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Accumulation of stressful events can render individuals susceptible to develop epilepsy and comorbidities. Whether such vulnerability can be predicted and reversed is not known. Here we show that social defeat, although not producing depression by itself, produced in 50% of rats reduced threshold for status epilepticus (SE), accelerated epileptogenesis, and once epilepsy was induced, depression-like profile and cognitive deficits. Low serum brain-derived neurotrophic factor (BDNF) levels measured before SE identified this vulnerable population. Treatment with a BDNF analog before SE prevented the occurrence of comorbidities. Thus, vulnerability to comorbidities after epilepsy onset due to unresolved past stressful events may be predicted and reversed.

Key points• Anxiety disorders reduce both the heart rate variability (HRV) and the sensitivity of the cardiac baroreflex (BRS). This may lead to sudden cardiac death.• To elucidate the mechanisms underlying these alterations, male rats were subjected to social defeat sessions that lead to an anxiety-like state.• In this model, HRV and BRS were reduced, reflex of a shift of the autonomic balance towards sympathetic predominance.• Pharmacological blockade of the dorsomedial hypothalamus (DMH) reversed all cardiovascular alterations, whereas blockade of the nucleus tractus solitarii (NTS) 5-HT 3 receptor by the local or systemic administration of granisetron restored only baroreflex gains and the parasympathetic component of HRV.• In conclusion, repeated social defeat in the rat leads to an anxiety-like state, in which the DMH and the NTS are chronically activated and are responsible for dysautonomia. These regions may constitute new targets against sudden cardiac death.Abstract Anxiety disorders in humans reduce both the heart rate variability (HRV) and the sensitivity of the cardiac baroreflex (BRS). Both may contribute to sudden death. To elucidate the mechanisms underlying these alterations, male rats were subjected to social defeat sessions on four consecutive days. Five days later, the rats were found to be in an anxiety-like state. At this time point, we analysed HRV and BRS in the defeated rats, with or without treatment with the anxiolytic chlordiazepoxide (CDZ). HRV was reduced after social defeat, due to changes in the autonomic balance favouring the sympathetic over the parasympathetic component. Spontaneous and pharmacological baroreflex gains were also reduced. CDZ abolished anxiety-like symptoms as well as HRV and BRS alterations. Inhibition of the dorsomedial hypothalamus (DMH) with muscimol reversed all cardiovascular alterations, whereas blockade of the nucleus tractus solitarii (NTS) 5-HT 3 receptor by the local or systemic administration of granisetron restored only baroreflex gains and the parasympathetic component of HRV. In conclusion, repeated social defeat in the rat lead to an anxiety-like state that was associated with lasting reduction in HRV and baroreflex gains. The DMH and the NTS were responsible for these chronic cardiovascular alterations. These regions may therefore constitute new therapeutic targets for reducing cardiac dysfunction and fibrillation in anxiety disorders. Abbreviations BP, blood pressure; BRR, cardiac baroreflex response; BRS, baroreflex sensitivity; CDZ, chlordiazepoxide; D, defeated rats; DMH, dorsomedial nucleus of the hypothalamus; GRANI, granisetron; HF, high-frequency domain; HR, heart rate; HRV, heart rate variability; LF, low-frequency domain; MBP, mean blood pressure; MUSC, muscimol; ND, non-defeated rats; NTS, nucleus tractus solitarii; rMSSD, root mean square of successive R-R interval differences; RSA, respiratory sinus arrhythmia; VEH, vehicle.

No abstract

Non-technical summary Defence reactions are physiological responses to imminent danger. They include increased blood pressure and heart rate, and a reduction in the reflex cardiac response to changes in blood pressure. Two regions in the brain, the hypothalamus and the periaqueductal grey area, known to be involved in pathological conditions such as anxiety, are involved in the production of these responses. However, there is no direct connection between those regions. In this study we report that the midbrain cuneiform nucleus links the hypothalamus and periaqueductal grey area. Our findings may explain how anxiety is related to cardiovascular pathologies.Abstract Defence responses triggered experimentally in rats by stimulation of the dorsomedial nucleus of the hypothalamus (DMH) and the dorsolateral periaqueductal grey matter (PAG) inhibit the cardiac baroreflex response (i.e. bradycardia). It has also been proposed that the midbrain cuneiform nucleus (CnF) is involved in active responses. Our aim was to identify the neurocircuitry involved in defence-induced baroreflex inhibition, with a particular focus on the link between DMH, CnF and dorsolateral PAG. Microinjection of the anterograde tracer Phaseolus vulgaris leucoaggutinin into the CnF revealed a dense projection to the dorsolateral PAG. Moreover, activation of neurons in the CnF induced increased expression of Fos protein in the dorsolateral PAG. Inhibition of neurons of the CnF or dorsolateral PAG prevented the inhibition of baroreflex bradycardia induced by DMH or CnF stimulation, respectively. These results provide a detailed description of the brain circuitry underlying acute baroreflex modulation by neurons of the DMH. Our data have shown for the first time that the CnF plays a key role in defence reaction-associated cardiovascular changes; its stimulation, from the DMH, activates the dorsolateral PAG, which, in turn, inhibits baroreflex bradycardia. Abbreviations BP, blood pressure; CnF, cuneiform nucleus; DMH, dorsomedial nucleus of the hypothalamus; HR, heart rate; MBP, mean blood pressure; PAG, periaqueductal grey matter; PHA-L, Phaseolus vulgaris leucoagglutinin; PrCnF, pre-cuneiform nucleus.

The aim of this study was to assess the circadian hormonal profile of two circadian markers, melatonin and cortisol, as well as other steroids in prepubertal boys (Tanner stage I). Nine volunteer healthy prepubertal boys aged 10.8 +/- 0.11 years participated in this study. Concentrations of daily salivary and urinary hormones were quantified around 24-hours, every 3 hours, in daytime samples (collected between 07.00 h +/- 30 min and 21.00 h +/- 30 min) and night-time samples (collected between 21.00 h +/- 30 min and 07.00 h +/- 30 min). Significant differences (p < 0.01) were found between day- and nighttime secretion of salivary melatonin and urinary 6-sulphatoxymelatonin, whereas no significant differences were found between day- and nighttime secretion of salivary and urinary cortisol nor between day- and nighttime secretion of 17-hydroxycorticosteroids (17-OHCS). The circadian profiles of salivary melatonin and cortisol showed large amplitude with a peak occurring at night (approximately 03.00 h) for melatonin and in the early morning (between 06.00 and 09.00 h) for cortisol. The curve patterns of the urinary 6-sulphatoxymelatonin and steroids (free cortisol and 17-OHCS) were coherent with data on saliva. The pattern of salivary androstenedione and testosterone were undetectable due to the very low concentrations of these steroids in the saliva of the prepubertal children. A strong significant positive correlation was observed between the daily salivary melatonin levels and the daily urinary 6-sulphatoxymelatonin excretion (R = 0.968, p < 0.001), and between free urinary cortisol and urinary 17-OHCS (R = 0.733, p = 0.025). The salivary and urinary hormones studied were independent of body mass index. This study shows the relevance of salivary cortisol and melatonin, although lower than in plasma, in testing adrenal and pineal function as markers of circadian rhythms. The data are of interest for the diagnosis and treatment of chronobiological disorders in prepubertal children.

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Because epidemiological studies report clinical disorders (mainly neurobehavioral alterations and/or cancer) that may be related to diminished melatonin secretion or to changes in its circadian rhythm in subjects living or working in environments exposed to magnetic fields, research on the effects of these fields in humans is particularly important. In this study, we examine the circadian rhythm of melatonin in 15 men exposed chronically and daily for a period of 1-20 yr, in the workplace and at home, to a 50-Hz magnetic field in search of any cumulative effect from those chronic conditions of exposure. The weekly geometric mean of individual exposures ranged from 0.1 to 2.6 microT. The results are compared with those for 15 unexposed men who served as controls (individual exposures ranged from 0.004 to 0.092 microT). Blood samples were taken hourly from 2000 to 0800. Nighttime urine was also collected and analyzed. This work shows that subjects exposed over a long period (up to 20 yr) and on a daily basis to magnetic fields experienced no changes in their plasma melatonin level, their urinary 6-sulfatoxymelatonin level, or the circadian rhythm of melatonin. Our data strongly suggest that magnetic fields do not have cumulative effects on melatonin secretion in humans and thus clearly rebut the "melatonin hypothesis" that a decrease in plasma melatonin concentration (or a disruption in its secretion) explains the occurrence of clinical disorders or cancers possibly related to magnetic fields.