Understanding sex differences in extinction retention: Pre-extinction stress and sex hormone status.

Difficulties in fear regulation can sometimes result in maladaptive fear responses. To better understand how to improve fear regulation, it is important to determine how known factors, such as sex hormone status and stress, might interact to influence fear memory. Research has shown that women with high estradiol levels (mid-cycle) and men exhibit better extinction retention compared to women with low estradiol levels (women in the early follicular cycle or using oral contraceptives). Stress has also been demonstrated to affect both the learning and retention of extinction. Despite documented interactions between stress and sex hormones, their combined effects have not been thoroughly studied. This study aims to examine the impact of stress as a function of sex hormone status on extinction learning and retention. A total of 168 non-clinical participants were studied, including men (n = 46), women using oral contraceptives (n = 38), women in the early follicular phase (n = 40), and women in mid-cycle (n = 44). On Day 1, fear acquisition training was performed. On day 2, prior to extinction training, half of the participants were exposed to a psychosocial stressor, while the other half performed a non-stressful control task. On day 3, extinction retention was tested. Fear was quantified using skin conductance responses, while stress hormones were quantified through saliva samples. Exposure to stress prior to extinction training did not affect extinction learning, regardless of sex hormone status. In contrast, pre-extinction stress exposure had different effects on extinction retention depending on hormone status. Stressed men showed impairment in extinction retention compared to controls, while the experimental condition had no effect on naturally cycling women. Regardless of stress exposure, early follicular women exhibited a deficit in fear regulation, while mid-cycle women showed effective fear regulation. Among women using oral contraceptives, the stress group demonstrated better extinction retention compared to the control group. These results demonstrate the importance of considering sex hormone status and stress exposure during extinction learning, as both components may modulate extinction retention. These results could help identifying hormonal conditions that may enhance the effectiveness of extinction-based psychological therapies used in the treatment of fear-related disorders.

Using unconditioned responses to predict fear acquisition, fear extinction learning, and extinction retention patterns: Sex hormone status matters.

Following a traumatic event, fear dysregulation can increase the likelihood of developing post-traumatic stress disorder (PTSD). This psychopathology is twice as prevalent in women than in men. High physiological reactivity following trauma may be an early risk indicator for the development of PTSD. Elevated physiological reactivity and low estradiol levels have individually been associated with higher fear acquisition and/or lower extinction retention. Thus, sex hormone status may also modulate fear regulation abilities. However, it is unknown whether these two vulnerability factors interact to modulate fear learning and regulation. Using a fear conditioning and extinction protocol, we examined whether physiological reactivity to the aversive stimulus during fear acquisition training predicted fear responses during fear learning, extinction learning, and extinction retention. We verified whether these associations differed according to sex hormone status. Seventy-seven non-clinical participants were recruited including oral contraceptive users (n = 18), early follicular women (n = 20, [low estradiol]), mid-cycle women (n = 20, [high estradiol]), and men (n = 19). Participants underwent a three-day fear conditioning and extinction protocol (day 1: fear acquisition training; day 2: extinction training; day 3: retention test). Skin conductance responses were recorded. In early follicular women, physiological reactivity predicted conditioned and extinguished stimulus fear responses during all phases. For the remaining women, this effect was only present during fear learning and extinction learning. These findings highlight the importance of considering physiological reactivity and sex hormone status following a traumatic event. This knowledge could aid in the early identification of those at higher risk of developing PTSD.

Glutamate and obesity - what is the link?

PURPOSE OF REVIEW: Many studies using metabolomics have tried to unravel the metabolic signature of obesity and understand the pathophysiology of this complex and heterogeneous disease. Circulating levels of the amino acid glutamate have been consistently associated with obesity and more specifically with measurements of abdominal fat accumulation. The purpose of this narrative review is to highlight recent studies documenting this association. RECENT FINDINGS: Circulating glutamate concentrations have been positively correlated with measurements of central fat accumulation such as waist circumference and visceral adipose tissue area. Moreover, elevated glutamate levels have been linked to a higher prevalence of type 2 diabetes, cardiovascular diseases and nonalcoholic fatty liver disease. The association with adiposity is detected in early life, and genetic predisposition does not appear as a major driver. Glutamate levels reflect in vivo synthesis rather than dietary intake. However, interventions generating metabolic improvements such as incretin receptor agonist treatment or dietary improvements may reduce plasma levels of this amino acid. SUMMARY: Recent findings confirm the consistent association between circulating glutamate and abdominal obesity and its cardiometabolic complications. The pathophysiological pathways underlying this phenomenon are still unclear. Furthermore, studies are needed to establish the usefulness of this analyte as a biomarker of abdominal obesity.

When asking 'are you stressed?' is not enough: Hair cortisol, subjective stress, and alcohol use during the first year of the pandemic.

The onset of the COVID-19 pandemic was accompanied by an increase in alcohol use in a third of the population worldwide. To date, the literature shows that subjective reports of stress predicted increased alcohol use during the early stages of the pandemic. However, no studies have investigated the effect of physiological stress (via the stress hormone cortisol) on alcohol use during the pandemic. This study aimed to identify the predictive value of cortisol and/or subjective stress on alcohol use during the first year of the pandemic. Every three months, between June 2020 and March 2021, 79 healthy adults (19-54 years old) answered online questionnaires assessing alcohol use. In May 2020, participants reported pre-pandemic alcohol use, while in June 2020, participants reported current alcohol use, subjective stress measures, and provided a 6 cm hair sample. The latter allowed us to quantify the cumulative levels of cortisol produced in the three months prior to and following the start of the mandatory lockdown measures in March 2020 in Quebec, Canada. A relative change in hair cortisol was computed to quantify the physiological stress response. While controlling for sex, age, and psychiatric diagnoses, multilevel linear regressions revealed that alcohol use increased only among people with concomitant high subjective stress and elevated hair cortisol concentrations. Moreover, this increased alcohol use remained elevated one year later. This study documents the importance of simultaneously considering stress biomarkers and subjective stress to identify people at risk of increasing their alcohol use during major stressful life events.

Diversity-oriented synthesis of functionalized pyrrolo[3,2-d]pyrimidines with variation of the pyrimidine ring nitrogen substituents.

Nine 2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-carboxylic acid benzyl esters 12 were synthesized in four steps from 4-oxo-N-(PhF)proline benzyl ester 7 by a general method in which elements of molecular diversity were readily added onto the pyrimidine nitrogens. Conversion of 4-oxoproline 7 into the corresponding aminopyrrole 8 using benzyl-, allyl-, and isopropylamine followed by treatment with phenyl, allyl, and ethyl isocyanate gave nine different ureas 9. 4-Ureido-1H-pyrrole-2-carboxylic acid benzyl esters 9 were then converted into the respective pyrrolo[3,2-d]pyrimidines 12 using trichloroacetyl chloride in acetonitrile followed by treatment with Cs(2)CO(3). Crystallization from toluene gave the desired deazapurines in 37-55% overall yield from proline 7.

An effective new synthesis of 4-aminopyrrole-2-carboxylates.

[reaction: see text] A series of 4-amino-1H-pyrrole-2-carboxylic acid benzyl esters has been synthesized in 61-84% yields on treatment of N-PhF-4-oxoproline benzyl ester and its 3-alkyl-substituted derivatives with different primary and secondary amines and a catalytic amount of TsOH in THF. 4-Hydroxy-1H-pyrrole-2-carboxylic acid benzyl esters were prepared in 59 and 70% yields by treatment of N-PhF-4-oxoproline benzyl esters with ammonium hydroxide in THF.

An unexpected [1,5]-h shift in the synthesis of nitroanilines.

Addition of methyl acetoacetate to 2-nitrovinamidinium hexafluorophosphate salts leads to the formation of anilines or phenols in good to excellent yields depending on the alkylamine substituents. Small substituents, e.g., pyrrolidine, lead to the formation of anilines while large substituents, e.g., N,N-diisopropyl, exclusively give phenols. Labeling studies implicate a [1,5]-H shift proceeding with excellent isotopic fidelity.