rats had a history of multiple poly(I:C) injections. In the final experiment the dose was increased to 3.0 mg/kg on consecutive days which resulted in significant reductions on injection days in females that were not accompanied by subsequent increases. The dose was increased to 9 mg/kg for one final pair of injections which led to reductions in intake in both males and females but only increased subsequent alcohol consumption in males. Overall, poly(I:C) was able to increase subsequent alcohol consumption in both sexes, with females being sensitive to lower doses than males both in terms of changes in alcohol consumption and general locomotor reduction. These findings show that TLR3 agonism may be involved in driving increased alcohol consumption and add to the body of work identifying the neuroimmune system as a potential therapeutic target for AUD.

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Adolescent stress sensitizes the adult neuroimmune transcriptome and leads to sex-specific microglial and behavioral phenotypes

Cited by 23 publications

References 92 publications

Adolescent Binge Alcohol Enhances Early Alzheimer’s Disease Pathology in Adulthood Through Proinflammatory Neuroimmune Activation

Adolescent Binge Alcohol Enhances Early Alzheimer’s Disease Pathology in Adulthood Through Proinflammatory Neuroimmune Activation

Brain–body responses to chronic stress: a brief review

Increased alcohol self-administration following repeated Toll-like receptor 3 agonist treatment in male and female rats

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