Differential effects of stress on fear learning and activation of the amygdala in pre-adolescent and adult male rats.

Adolescence is accompanied by the maturation of several stress-responsive areas of the brain including the amygdala, a key region for the acquisition and expression of conditioned fear. These changes may contribute to the development of stress-related disorders in adolescence, such as anxiety and depression, and increase the susceptibility to these psychopathologies later in life. Here, we assessed the effects of acute restraint stress on fear learning and amygdala activation in pre-adolescent and adult male rats. Pre-adolescents exposed to stress prior to fear conditioning showed greater resistance to the extinction of fear memories than adults. At the cellular level, the combination of stress and fear conditioning resulted in a greater number of FOS-positive cells in the basolateral nucleus of the amygdala (BLA) than fear conditioning alone, and this increase was greater in pre-adolescents than in adults. Despite age-dependent differences, we found no changes in glucocorticoid receptor (GR) levels in the amygdala of either pre-adolescent or adult males. Overall, our data indicate that stress prior to fear conditioning leads to extinction-resistant fear responses in pre-adolescent animals, and that the BLA may be one neural locus mediating these age-dependent effects of stress on fear learning.

Prediction of cognition in Parkinson's disease with a clinical-genetic score: a longitudinal analysis of nine cohorts.

BACKGROUND: Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical-genetic score to predict global cognitive impairment in patients with the disease. METHODS: In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generated from the entire study population. FINDINGS: 3200 patients with Parkinson's disease who were longitudinally assessed with 27 022 study visits between 1986 and 2016 in nine cohorts from North America and Europe were assessed for eligibility. 235 patients with MMSE ≤25 at baseline and 135 whose first study visit occurred more than 12 years from disease onset were excluded. The discovery population comprised 1350 patients (after further exclusion of 334 with missing covariates) from six longitudinal cohorts with 5165 longitudinal visits over 12·8 years (median 2·8, IQR 1·6-4·6). Age at onset, baseline MMSE, years of education, motor exam score, sex, depression, and ß-glucocerebrosidase (GBA) mutation status were included in the prediction model. The replication population comprised 1132 patients (further excluding 14 patients with missing covariates) from three longitudinal cohorts with 19 127 follow-up visits over 8·6 years (median 6·5, IQR 4·1-7·2). The cognitive risk score predicted cognitive impairment within 10 years of disease onset with an area under the curve (AUC) of more than 0·85 in both the discovery (95% CI 0·82-0·90) and replication (95% CI 0·78-0·91) populations. Patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile (hazard ratio 18·4 [95% CI 9·4-36·1]). Dementia or disabling cognitive impairment was predicted with an AUC of 0·88 (95% CI 0·79-0·94) and a negative predictive value of 0·92 (95% 0·88-0·95) at the predefined cutoff of 0·196. Performance was stable in 10 000 randomly resampled subsets. INTERPRETATION: Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson's disease. This model could improve trials of cognitive interventions and inform on prognosis. FUNDING: National Institutes of Health, US Department of Defense.

The influence of puberty on stress reactivity and forebrain glucocorticoid receptor levels in inbred and outbred strains of male and female mice.

OBJECTIVE: To examine stress-induced corticosterone responses and forebrain glucocorticoid receptor (GR) levels in prepubertal and adult, male and female mice of three commonly used inbred (C57BL/6, BALB/c) and outbred (Swiss Webster) strains. METHODS: Prepubertal (30 days of age) and adult (75 days of age), male and female C57BL/6, BALB/c, and Swiss Webster mice were exposed to a 30 min session of restraint stress. Plasma corticosterone was measured before (basal), or 0, 30, or 60 min after termination of the stressor. GR protein levels of the medial prefrontal cortex, paraventricular nucleus of the hypothalamus, and hippocampus were also measured via tissue punches and western blots in the prepubertal and adult males and females at the basal time point. RESULTS: In response to acute stress, prepubertal males of both inbred strains showed greater hormonal responsiveness than their adult counterparts, while females of these strains displayed similar stress-induced corticosterone responses, independent of age. Conversely, only the females of the outbred Swiss Webster strain showed pubertal-related changes, with adult females showing greater hormonal reactivity compared to prepubertal females. Despite these significant differences in hormonal reactivity, we found little difference in GR protein levels in the brain regions examined. CONCLUSIONS: These data indicate that pubertal-dependent differences in stress reactivity can be significantly influenced by sex and genetic background. Moreover, these data provide points of departure for future studies investigating how puberty, sex, and genetic background interact to shape both short- and long-term effects of stress on mental and physical health.

Divergent stress-induced neuroendocrine and behavioral responses prior to puberty.

Following an acute stressor, pre-adolescent rats exhibit a protracted hormonal response compared to adults, while after repeated exposure to the same stressor (i.e., homotypic stress) prepubertal males fail to habituate like adults. Though the neurobehavioral implications of these changes are unknown, studying pubertal shifts in stress reactivity may help elucidate the mechanisms that underlie the increase in stress-related psychological and physiological disorders often observed during adolescence. Here, we investigated hormonal, behavioral, and neural responses of prepubertal (30d) and adult (77d) male rats before, during, or after acute stress (restraint), homotypic stress (repeated restraint) or heterotypic stress (repeated cold exposure followed by restraint). We found that prepubertal males exhibit prolonged corticosterone responses following acute and heterotypic stress, and higher adrenocorticotropic hormone and corticosterone responses after homotypic stress, compared to adults. Despite these significant age-dependent changes in hormonal responsiveness, we found that struggling behavior during restraint was similar at both ages, such that both prepubertal and adult animals exposed to homotypic stress struggled less than animals exposed to either acute or heterotypic stress. Across these different stress paradigms, we found greater neural activation, as indexed by FOS immunostaining, in the prepubertal compared to adult paraventricular nucleus of the hypothalamus, a nucleus integral for initiating the hormonal stress response. Interestingly, however, we did not find any influence of pubertal development on stress-induced activation of the posterior paraventricular thalamic nucleus, a brain region involved in experience-dependent changes in stress reactivity. Collectively, our data indicate that prepubertal and adult males display divergent hormonal, behavioral, and neural responses following a variety of stressful experiences, as well as a distinct dissociation between hormonal and behavioral reactivity in prepubertal males under homotypic conditions.