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Sex hormones may influence many physiological processes. Recently, we demonstrated that hormonal fluctuations of cycling female rats do not affect respiratory parameters during hypercapnia. However, it is still unclear whether sex hormones and hormonal fluctuations that occur during the estrous cycle can affect breathing during a hypoxic challenge. Our study aimed to evaluate respiratory, metabolic, and thermal responses to hypoxia in female rats on different days of the estrous cycle (proestrus, estrus, metestrus, and diestrus) and in ovariectomized rats that received replacement with oil (OVX), estradiol (OVX + E 2 ), or a combination of estradiol and progesterone (OVX + E 2 P). Ventilation ( V E ), tidal volume ( V T ), respiratory frequency (fR), oxygen consumption (VO 2 ), and V E /VO 2 were not different during the estrous cycle in normoxia or hypoxia. Body temperature (Tb) was higher during estrus, but decreased similarly in all groups during hypoxia. Compared with intact females in estrus, gonadectomized rats also had lower Tb in normoxia, but not in hypoxia. OVX rats experienced a significant drop in the ventilatory response to hypoxia, but hormonal replacement did not restore values to the levels of an intact animal. Our data demonstrate that the different phases of the estrous cycle do not alter ventilation during normoxia and hypoxia, but OVX animals display lower ventilatory responses to hypoxia compared with ovary-intact rats. Because estradiol and progesterone replacement did not cause significant differences in ventilation, our findings suggest that a yet-to-be-defined non-steroidal ovarian hormone is likely to stimulate the ventilatory responses to hypoxia in females.

Although loneliness is a human experience, it can be estimated in laboratory animals deprived from physical contact with conspecifics. Rodents under social isolation (SI) tend to develop emotional distress and cognitive impairment. However, it is still to be determined whether those conditions present a common neural mechanism. Here, we conducted a series of behavioral, morphological, and neurochemical analyses in adult mice that underwent to 1 week of SI. We observed that SI mice display a depressive-like state that can be prevented by enriched environment, and the antidepressants fluoxetine (FLX) and desipramine (DES). Interestingly, chronic administration of FLX, but not DES, was able to counteract the deleterious effect of SI on social memory. We also analyzed cell proliferation, neurogenesis, and astrogenesis after the treatment with antidepressants. Our results showed that the olfactory bulb (OB) was the neurogenic niche with the highest increase in neurogenesis after the treatment with FLX. Considering that after FLX treatment social memory was rescued and depressive-like behavior decreased, we propose neurogenesis in the OB as a possible mechanism to unify the FLX ability to counteract the deleterious effect of SI.

Amebiasis is a globally prevalent infection that can lead to fatal outcomes if not adequately treated. Conventional treatment with imidazoles often fails due to side effects and resistance, emphasizing the need for alternative therapies. The probiotic Escherichia coli Nissle 1917 (EcN) has shown potential in combating intestinal pathogens. This study aimed to evaluate the amebicidal activity of EcN in vitro and its effect on the production of reactive oxygen species (ROS). Trophozoites of Entamoeba histolytica (2.5 × 10⁴ cells/mL) were cultured in 96-well plates and exposed to varying concentrations of EcN (102–109 cells/mL). Plates were incubated at 36 °C for 6, 12, and 18 h, after which trophozoite viability was assessed. Intracellular ROS production, including superoxide and hydrogen peroxide, was measured using fluorescent probes. The highest efficacy was observed after 18 h at a CFU concentration of 109 cells/mL. Increased ROS production at all probiotic concentrations suggested a role in EcN’s amebicidal mechanism. Morphological changes in trophozoites, such as rounding, vacuolization, and size reduction, were noted after EcN exposure, indicating growth inhibition. These findings suggest EcN induces structural and morphological changes in E. histolytica, inhibiting its growth in vitro. The findings suggest the potential efficacy of EcN; however, definitive confirmation requires data from human clinical trials.

The prevalence of panic disorder is two to four times higher in women compared to that in men, and hormonal changes during the menstrual cycle play a role in the occurrence of panic attacks. Here, we investigated the effect of the estrous cycle on the ventilatory and behavioral responses to CO 2 in mice. Female mice in proestrus, estrus, metestrus, or diestrus were exposed to 20% CO 2 , and their escape behaviors, brain monoamines, and plasma levels of 17β-estradiol (E 2 ) and progesterone (P 4 ) were measured. Pulmonary ventilation (V̇ E ), oxygen consumption (V̇O 2 ), and body core temperature (T B ) were also measured during normocapnia followed by CO 2 . Females exposed to 20% CO 2 exhibited an escape behavior, but the estrous cycle did not affect this response. Females in all phases of the estrous cycle showed higher V̇ E and lower T B during hypercapnia. In diestrus, there was an attenuation of CO 2 -induced hyperventilation with no change in V̇O 2 , whereas in estrus, this response was accompanied by a reduction in V̇O 2 . Hypercapnia also increased the concentration of plasma P 4 and central DOPAC, the main dopamine metabolite, in all females. There was an estrous cycle effect on brainstem serotonin, with females in estrus showing a higher concentration than females in the metestrus and diestrus phases. Therefore, our data suggest that hypercapnia induces panic-related behaviors and ventilatory changes that lead to an increase in P 4 secretion in female mice, likely originating from the adrenals. The estrous cycle does not affect the behavioral response but interferes in the ventilatory and metabolic responses to CO 2 in mice.

Pregnancy is highly affected by anxiety disorders, which may be treated with benzodiazepines, especially diazepam (DZP), that can cross the placental barrier and interact with the fetal GABAergic system. We tested whether prenatal exposure to DZP promotes sex-specific postnatal changes in the respiratory control of rats. We evaluated ventilation (VE˙) and oxygen consumption (V˙ O2) in resting conditions and under hypercapnia (7% CO2) and hypoxia (10% O2) in newborn [postnatal day (P) 0–1 and P12–13)] and young (P21–22) rats from mothers treated with DZP during pregnancy. We also analyzed brainstem monoamines at the same ages. DZP exposure had minimal effects on room air–breathing variables in females, but caused hypoventilation (drop in VE˙/V˙ O2) in P12–13 males, lasting until P21–22. The hypercapnic ventilatory response was attenuated in P0–1 and P12–13 DZP-treated females mainly by a decrease in tidal volume (VT), whereas males had a reduction in respiratory frequency (fR) at P12–13. Minor changes were observed in hypoxia, but an attenuation in V˙E was seen in P12–13 males. In the female brainstem, DZP increased dopamine concentration and decreased 5-hydroxyindole-3-acetic acid (5-HIAA) and the 3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine ratio at P0–1, and reduced DOPAC concentration at P12–13. In males, DZP decreased brainstem noradrenaline at P0–1. Our results demonstrate that prenatal DZP exposure reduces CO2 chemoreflex only in postnatal females and does not affect hypoxia-induced hyperventilation in both sexes. In addition, prenatal DZP alters brainstem monoamine concentrations throughout development differently in male and female rats.

To assess the influence of physical training on neuronal activation and hypothalamic expression of vasopressin and oxytocin in spontaneously hypertensive rats (SHR), untrained and trained normotensive rats and SHR were submitted to running until fatigue while internal body and tail temperatures were recorded. Hypothalamic c-Fos expression was evaluated in thermoregulatory centers such as the median preoptic nucleus (MnPO), medial preoptic nucleus (mPOA), paraventricular nucleus of the hypothalamus (PVN), and supraoptic nucleus (SON). The PVN and the SON were also investigated for vasopressin and oxytocin expressions. Although exercise training improved the workload performed by the animals, it was reduced in SHR and followed by increased internal body temperature due to tail vasodilation deficit. Physical training enhanced c-Fos expression in the MnPO, mPOA, and PVN of both strains, and these responses were attenuated in SHR. Vasopressin immunoreactivity in the PVN was also increased by physical training to a lesser extent in SHR. The already-reduced oxytocin expression in the PVN of SHR was increased in response to physical training. Within the SON, neuronal activation and the expressions of vasopressin and oxytocin were reduced by hypertension and unaffected by physical training. The data indicate that physical training counterbalances in part the negative effect of hypertension on hypothalamic neuronal activation elicited by exercise, as well as on the expression of vasopressin and oxytocin. These hypertension features seem to negatively influence the workload performed by SHR due to the hyperthermia derived from the inability of physical training to improve heat dissipation through skin vasodilation.

Flame retardants (FRs) are used in a variety of common items from furniture to carpet to electronics to reduce flammability and combustion, but the potential toxicity of these compounds is raising health concerns globally. Organophosphate FRs (OPFRs) are becoming more prevalent as older, brominated FRs are phased out, but the toxicity of these compounds, and the FR mixtures that contain them, is poorly understood. Work in a variety of in vitro model systems has suggested that FRs may induce metabolic reprogramming such that bone density is compromised at the expense of increasing adiposity. To address this hypothesis, the present studies maternally exposed Wistar rat dams orally across gestation and lactation to 1000 µg daily of the FR mixture Firemaster 550 (FM 550) which contains a mixture of brominated FRs and OPFRs. At six months of age, the offspring of both sexes were examined for evidence of compromised bone composition. Bone density, composition, and marrow were all significantly affected, but only in males. The fact that the phenotype was observed months after exposure suggests that FM 550 altered some fundamental aspect of mesenchymal stem cell reprogramming. The severity of the phenotype and the human-relevance of the dose employed, affirm this is an adverse outcome meriting further exploration.

This study evaluated the hypothalamic neuronal activation during exercise and investigated whether this activation is related to heat storage and exercise duration. Rats were subjected to a treadmill running that was interrupted at three different moments: (1) at the early phase, when minimal heat dissipation occurred due to tail vasoconstriction and the tail skin temperature (Tskin) reached its nadir; (2) at the steady-state phase, when both the Tskin and core body temperature (Tcore) plateaued at a high level (~ 20 min); and (3) at fatigue, when Tcore and Tskin were still elevated. c-Fos expression in the medial and ventromedial preoptic areas (mPOA and vmPOA), median preoptic nucleus (MnPO), paraventricular and supraoptic nucleus (PVN and SON), and septohypothalamic nucleus (SHy) was determined. Exercise increased the expression of c-Fos in all brain areas, but with different activation patterns of activation. c-Fos expression in the SHy and vmPOA was similar in all exercising groups, while in the mPOA, MnPO, and PVN, c-Fos expression gradually increased during exercise. Increased c-Fos in the SON was only evident after 20 min of exercise. Neuronal activation in the mPOA, MnPO, PVN, and SON was positively correlated with both exercise duration and heat storage. Our findings indicate that with the exception of SON, the brain areas analyzed are recruited following small changes in Tcore (~ 0.5 °C), while the SON is recruited only when Tcore reaches higher values (greater than 1.0 °C increase). c-Fos expression in the PVN, mPOA, MnPO, and SON is also influenced by exercise duration, which does not occur in the SHy and vmPOA.

The locus coeruleus (LC) is a noradrenergic nucleus that plays an important role in the ventilatory response to hypercapnia. This nucleus is densely innervated by serotonergic fibers and contains high density of serotonin (5-HT) receptors, including 5-HT 1A and 5-HT 2 . We assessed the possible modulation of respiratory response to hypercapnia by 5-HT, through 5-HT 1A and 5-HT 2 receptors, in the LC. To this end, we determined the concentrations of 5-HT and its metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) in the LC after hypercapnic exposure. Pulmonary ventilation ( V e , plethysmograph) was measured before and after unilateral microinjection (100 nL) of WAY-100635 (5-HT 1A antagonist, 5.6 and 56 mM), 8-OHDPAT (5-HT 1A/7 agonist, 7 and 15 mM), Ketanserin (5-HT 2A antagonist, 3.7 and 37 mM), or (±)-2,5-dimethoxy-4-iodoamphetaminehydrochloride (DOI; 5-HT 2A agonist, 6.7 and 67 mM) into the LC, followed by a 60-min period of 7% CO 2 exposure. Hypercapnia increased 5-HTIAA levels and 5-HIAA/5-HT ratio within the LC. WAY-100635 and 8-OHDPAT intra-LC decreased the hypercapnic ventilatory response due to a lower tidal volume. Ketanserin increased CO 2 drive to breathing and DOI caused the opposite response, both acting on tidal volume. The current results provide evidence of increased 5-HT release during hypercapnia in the LC and that 5-HT presents an inhibitory modulation of the stimulatory role of LC on hypercapnic ventilatory response, acting through postsynaptic 5-HT 2A receptors in this nucleus. In addition, hypercapnic responses seem to be also regulated by presynaptic 5-HT 1A receptors in the LC.

Disclosure: A.C. Campideli-Santana: None. K.S. da Costa Silva: None. R. Araújo-Lopes: None. L.M. Antunes: None. R.E. Szawka: None. Kisspeptin is a powerful stimulator neuropeptide in the hypothalamus-pituitary-gonadal axis and is essential for fertility. Neurons in the arcuate nucleus (ARC) of the hypothalamus that coexpress kisspeptin, neurokinin B, and dynorphin (KNDy) play a crucial role in the control of luteinizing hormone (LH) secretion, but the neuroendocrine mechanisms involved in this regulation are not fully understood. Our previous study demonstrated that the moderate loss of KNDy neurons amplifies the LH surge induced by estradiol in ovariectomized rats (1). The current study aimed to perform a longitudinal evaluation of female rats in which KNDy neurons were ablated to determine the integrated role of this neuronal population in the control of pulsatile LH secretion. Adult female rats underwent a neurochemical ablation of KNDy neurons via intra-ARC stereotaxic injections of neurokinin-3 receptor agonist conjugated with saporin (NK3-SAP), while control animals received blank-saporin (Control). Estrous cyclicity was monitored over 21 days before and after the stereotaxic surgery. Three weeks after surgery, blood samples (10 µL) were withdrawn from the tail tip at 6-minute intervals for 180 minutes on the day of diestrus. Rats were then ovariectomized and the ovaries were processed for histological analysis. Whole blood LH levels were measured by ELISA and brains were immunohistochemically labeled for neurokinin B in the ARC. NK3-SAP rats bearing a submaximal loss of KNDy neurons (between 55-95%; n = 8) displayed irregular estrous cycles. The ovarian weight and the number of corpora lutea and atretic follicles were unaltered, whereas the number of healthy early antral follicles decreased in NK3-SAP rats. The frequency of LH pulses was increased and both pulse amplitude and mean LH levels were higher in NK3-SAP compared with Control rats. Thus, the submaximal loss of KNDy neurons affects the regularity of estrous cyclicity but does not preclude ovulation, while seems to stimulate the maturation of early antral follicles. Notably, KNDy neuron loss accelerates and amplifies LH pulsatile secretion during the rat estrous cycle. These results suggest a new role for KNDy neurons in restraining the frequency and amplitude of LH pulses in ovary-intact animals, with possible implications in the rate of recruitment of early antral follicles. Reference: Campideli-Santana et al., J Neuroendocrinol. 2022 Nov;34(11):e13204. Support: FAPEMIG, CNPq, CAPES, and Pro-reitoria de Pesquisa-UFMG. Presentation: Friday, June 16, 2023