Real-World Intake of Dietary Sugars Is Associated with Reduced Cortisol Reactivity Following an Acute Physiological Stressor.

There is increasing academic and clinical interest in understanding the nature of the relation between diet and response to stress exposure as a risk factor for mental illness. Cross-species evidence shows that conditions of chronic and acute stress increase the intake of, and preference for, caloric-dense palatable foods, a phenomenon thought to be explained by the mitigating effects of comfort foods on the activity of the stress-response network. It is largely unknown whether and how real-world dietary intake of saturated fat and sugars impacts stress responsivity in humans. Therefore, here we examined whether real-world dietary intake of saturated fat and sugars predicted salivary cortisol reactivity following an acute physiological stressor. Multilevel modelling of four salivary cortisol measures collected up to 65 min after the stressor on 54 participants (18-49 years old) were analyzed using a quadratic growth curve model. Sugar intake significantly predicted a weaker cortisol response following the Cold Pressor Test (CPT) controlling for BMI and gender, revealing an inhibitory effect of caloric-dense diets on cortisol reactivity to stress. As the consumption of sugar rose individuals had lower post-stressor cortisol levels, a smaller rate of increase in cortisol 20 and 35 min after the CPT, a lower cortisol peak, and an overall weaker quadratic effect. These observations add to a growing body of evidence reporting suppressive effects of high-energy foods on stress-associated glucocorticoids reactivity and are consistent with the comfort food hypothesis, where people are seen as motivated to eat palatable foods to alleviate the detrimental repercussions of stressor exposure.

Pharmacological Enhancement of Extinction Retention in Non-stressed Adolescent Rats but Not Those Exposed to Chronic Corticosterone.

Individuals exposed to chronic adverse experiences in childhood and adolescence are at increased risk of developing neuropsychiatric illnesses such as mood and anxiety disorders. Symptoms of anxiety disorders can often be reduced through exposure therapy, which is based on the process of extinction. Although chronic stress in adolescence is known to exacerbate the impaired extinction of learned fear during this period of development, it remains unclear whether exposure to stressors in adolescence qualitatively affects the mechanisms underlying fear extinction. Brain-derived neurotrophic factor (BDNF) and its principle receptor, tropomyosin receptor kinase B (TrkB), are involved in neuroplasticity underlying fear extinction. The small-molecule TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) improves fear extinction and reduces fear relapse (reinstatement) in adult mice when administered prior to extinction training but its effects in younger ages are unknown. In this study we tested whether 7,8-DHF enhances extinction retention and leads to less renewal in both stressed and non-stressed adolescent rats. Pre-extinction injection of 7,8-DHF led to lower levels of CS-elicited freezing in both the extinction and conditioning contexts in non-stressed adolescent male rats, but not in those given 7 days of corticosterone. These findings indicate that chronic stress interferes with the effectiveness of pharmacological agonism of TrkB in enhancing fear extinction in adolescence. A greater understanding of the mechanisms underlying extinction in adolescence and the effect of chronic corticosterone exposure on those mechanisms may inform a deeper understanding of the etiology and treatment of pediatric stress-related disorders.

Fear extinction learning and retention during adolescence in rats and mice: A systematic review.

Despite exposure-based treatments being recommended for anxiety disorders, these treatments are ineffective for over half of all adolescents who receive them. The limited efficacy of exposure during adolescence may be driven by a deficit in extinction. Although indications of diminished extinction learning during adolescence were first reported over 10 years ago, these findings have yet to be reviewed and compared. This review (k = 34) found a stark inter-species difference in extinction performance: studies of adolescent mice reported deficits in extinction learning and retention of both cued and context fear. In contrast, studies of adolescent rats only reported poor extinction retention specific to cued fear. Adolescent mice and rats appeared to have only one behavioral outcome in common, being poor extinction retention of cued fear. These findings suggest that different behavioral phenotypes are present across rodent species in adolescence and highlight that preclinical work in rats and mice is not interchangeable. Further investigation of these differences offers the opportunity to better understand the etiology, maintenance, and treatment of fear-based disorders.

Timing is everything: Developmental differences in the effect of chronic corticosterone exposure on extinction retention.

Adolescence is noted as a time of "storm and stress." In this developmental stage both rodents and humans exhibit an impairment in the extinction of learned fear; however, this impairment can be alleviated, at least in rodents, by increasing the amount of extinction training given or by administering the partial NMDA receptor agonist D-Cycloserine. In the present study we explored whether the benefits of these treatments would be reduced by chronic exogenous corticosterone (a commonly studied stress-related hormone). In 2 experiments, adolescent rats were given pairings of a white noise and shock (acquisition) and then given extinction training (white noise presented alone). In Experiment 1, adolescents exhibited impaired extinction retention even after 2 days of extinction training if they had been exposed to corticosterone in adolescence but not if the exposure occurred when they were juveniles. In Experiment 2, exposure to exogenous corticosterone in adolescence, but not during the juvenile period, reduced the efficacy of the pharmacological adjunct D-Cycloserine at enhancing extinction retention after 1 day of extinction training. Taken together, the results support the idea that adolescence is a time of particular susceptibility to elevated levels of the stress hormone corticosterone. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Early-life stress, microbiota, and brain development: probiotics reverse the effects of maternal separation on neural circuits underpinning fear expression and extinction in infant rats.

Early-life stress has pervasive, typically detrimental, effects on physical and mental health across the lifespan. In rats, maternal-separation stress results in premature expression of an adult-like profile of fear regulation that predisposes stressed rats to persistent fear, one of the hallmarks of clinical anxiety. Probiotic treatment attenuates the effects of maternal separation on fear regulation. However, the neural pathways underlying these behavioral changes are unknown. Here, we examined the neural correlates of stress-induced alterations in fear behavior and their reversal by probiotic treatment. Male Sprague-Dawley rats were exposed to either standard rearing conditions or maternal-separation stress (postnatal days [P] 2-14). Some maternally-separated (MS) animals were also exposed to probiotics (Lactobacillus rhamnosus and L. helveticus) via the maternal drinking water during the period of stress. Using immunohistochemistry, we demonstrated that stressed rat pups prematurely exhibit adult-like engagement of the medial prefrontal cortex during fear regulation, an effect that can be prevented using a probiotic treatment. The present results add to the cross-species evidence that early adversity hastens maturation in emotion-related brain circuits. Importantly, our results also demonstrate that the precocious neural maturation in stressed infants is prevented by a non-invasive probiotic treatment.

A precision medicine approach to pharmacological adjuncts to extinction: a call to broaden research.

There is a pressing need to improve treatments for anxiety. Although exposure-based therapy is currently the gold-standard treatment, many people either do not respond to this therapy or experience a relapse of symptoms after treatment has ceased. In recent years, there have been many novel pharmacological agents identified in preclinical research that have potential as adjuncts for exposure therapy, yet very few of these are regularly integrated into clinical practice. Unfortunately, the robust effects observed in the laboratory animal often do not translate to a clinical population. In this review, we discuss how age, sex, genetics, stress, medications, diet, alcohol, and the microbiome can vary across a clinical population and yet are rarely considered in drug development. While not an exhaustive list, we have focused on these factors because they have been shown to influence an individual's vulnerability to anxiety and alter the neurotransmitter systems often targeted by pharmacological adjuncts to therapy. We argue that for potential adjuncts to be successfully translated from the lab to the clinic empirical research must be broadened to consider how individual difference factors will influence drug efficacy.

Differences in the persistence of spatial memory deficits induced by a chronic stressor in adolescents compared to juveniles.

Adolescence is thought of as a stress-sensitive developmental period. While many studies have compared adolescent responses to stress relative to that of adults, a growing body of work has examined stress responses in juveniles. Here we investigated if a chronic stressor has a differential effect on spatial memory in rats depending on whether it occurs during adolescence or the juvenile period. Male rats were exposed to the stress hormone corticosterone (Cort) in their drinking water, a vehicle control (2.5% ethanol), or water, for 7 days before being tested on a novel Object/Place task 6 days or 6 weeks later. Exposure to Cort or ethanol at either age impaired spatial memory at the 6-day test. The ethanol induced impairment was attenuated 6 weeks later. However, rats given Cort during adolescence, but not the juvenile period, were still impaired. Together, these results suggest that adolescence is indeed a stress-sensitive period.