Vagus nerve stimulation (VNS) is used as therapy for treatment-resistant depression or epilepsy. This study used immunohistochemistry for biomarkers of short-term (c-Fos) and long-term (DFosB) neuronal activation to map regions in brain that are activated by acute (2 h) or chronic (3 weeks) VNS in conscious Sprague-Dawley rats. Electrodes (Cyberonics Inc.) were implanted on the left vagus nerve and 1 week after surgery, stimulation began using parameters employed clinically (one burst of 20 Hz, 250 ms pulse width, 0.25 mA stimulation for 30 s every 5 min). Radio telemetry transmitters were used for monitoring blood pressure, heart rate, activity, and respiratory rate during VNS; neither acute nor chronic VNS significantly affected these parameters. Acute VNS significantly increased c-Fos staining in the nucleus of the solitary tract, paraventricular nucleus of the hypothalamus, parabrachial nucleus, ventral bed nucleus of the stria terminalis, and locus coeruleus but not in the cingulate cortex or dorsal raphe nucleus (DRN). Acute VNS did not affect DFosB staining in any region. Chronic VNS significantly increased DFosB and c-Fos staining bilaterally in each region affected by acute VNS as well as in the cingulate cortex and DRN. Using these stimulation parameters, VNS was tested for antidepressant-like activity using the forced swim test (FST). Both VNS and desipramine significantly decreased immobility in the FST; whereas desipramine decreased immobility by increasing climbing behavior, VNS did so by increasing swimming behavior. This study, then, identified potential sites in brain where VNS may produce its clinical effects.

Chronic intermittent hypoxia (CIH) models repetitive bouts of arterial hypoxemia that occur in humans suffering from obstructive sleep apnea. CIH has been linked to persistent activation of arterial chemoreceptors and the renin-angiotensin system, which have been linked to chronic elevations of sympathetic nerve activity (SNA) and mean arterial pressure (MAP). Because Fos and FosB are transcription factors involved in activator protein (AP)-1 driven central nervous system neuronal adaptations, this study determined if CIH causes increased Fos or FosB staining in brain regions that regulate SNA and autonomic function. Male Sprague Dawley rats were instrumented with telemetry transmitters for continuous recording of MAP and heart rate (HR). Rats were exposed to continuous normoxia (CON) or to CIH for 8 h/day for 7 days. CIH increased MAP by 7-10 mmHg without persistently affecting HR. A separate group of rats was killed 1 day after 7 days of CIH for immunohistochemistry. CIH did not increase Fos staining in any brain region examined. Staining for FosB/ΔFosB was increased in the organum vasculosum of the lamina terminalis (CON: 9 ± 1; CIH: 34 ± 3 cells/section), subfornical organ (CON: 7 ± 2; CIH: 31 ± 3), median preoptic nucleus (CON 15 ± 1; CIH: 38 ± 3), nucleus of the solitary tract (CON: 9 ± 2; CIH: 28 ± 4), A5 (CON: 3 ± 1; CIH: 10 ± 1), and rostral ventrolateral medulla (CON: 5 ± 1; CIH: 17 ± 2). In the paraventricular nucleus, FosB/ΔFosB staining was located mainly in the dorsal and medial parvocellular subnuclei. CIH did not increase FosB/ΔFosB staining in caudal ventrolateral medulla or supraoptic nucleus. These data indicate that CIH induces an increase in FosB/ΔFosB in autonomic nuclei and suggest that AP-1 transcriptional regulation may contribute to stable adaptive changes that support chronically elevated SNA.

The arterial chemoreceptors play an important role in the reflex regulation of blood pressure and respiration. To investigate the initial integration of chemoreceptor inputs within the central nervous system, intracellular recordings were obtained in pentobarbital-anesthetized, paralyzed, and mechanically ventilated cats, from 58 cells within the nucleus of the tractus solitarius (NTS) that were depolarized by activation of the ipsilateral carotid body chemoreceptors. Close arterial injection of less than 100 microliters CO2-saturated bicarbonate evoked depolarizations of membrane potential with amplitudes of 2.2-4.6 mV and durations of 1.8-6.7 s in 46 cells. In 12 cells, activation of the carotid body chemoreceptors evoked a depolarization-hyperpolarization sequence. Electrical stimulation of the carotid sinus nerve (500 microA, 0.2 ms) evoked EPSPs [mean latency 6.4 +/- 0.5 (SE) ms; range 2.1-18.4 ms] in 46 cells and EPSP-IPSPs (7.3 +/- 0.8 ms; range 4.2-12.4 ms) in 12 cells. The distribution of EPSP latencies exhibited two peaks, one in the 2- to 4-ms range and another in the 7- to 8-ms range. Twenty-nine chemoreceptive cells were tested for the presence of convergent inputs from the ipsilateral carotid sinus baroreceptors. No evidence was found of a convergent postsynaptic inhibitory input from the baroreceptors within the NTS; however, seven cells were found that received an excitatory input from the baroreceptors. The observation that NTS neurons do not integrate chemoreceptor afferent inputs in a homogeneous manner suggests that the multiplicity of NTS unit responses might be related to the specific reflex function of an individual cell (e.g., vagal or sympathetic outflow, respiration).(ABSTRACT TRUNCATED AT 250 WORDS)

1. In pentobarbitone-anaesthetized cats extracellular activity of neurones in the vicinity of the nucleus tractus solitarius receiving inputs from the carotid sinus nerve (SN) and/or vagus nerve (VN) during stimulation of the hypothalamic defence area (HDA) and application of gamma-aminobutyric acid (GABA) and glycine and their antagonists have been studied. 2. A total of forty neurones have been tested, of which twenty-four only had an input from the SN, one only from the VN, twelve from both nerves and three had neither SN or VN inputs. 3. Short trains of stimuli to the HDA inhibited both the ongoing activity (if present) and evoked discharge in thirty-nine of the forty neurones tested. 4. In the forty cells tested ionophoretic application of GABA reduced (4) or totally inhibited (35) neuronal discharge whilst in the thirty-eight tested with glycine discharge was totally (25) or partially (12) suppressed. 5. Ionophoresis of bicuculline totally (14) or partially (6) antagonized the inhibitory actions of GABA in the twenty-five cells tested, and in eighteen of these the ongoing and/or evoked activity was simultaneously increased. In eighteen of the nineteen cells tested this level of bicuculline also antagonized the inhibitory actions of HDA stimuli whereas in none of the sixteen cells tested did it affect glycine-evoked inhibitions. 6. Ionophoretic application of strychnine antagonized the inhibitory effects of glycine in eight of nine cells tested but in these eight cells strychnine had no effect on ongoing or evoked discharges, GABA- or HDA-evoked inhibitions. 7. In a chloralose-anaesthetized cat five neurones receiving SN inputs (three also receiving VN inputs) were recorded. All could be inhibited by HDA stimuli and by application of GABA. In the three of four cells in which bicuculline antagonized GABA inhibitions, the effects of HDA stimuli were simultaneously antagonized whereas glycine-evoked inhibitions were unaffected. 8. In two neurones, in addition to inhibiting neuronal discharge HDA stimulation also evoked activity in the cells. In a further four neurones similar excitatory responses were uncovered when the HDA inhibitory effects were antagonized by bicuculline. 9. The importance of these observations in cardiovascular control and in the functioning of the baroreceptor reflex is discussed.

3. The specificity of the HDA stimulation was investigated by generalized

No abstract

Abstract-Intermittent hypoxia is used to mimic the arterial hypoxemia that occurs during sleep apnea. The present study examined the blood pressure and heart rate responses to exposure to intermittent hypoxia in male rats and in female rats before and after ovariectomy. Rats were instrumented with telemetry transmitters and blood pressure, heart rate, and activity measured during 7 days of exposure to intermittent hypoxia (3 minutes of normoxia [21% oxygen] alternating with 3 minutes 10% oxygen between 8 AM and 4 PM, remainder of day at normoxia). Blood pressure increased in males, females, and ovariectomized females in response to 7 days of intermittent hypoxia during the hours of exposure to hypoxia. Blood pressure increased less in intact females (average change in blood pressure 1.6Ϯ0.6 mm Hg, nϭ11) than in females studied after ovariectomy (5.1Ϯ1.1 mm Hg, nϭ6) or males (5.4Ϯ1.0 mm Hg, nϭ10). This elevated blood pressure persisted throughout the remainder of the day when the animals were not exposed to intermittent hypoxia and remained significantly attenuated in female rats. Ovariectomy abolished the protection against the elevated blood pressure response to intermittent hypoxia in females. Heart rate increased only in males, and only during the period of the day associated with intermittent hypoxia. Female rats were protected against this tachycardia independent of the ovarian hormones. These results indicate that females are protected from the hypertensive and tachycardia effects of intermittent hypoxia. Key Words: blood pressure Ⅲ heart rate Ⅲ sleep apnea syndromes S leep apnea is a significant health problem in the US. Whether of central or peripheral (obstructive) origin, periodic cessation of ventilation during sleep is associated with increased arterial pressure 1 and elevated sympathetic nerve discharge 2 during waking hours. There is also gender specificity in the incidence of sleep apnea. Premenopausal women have a lower occurrence of sleep apnea, whereas in postmenopausal women the incidence is the same as in males. [3][4][5] Even though premenopausal women have a lower incidence of sleep apnea, they do experience sleep apnea; however, whether blood pressure increases in young women with sleep apnea is unknown.Intermittent hypoxia (IH) is used to model the arterial hypoxemia that occurs during sleep apnea. In both animals and humans, repetitive exposures to hypoxia increase blood pressure 6 -9 and sympathetic nerve discharge. 10,11 However, all of these studies have been performed in males. In light of the evidence that premenopausal women and ovary-intact female animals exhibit reduced responses to a variety of sympatho-excitatory stimuli, we hypothesized that female rats exposed to episodes of intermittent hypoxia will be protected against the associated hypertension, and this protection will be dependent on circulating female sex hormones. The goal of the present study was to compare the cardiovascular responses to intermittent exposure in male, female, and ovariectomized female rats. Methods ...

This brief review summarizes recent electrophysiological studies concerning the initial processing of cardiovascular afferent inputs within the central nervous system. This work has shown that the site of termination of baroreceptor afferent fibers, the nucleus of the tractus solitarius (nTS), is much more than a simple relay station. Interactions between afferent inputs from different reflexogenic areas and interactions that depend on the timing of the afferent inputs can influence the output of nTS neurons in either an inhibitory or facilitatory manner and thereby determine the signal that these neurons relay to subsequent central nuclei involved in cardiovascular regulation. In addition, descending inputs from more rostral structures (e.g., the hypothalamic defense area and the parabrachial nucleus) can further alter the responsiveness of nTS neurons to baroreceptor inputs. The evidence suggests that the neural substrates exist for a modulation of baroreflex gain at an early stage in the reflex pathway.