Abstract The perinatal period is characterized by profound psychological, physiological, and behavioral changes that may increase sleep, circadian, and affective disturbances. While sleep disruption across pregnancy and postpartum has been widely documented, far less is known about how this transition shapes circadian health and whether circadian characteristics during pregnancy predict postpartum circadian and affective outcomes. In this study, we characterize circadian preference, circadian phase, circadian function, and light exposure across the transition from late pregnancy to early postpartum, and examine their predictive value for postpartum circadian function and depressive and anxiety symptomatology. Women were followed from the third trimester of pregnancy to 1 month postpartum. At both time points, participants wore a wrist actigraph to derive circadian parameters including the circadian function index (CFI) and circadian phase (L5c), and to quantify mean light exposure. Circadian preference and affective states were also assessed by questionnaires (MEQ, EPDS, STAI‐T). Within‐subject changes from pregnancy to postpartum were examined, and regression models were used to test whether prenatal circadian and affective measures predicted postpartum circadian function and depressive symptomatology. The transition to postpartum was marked by a significant reduction in CFI and mean light exposure, whereas circadian preference and L5c remained largely stable. During pregnancy, higher CFI was associated with morningness and greater light exposure; however, these associations were no longer evident postpartum. Postpartum CFI was predicted by prenatal CFI and circadian preference, with lower values observed among women with more evening‐oriented profiles. In parallel, prenatal affective symptoms showed continuity into the postpartum period, and both prenatal CFI and circadian preference contributed to the prediction of postpartum depressive symptoms. Together, these findings indicate that early postpartum is characterized by a decay in circadian function rather than a shift in circadian phase, identify eveningness as a vulnerability factor during the transition to motherhood, support the use of CFI as an integrative marker of maternal circadian health, and highlight pregnancy as a potential window for circadian‐informed interventions aimed at improving postpartum circadian and mood outcomes.
Abstract Early‐life adversity increases risk for disease with sex‐specific effects on brain development. While the association between early‐life stress and neuropsychiatric disorders is well established, its impact on respiratory health is poorly documented, particularly in females. Here, we review recent studies using neonatal maternal separation (NMS) to examine the long‐term consequences of early‐life stress on cardiorespiratory function in females. Panic disorder (PD) is an anxiety disorder that is ⁓2 times more prevalent in women. The respiratory subtype is characterised by an exaggerated ventilatory response to CO 2 . NMS augmented the response to 5% CO 2 of adult female rats; this effect was most pronounced during proestrus and absent in males. Orexin (ORX) neurons potentiate the CO 2 response and are normally inhibited by 17β‐estradiol (E2). Electrophysiological measurements showed that in control females, excitatory postsynaptic current frequency varied inversely with E2 levels. However, NMS disrupted this E2‐mediated inhibition, particularly during proestrus, implicating impaired estrogen action in PD‐related respiratory dysfunction. Age‐related ovarian decline increases the risk of sleep apnea and associated comorbidities. Whereas apnea frequency decreased with age in control females, 1 year‐old NMS females exhibited a 75% higher apnea index than age‐matched controls, together with greater adiposity and hypertension. Arterial pressure was inversely correlated with circulating E2 levels only in NMS females, indicating heightened vulnerability to age‐related estrogen decline. Although physiological fluctuations in E2 levels exert modest effects in healthy females, we propose that early‐life stress persistently alters responsiveness to E2 and acts synergistically with ageing to increase cardiovascular vulnerability throughout the female lifespan.
Abstract Social isolation during adolescence represents a significant risk factor for the development of psychopathologies later in life. While numerous preclinical studies have modeled psychopathologies using prolonged and continuous social isolation stress (SIS), the detrimental effects of shorter periods of SIS, particularly during critical developmental windows, are less explored. Here, we characterized a paradigm of brief and repeated SIS (bSIS) during early‐adolescence, a stress‐sensitive period, and examined its behavioral and neurobiological consequences in adulthood. Male rats were subjected to bSIS (2 h/day, postnatal days, [PND] 28–34), and effects on emotionality and memory function were later assessed using several behavioral tests. We found that bSIS induced long‐lasting alterations selectively in the emotional domain (e.g., increased anxious‐like behavior in the elevated plus maze test, and enhanced acoustic startle response). In a separate cohort, we investigated the brain regions bSIS‐activated and identified cingulate cortex area 1 (Cg1) as a potential key region mediating its effects. Given previous evidence that the glucocorticoid receptor (GR) antagonist mifepristone can reverse stress‐induced effects, we tested its efficacy in adulthood in our model (PND 83, 85, and 87) and found that it remarkably normalized the behavioral bSIS‐induced alterations. To explore the underlying molecular mechanisms, we performed bulk RNA sequencing in the Cg1, but no significant transcriptomic changes were detected, likely due to the transient nature of bSIS‐induced effects. Overall, our findings demonstrate that bSIS during early‐adolescence produces programming alterations, and that late GR antagonism effectively reverses these outcomes, highlighting a potential pharmacological target for stress‐related disorders.
Abstract Prolactin (PRL) is involved in the modulation of sexual function. Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) have been proposed to modulate reward‐related processes beyond their effects on appetite, including sexual desire. In our previously published randomized parent trial of dulaglutide and sexual desire, we hypothesized that any potential effect on sexual desire could involve changes in PRL concentrations. Predefined secondary analysis of a single‐center randomized, double blind, placebo‐controlled, crossover trial involving 24 healthy eugonad men of normal weight (BMI 18.5–25 kg/m 2 or BMI 25.1–30 kg/m 2 and waist circumference <102 cm). PRL concentrations were the primary outcome of the present analysis and were measured at baseline and after 4 weeks of dulaglutide (1.5 mg s.c. weekly) and placebo treatment, alongside weight, appetite, and sexual desire. Median age of participants was 24.5 years (IQR [21.0, 29.0]), median BMI was 23.9 kg/m 2 (IQR [22.2, 25.0]). PRL levels changed by −31.1 mU/L (SD 87.0 mU/L) on dulaglutide and +44.6 mU/L (SD 113.1 mU/L) on placebo over 4 weeks (estimated difference: −149.3 mU/L; 95% CI: [−298.5, −0.1]). On dulaglutide treatment, reductions in PRL correlated weakly with weight loss ( r = 0.25), and more than half of participants (13/24) showed parallel decreases in PRL and appetite scores. Regarding sexuality, we found no association of PRL levels and sexual desire. Four weeks of dulaglutide treatment reduced PRL concentrations compared with placebo in healthy men. These findings may point to broader neuroendocrine effects of GLP‐1 receptor activation and warrant further investigation. Trial registration: ClinicalTrials.gov NCT04687514.
Abstract Excitatory synapses in neurons of the ventrolateral ventromedial nucleus of the hypothalamus (vlVMH) use glutamine (Gln) provided by the Gln–glutamate cycle (GGC) to synthesize the glutamate required to sustain glutamatergic synaptic transmission in rat pups. Depending on neuronal activity, these synapses exhibit sexual dimorphic phenotypes. Female pups use Gln to sustain both basal and high‐level neuronal activity, whereas male pups use Gln to sustain only high‐level neuronal activity. Early postnatal GGC blockade alters glutamatergic synaptic transmission in adult female rats and shifts vlVMH neuronal morphology toward that of males. It further attenuates reproductive behavior expression in female rats, but not male rats. Because sexually dimorphic Gln‐dependent synaptic phenotypes differ between sexes at basal synaptic activity, we hypothesized that early postnatal GGC blockade would shift GGC (Gln)‐dependent excitatory synaptic phenotypes in adult female vlVMH neurons toward a male pup‐like phenotype. Sprague‐Dawley rats in the early postnatal period were treated with the neuronal Gln transport blocker alpha‐(methylamino) isobutyric acid (MeAIB; 5 mM; intracerebroventricular injection) or vehicle (distilled water) and raised until adulthood. Brain slices from the treated rats were subjected to whole‐cell patch‐clamp recording of miniature excitatory postsynaptic currents (mEPSCs) to assess unitary (quantal) excitatory synaptic transmission in vlVMH neurons. Furthermore, the sensitivity of mEPSCs to acute MeAIB perfusion was examined. Early postnatal MeAIB treatment reduced quantal and synaptic cleft glutamate levels in adult female rats and increased mEPSC frequency in adult male rats. In vehicle‐treated male and female rats, acute MeAIB perfusion reduced synaptic cleft glutamate levels and mEPSC amplitudes, but not mEPSC kinetics, highlighting a Gln‐dependent phenotype in adult male and female rats, which differs from that observed in male pups. In MeAIB‐treated adult female rats, acute MeAIB perfusion did not further reduce synaptic cleft glutamate level or mEPSC amplitude, suggesting that early postnatal MeAIB treatment induced long‐term impairment of Gln‐dependent excitatory synapses. Conversely, in MeAIB‐treated male rats, acute MeAIB perfusion reduced mEPSC amplitude and increased mEPSC rise time but exerted no significant effect on synaptic cleft glutamate level. Early postnatal neuron Gln transport blockade by MeAIB sex‐specifically disrupts Gln‐dependent excitatory synaptic responses in the vlVMH neurons of adult rats. In female rats, early postnatal MeAIB administration impairs Gln‐dependent synaptic responses by reducing vesicular glutamate content and glutamate release, resulting in a male pup‐like phenotype. By contrast, in male rats, early postnatal MeAIB administration partially preserves the female‐like Gln‐dependent excitatory synaptic phenotype, despite exerting mild effects on postsynaptic receptor sensitivity during adulthood.
