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.

Taken together, these data show that Htr3a deletion promotes SSRI efficacy and prevents the occurrence of stress-induced deleterious effects, suggesting that the 5-HT receptor may represent an interesting target for the treatment of stress-related disorders.

Female Wistar rats were instrumented to record bladder pressure and to stimulate the left pelvic nerve. Repeated voids were induced by continuous infusion of saline into the bladder (11.2 ml/h) via a T-piece in the line to the bladder catheter. In each animal tested (n = 6) high frequency pelvic nerve stimulation (1–3 kHz, 1–2 mA sinusoidal waveform for 60 s) applied within 2 s of the onset of a sharp rise in bladder pressure signaling an imminent void was able to inhibit micturition. Voiding was modulated in three ways: (1) Suppression of voiding (four rats, n = 13 trials). No fluid output or a very small volume of fluid expelled (<15% of the volume expected based on the mean of the previous 2 or 3 voids). Voiding suppressed for the entirety of the stimulation period (60 s) and resumed within 37 s of stopping stimulation. (2) Void deferred (four rats, n = 6 trials). The imminent void was suppressed (no fluid expelled) but a void occurred later in the stimulation period (12–44 s, mean 24.5 ± 5.2 s after the onset of the stimulation). (3) Reduction in voided volume (five rats, n = 20 trials). Voiding took place but the volume of fluid voided was 15–80% (range 21.8–77.8%, mean 45.3 ± 3.6%) of the volume expected from the mean of the preceding two or three voids. Spontaneous voiding resumed within 5 min of stopping stimulation. Stimulation during the filling phase in between voids had no effect. The experiments demonstrate that conditional high frequency stimulation of the pelvic nerve started at the onset of an imminent void can inhibit voiding. The effect was rapidly reversible and was not accompanied by any adverse behavioral side effects.

peated social defeat in the rat induces long-lasting cardiovascular changes associated with anxiety. In this study, we investigated the effects of repeated social defeat on breathing. Respiratory rate was extracted from the respiratory sinus arrhythmia (RSA) peak frequency of the ECG in rats subjected to social defeat for 4 consecutive days. Respiratory rate was recorded under anesthesia 6 days (Dϩ10) or 26 days (Dϩ30) after social defeat. At Dϩ10, defeated (D) rats spent less time in the open arms of the elevated plus maze test, had heavier adrenal glands, and displayed bradypnea, unlike nondefeated animals. At Dϩ30, all signs of anxiety had disappeared. However, one-half of the rats still displayed bradypnea (D L rats, for low respiratory rate indicated by a lower RSA frequency), whereas those with higher respiratory rate (D H rats) had recovered. Acute blockade of the dorsomedial hypothalamus (DMH) or nucleus tractus solitarii (NTS) 5-HT 3 receptors reversed bradypnea in all D rats at Dϩ10 and in DL rats at Dϩ30. Respiratory rate was also recorded in conscious animals implanted with radiotelemetric ECG probes. DH rats recovered between Dϩ10 and Dϩ18, whereas DL rats remained bradypneic until Dϩ30. In conclusion, social stress induces sustained chronic bradypnea mediated by DMH neurons and NTS 5-HT3 receptors. These changes are associated with an anxiety-like state that persists until Dϩ10, followed by recovery. However, bradypnea may persist in one-half of the population up until Dϩ30, despite apparent recovery of the anxiety-like state.anxiety; breathing; serotonin; social defeat; telemetric recording BREATHING AND ANXIETY ARE intimately related (44). For example, respiratory distress and asphyxia are associated with dreadful feelings, and fear and anxiety can have profound effects on breathing. Clinical studies have shown that panic disorder, characterized by acute and unexpected anxiety attacks and substantial anxiety over the possibility of experiencing further attacks, is associated with symptoms including palpitations, shortness of breath, sweating, and hyperventilation (1). In addition, high levels of anxiety-related behavior in rats are associated with elevation of the resting respiratory rate (9). The respiratory rate also decreases during certain specific responses to stress, for instance during freezing behavior in the rat, when it is associated with ultrasonic vocalizations (19). However, much less is known about the long-term effects of emotional stress on breathing. In adult rats, intense neonatal emotional stress, such as maternal separation, can lead to a decrease in breathing rate during non-rapid-eye-movement sleep (24). A lower respiratory rate was also observed in anesthetized Flinder-Sensitive rats, a well-validated animal model of depression (33). However, respiratory rate does not appear to be altered in patients with major depression, although cardiovascular changes are observed (4). Clearly, more work needs to be done to understand the long-term effects of emotional stress on breathin...

Chronic implantation of cuff electrodes on the pelvic nerve was found to be a well-tolerated procedure in rats and high frequency stimulation did not lead to loss of nerve functionality. Pelvic nerve stimulation has development potential for normalizing voiding dysfunction in conscious rats.

Objectives: High-frequency (kHz) stimulation of preganglionic pelvic nerve afferents can inhibit voiding in both anesthetized and conscious rats. The afferents travel via the S1 sacral nerve root, which is easier to access than the distal pelvic nerve fibers within the abdominal cavity. We therefore investigated whether voiding could be inhibited by high-frequency stimulation at S1 and how this compared to distal pelvic nerve stimulation.Methods: Urethane-anesthetized rats were instrumented to record bladder pressure and abdominal wall electromyogram and to stimulate the distal preganglionic pelvic nerve bundle and S1 sacral root. Saline was infused continuously into the bladder to evoke repeated voiding. Stimulation was initiated within 1-2 sec of the onset of the steep rise in bladder pressure signaling an imminent void.Results: In six rats, stimulation of the distal pelvic nerve bundle (1-3 kHz sinusoidal waveform 1 mA, 60 sec) supressed the occurrence of an imminent void. Voiding resumed within 70 AE 13.0 sec (mean AE SEM) of stopping stimulation. Stimulation (using the same parameters) of the S1 root at the level of the sacral foramen suppressed voiding for the entire stimulation period in three rats and deferred voiding for 35-56 sec (mean 44.0 AE 3.2 sec) in the remaining three. Stimulation at either site when the bladder was approximately half full, as estimated from previous intervoid intervals, had no effect on voiding.Conclusions: This preliminary study provides proof-of-concept for the sacral root as an accessible target for high-frequency stimulation that may be developed as an "on demand" neuromodulation paradigm to suppress unwanted urinary voids.

Recording of breathing frequency is a basic requirement for respiratory physiology. Usual techniques are invasive and constraining. Respiratory sinus arrhythmia (RSA) has recently been demonstrated to be a simple way to obtain respiration frequency at rest. In this study, we investigated whether this correlation is also observed during activity. We first compared RSA to the respiration frequency obtained in anesthetized rats using a pneumotachograph connected to the trachea (TRF). Data analyses using Passing and Bablok regression confirmed the absence of bias and proportional differences. Accordingly, the Bland-Altman plot did not show any significant differences in data sets. In a second experiment, we compared RSA to the respiration frequency obtained in freely moving rats using a subpleurally inserted telemetric catheter (PRF). Comparisons between RSA and PRF revealed no significant difference in determination of respiratory rate with the two methods, although the bias and confidence interval were greater when activity increased. This was, however, not the case during short episodes of sniffing-like tachypnea, during which no matching RSA peaks were observed. In conclusion, RSA frequency reflected regular respiration frequency independently of the level of activity and appears to be a good surrogate to usual techniques.

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