Effects of sleep deprivation on cardiac autonomic and pituitary-adrenocortical stress reactivity in rats.

A demanding life style, often associated with restricted time for sleep, is a growing problem in our society and may become a major health issue in the near future. Since the physiological stress system plays a critical role in coping with a challenge, it is important to know whether this system is affected by sleep loss. Although some information is available concerning the effect of sleep loss on the basal activity of the two main limbs of the stress system, the sympathetic-adrenomedullary (SAM) and the hypothalamic-pituitary-adrenocortical (HPA) axes, little is known about the effect of sleep loss on the subsequent response to a stressor. This study investigated the effects of sleep deprivation on cardiac autonomic and HPA axis (re)activity, under baseline conditions and in response to an acute emotional stressor (15-min of restraint). Rats were subjected to 48 h of sleep deprivation by placing them in slowly rotating wheels. Electrocardiographic recordings were performed via radiotelemetry and autonomic balance was quantified via time-domain indexes of heart rate variability. HPA axis activity was examined by collecting blood samples which were analyzed for plasma ACTH and corticosterone concentrations. The results show that sleep deprivation produced a tonic increase of heart rate and HPA axis activity. When the animals in a state of sleep debt were exposed to an acute restraint stress, a blunted parasympathetic antagonism was observed following sympathetic activation, together with an increased susceptibility to cardiac arrhythmias. The HPA axis response to restraint stress was also altered, but while pituitary ACTH response was attenuated, adrenal corticosterone release was unchanged, indicating an increased adrenocortical sensitivity to ACTH. The data show that sleep deprivation not only affects the baseline activity of the stress system, but it also alters its response to a subsequent stressor.

Individual differences in cardiovascular response to social challenge.

An important determinant of cardiovascular stress reactivity and morbidity is the individual behavioral strategy of coping with social challenge. This review summarizes the results of a number of studies that we performed in rats, aimed at investigating the relationship between aggression and cardiovascular responsivity under social stress conditions. We show that rats belonging to the 'aggressive tail' of a population are characterized by a higher sympathetic-adrenomedullary activation during social and non-social stress episodes. Wild-type rats are characterized by a larger sympathetic dominance and a higher susceptibility to cardiac arrhythmias during defeat as compared to Wistars. Cardiovascular habituation takes place when social challenge is an intermittent victory experience, whereas no habituation is observed across repeated defeat episodes. Dominant rats whose social dominance is challenged by the aggression of another subject display long-term alterations of heart rate circadian rhythmicity. Such changes are linked to individual proness to defend social dominance: the more the animal counterattacks the aggressor, the smaller the subsequent rhythm disturbance. These data underline how important it is to carefully consider individual differences in aggression and the context in which aggression is expressed, when studying cardiovascular effects of social interactions.

Behavioural, neural and cardiovascular adaptations in mice lacking the NPY Y1 receptor.

Neuropeptide Y (NPY) is primarily synthesised and released by neurones, it is co-localised with noradrenaline and is involved in the regulation of cardiovascular function. In a mouse model lacking NPY Y1 receptor (KO), the ability of NPY to potentiate noradrenaline-induced vasoconstriction is abolished during stress but normal in baseline conditions, locomotor activity and metabolic rate are lowered, blood insulin levels and glucose storage activity are increased. The present study was aimed at further characterising NPY Y1 mutants, with special emphasis on: behavioural responses to novelty seeking and open-field with objects tests, heart rate responsiveness during acute social defeat, alpha2-adrenoceptor (alpha2-ARs) function in brain areas involved in cardiovascular regulation, and cardiac structure. As compared to wild-type controls (n=9), NPY Y1 KOs (n=9) showed: reduced somatomotor activation during non-social challenges, lower heart rate in baseline conditions, larger heart rate responsiveness during social defeat, increased number of alpha2-ARs in the dorsal motor nucleus of the vagus (nX) and the locus coeruleus (LC), moderately larger volume fraction of myocardial fibrosis. The remarkable increment of alpha2-adrenoceptor density in the nX and LC allows to view KO mice behavioural and anatomo-physiological peripheral characteristics as 'adaptations' to central adrenergic rearrangement due to NPY Y1 receptor deletion.

Effects of chronic psychosocial stress on cardiac autonomic responsiveness and myocardial structure in mice.

Repeated single exposures to social stressors induce robust shifts of cardiac sympathovagal balance toward sympathetic dominance both during and after each agonistic interaction. However, little evidence is available regarding possible persistent pathophysiological changes due to chronic social challenge. In this study, male CD-1 mice (n = 14) were implanted with a radiotelemetry system for electrocardiographic recordings. We assessed the effects of chronic psychosocial stress (15-day sensory contact with a dominant animal and daily 5-min defeat episodes) on 1) sympathovagal responsiveness to each defeat episode, as measured via time-domain indexes of heart rate variability (R-R interval, standard deviation of R-R interval, and root mean square of successive R-R interval differences), 2) circadian rhythmicity of heart rate across the chronic challenge (night phase, day phase, and rhythm amplitude values), and 3) amount of myocardial structural damage (volume fraction, density, and extension of fibrosis). This study indicated that there was habituation of acute cardiac autonomic responsiveness, i.e., the shift of sympathovagal balance toward sympathetic dominance was significantly reduced across repeated defeat episodes. Moreover, animals exhibited significant changes in heart rate rhythmicity, i.e., increments in day and night values and reductions in the rhythm amplitude, but these were limited to the first 5 days of chronic psychosocial stress. The volume fraction of fibrosis was sixfold larger than in control animals, because of the appearance of many microscopic scarrings. In summary, although mice appeared to adapt to chronic psychosocial stress in terms of acute cardiovascular responsiveness and heart rate rhythmicity, structural alterations occurred at the myocardial level.

Chronic psychosocial stress persistently alters autonomic function and physical activity in mice.

We investigated heart rate (HR), temperature (T), and physical activity (Act) (by means of radiotelemetry) in male mice subjected to chronic psychosocial stress. Resident/intruder dyads lived in sensory contact for 15 days with the possibility to physically interact daily during the light phase for a maximum of 15 min. Intruders becoming dominants (InD) or subordinates (InS) were investigated here. The aims were to investigate; if a daily aggressive interaction would result in adaptation of autonomic responses; the effects of the social stress on daily rhythmicity and the way these effects change over time; whether acute and long-term autonomic changes do correlate; to compare dominants and subordinates. InD and InS showed a strong autonomic activation during the interactions, with moderate (InS) or no (InD) habituation over time. On the long term, InD showed tachycardia and marked hyperthermia but normal physical activity, while InS showed tachycardia, slight hyperthermia, and depressed physical activity. No correlation emerged between the acute and the long-term autonomic responses. These results highlight the existence of a sustained autonomic activation under chronic stress, which was also affected by mice social status.

Cardiac autonomic reactivity and salivary cortisol in men and women exposed to social stressors: relationship with individual ethological profile.

The degree of cardiovascular stress responsivity and its possible implications for the onset and progression of cardiovascular pathologies seem to be linked to the individual strategy of behavioral coping with stressors. This study was designed to investigate the relationship among cardiac autonomic, endocrine and behavioral responses to real-life stress episodes. Thirty university students were exposed to two brief social challenges (stress interviews), during which the state of sympathovagal balance (time-domain indexes of heart rate variability) and a number of non-verbal behaviors were quantified. Psychometric measurements were also obtained via SPRAS questionnaire, administered just after each stress interview. Samples of saliva were collected for cortisol determination immediately prior and after the experimental session. Subjects showing higher levels of sympathetic dominance were characterized by higher scores of submissive behavior, larger cortisol increments, and higher perception of psychophysiological arousal. A clear consistency in the individual response to the two stress interviews was found, at the behavioral, physiological and psychophysiological level. Finally, the gender of the subjects did not clearly influence their stress responsivity. These results support the hypothesis of a close relationship between the degree of physiological arousal and the style of behavioral adaptation to social stressors.

Intermittent exposure to social defeat and open-field test in rats: acute and long-term effects on ECG, body temperature and physical activity.

This study investigated the effects of exposure to an intermittent homotypic stressor on: (i) habituation of acute autonomic responsivity (i.e. cardiac sympathovagal balance and susceptibility to arrhythmias), and (ii) circadian rhythmicity of heart rate, body temperature, and physical activity. After implantation of a transmitter for the radiotelemetric recording of electrocardiogram (ECG), body temperature and physical activity, adult male rats (Rattus norvegicus, Wild Type Groningen strain) were repeatedly exposed (10 consecutive times, on alternate days) to either a social stressor (defeat by a con-specific, n = 15) or an open-field, control challenge (transfer to a new cage; n = 8). ECGs, body temperature and physical activity were continuously recorded in baseline, test and recovery periods (each lasting 15 min), at the 1st and 10th episodes of both defeat and open-field challenge. The circadian rhythms of heart rate, body temperature and physical activity were monitored before (5 days), during (16 days) and after (21 days) the intermittent stress protocol. This study indicates that there is no clear habituation of either acute cardiac autonomic responsivity (as estimated by means of time-domain indexes of heart rate variability) or arrhythmia occurrence to a brief, intermittent, homotypic challenge, regardless of the nature of the stressor (social or non-social). On the other hand, rats exposed to social challenge also failed to show adaptation of acute temperature and activity stress responsiveness, whereas rats facing open-field challenge developed habituation of activity and sensitization of temperature responses. Repeated social challenge produced remarkable reductions of the heart rate circadian rhythm amplitude (this effect being significantly greater than that produced by intermittent open-field), but only minor changes in the daily rhythms of body temperature and physical activity.