Autonomic Substrates of the Response to Pups in Male Prairie Voles

Caregiving by nonparents (alloparenting) and fathers is a defining aspect of human social behavior, yet this phenomenon is rare among mammals. Male prairie voles (Microtus ochrogaster) spontaneously exhibit high levels of alloparental care, even in the absence of reproductive experience. In previous studies, exposure to a pup was selectively associated with increased activity in oxytocin and vasopressin neurons along with decreased plasma corticosterone. In the present study, physiological, pharmacological and neuroanatomical methods were used to explore the autonomic and behavioral consequences of exposing male prairie voles to a pup. Reproductively naïve, adult male prairie voles were implanted with radiotransmitters used for recording ECG, temperature and activity. Males responded with a sustained increase in heart-rate during pup exposure. This prolonged increase in heart rate was not explained by novelty, locomotion or thermoregulation. Although heart rate was elevated during pup exposure, respiratory sinus arrhythmia (RSA) did not differ between these males and males exposed to control stimuli indicating that vagal inhibition of the heart was maintained. Blockade of beta-adrenergic receptors with atenolol abolished the pup-induced heart rate increase, implicating sympathetic activity in the pup-induced increase in heart rate. Blockade of vagal input to the heart delayed the males’ approach to the pup. Increased activity in brainstem autonomic regulatory nuclei was also observed in males exposed to pups. Together, these findings suggest that exposure to a pup activates both vagal and sympathetic systems. This unique physiological state (i.e. increased sympathetic excitation of the heart, while maintaining some vagal cardiac tone) associated with male caregiving behavior may allow males to both nurture and protect infants

The measurement of central nervous system peptides via chronic microdialysis as a function of social environment in the WHHL rabbit

Our laboratory previously has shown that Watanabe Heritable Hyperlipidemic (WHHL) rabbits exposed to a stable social environment exhibited more affiliative social behavior and less aortic atherosclerosis compared to other social groups. Additional data suggests that central oxytocin (OXT) may be related to the expression of affiliative behavior and attenuation of peripheral stress responses. The purpose of this study is to examine central OXT responses and peripheral catecholamine and glucocorticoid responses during manipulations of the WHHL rabbit\u27s social environment.Canulae implanted dorsal to the hypothalamic paraventricular nucleus (PVN) allowed chronic sampling via microdialysis. Rabbits were assigned to 1 of 3 social groups: an unstable group, with unfamiliar rabbits paired daily and pairings switched weekly; a stable group; with the same littermates remaining paired the entire study; and an individually caged group. Dialysates from the PVN and blood from the marginal ear vein were collected weekly from rabbits following 2-hours of exposure to their respective social condition. Dialysate was assayed for CNS OXT; plasma OXT, AVP, catecholamines and glucocorticoids also were measured.Mean changes (pre- post-pairing) in central OXT levels did not differ between the Stable group and the Unstable group following initial pairings. In contrast, hypothalamic OXT increased significantly in the Unstable group, but was relatively unchanged in the Stable group after 3 weeks of daily pairings. Because the Unstable group exhibited more agonistic behaviors and continued to exhibit hormonal stress responses on day 22, these results imply central OXT is a stress-sensitive neuropeptide. Interestingly, the Unstable group exhibited more atherosclerotic lesion area in the aortic arch than the other groups. Further analysis examined CNS OXT, peripheral OXT, AVP, catecholamines and glucocorticoids and their relation to specific social behaviors. CNS OXT was shown to correlate with corticosterone and to be inversely related to OXT and AVP found in the systemic blood supply. These data may further our knowledge of mechanisms underlying complex social behavior and its relationship to progression of atherosclerosis. Supported by NIH grants HL 36588 and HL 04726

Social experience influences hypothalamic oxytocin in the WHHL rabbit

Social experience influences behavior and the progression of atherosclerosis in the Watanabe Heritable Hyperlipidemic (WHHL) rabbit, such that WHHL rabbits exposed to a consistent, stable social experience exhibited more affiliative social behavior and less aortic atherosclerosis compared to other social groups. Oxytocin (OT) has been implicated in the expression of social behavior, stress responses, and may provide a mechanism by which social experience influences atherogenesis in WHHL rabbits. The current study examined acute and chronic changes in central and peripheral OT before and after WHHL rabbits were exposed to one of three social conditions. Cannula implanted adjacent to the hypothalamic paraventricular nucleus (PVN) allowed chronic sampling of extracellular OT concentration via microdialysis. Rabbits were exposed to one of three social conditions: an Unstable group, with initially unfamiliar rabbits paired daily for 4 h during the initial week and similarly paired with a different, unfamiliar rabbit each week; a Stable group; with the same 2 littermates paired daily for 4 h the entire study; and an Individually Caged group. Dialysates from the PVN and blood from the marginal ear vein were collected twice, 20 days apart, from rabbits before and after 2 h of exposure to their respective social condition. Dialysates were assayed for OT and plasma was assayed for OT, catecholamines and glucocorticoids. There were no changes in PVN OT in any group following the initial social experience. In contrast, after 20 consecutive days of exposure to their respective social condition, PVN OT increased significantly in the Unstable group, but was relatively unchanged in the Stable group following the social experience on day 22. Peripheral OT was not altered in any group following the 2 h social experience on day 1 or 22. The concentration of peripheral OT was the highest in the Stable group at all times. The Stable group also exhibited significantly less aortic atherosclerosis, consistent with earlier findings from our laboratory. Data from the present study suggest that the type of social experience WHHL rabbits are exposed influences PVN OT, social behavior and the progression of atherosclerosis in the WHHL rabbit model of disease

The effect of social environment on markers of vascular oxidative stress and inflammation in the Watanabe heritable hyperlipidemic rabbit

Previous research demonstrated that social environment can influence progression of atherosclerosis in the Watanabe Heritable Hyperlipidemic (WHHL) rabbit. This study examined the effect of social environment on markers of oxidative stress and inflammation to clarify the physiological pathways potentially responsible for the influence of social environment on disease. WHHL rabbits were assigned to 1 of 3 social groups: an unstable group, in which unfamiliar rabbits were paired daily, with the pairing switched each week; a stable group, in which littermates were paired daily; and an individually-caged group. The stable group engaged in more affiliative social behavior than the unstable group. The unstable group showed more agonistic behavior compared with the stable group and higher C-reactive protein levels than the individually caged group. The individually caged group was behaviorally sedentary, had higher 24-hour urinary catecholamine levels than the other groups, and exhibited higher NAD(P)H-oxidase activity in the aortic arch relative to the stable group. The results suggest that social environment creates distinct behavioral contexts that can affect markers of inflammation and oxidative stress early in the development of atherosclerosis. Specifically, physical inactivity associated with individual caging affects indices of oxidative stress and inflammation. These pathophysiological markers may help to explain behaviorally related differences in the extent of atherosclerosis observed in prior studies

The cardiovascular response to a pup does not readily habituate.

<p>(<b>A</b>) Heart rate during interaction with a pup did not differ during repeated pup exposures (1st three bars) or during prolonged pup exposure (4th bar) (p>0.05). Time was collapsed across the 10 minutes of each condition (baseline, divided cage, united with pup) to yield a main effect of condition on heart rate (<b>B</b>), no effect on activity (<b>C</b>) and a trend towards an effect on RSA (<b>D</b>) (p>0.05). * indicates p<0.05 in comparison to both other conditions.</p

Pharmacological manipulations illustrate the contributions of the sympathetic and parasympathetic branches of the autonomic nervous system.

<p>(<b>A</b>) Atenolol (8 mg/kg, i.p.) blocked the pup-induced heart rate increase, with main effects of time and treatment. * indicates the effect of treatment, such that the saline treatment produced a higher heart rate than the atenolol treatment. (<b>B</b>) Atropine (4 mg/kg, i.p.) delayed initial approach to the pup. * indicates p<0.05.</p

Respiratory sinus arrhythmia (RSA) is maintained and heart rate increased during alloparental behavior which is not explained by locomotor activity.

<p>(<b>A</b>) Heart rate during exposure to social (pup, female) and non-social (dowel) stimuli yielded main effects of stimulus and time, with the pup condition generally highest. (<b>B</b>) The correlation between heart rate and RSA during exposure was highest in the pup condition. (<b>C</b>) There were no effects on RSA other than a main effect of time. (<b>D</b>) Locomotor activity yielded main effects of stimulus and time as well as an interaction between stimulus and time. * indicates the effect of stimulus, such that both the dowel and female stimuli were significantly different than the pup condition (p<0.05), # difference significant only between the female and pup groups (p<0.05).</p

c-Fos activity is higher in brainstem autonomic nuclei related to parasympathetic function (A).

<p>Mean c-Fos optical density (+/− SEM) in the dorsal motor nucleus of the vagus (DMX), nucleus ambiguus (NA), nucleus tractus solitarius (NTS), and rostral ventrolateral medulla (RVLM) following exposure to either a dowel (gray) or pup (blue). † indicates p<0.1 * indicates p<0.05. Representative photomicrographs at 4× magnification (<b>B</b>).</p

Autonomic Substrates of the Response to Pups in Male Prairie Voles

Caregiving by nonparents (alloparenting) and fathers is a defining aspect of human social behavior, yet this phenomenon is rare among mammals. Male prairie voles (Microtus ochrogaster) spontaneously exhibit high levels of alloparental care, even in the absence of reproductive experience. In previous studies, exposure to a pup was selectively associated with increased activity in oxytocin and vasopressin neurons along with decreased plasma corticosterone. In the present study, physiological, pharmacological and neuroanatomical methods were used to explore the autonomic and behavioral consequences of exposing male prairie voles to a pup. Reproductively naïve, adult male prairie voles were implanted with radiotransmitters used for recording ECG, temperature and activity. Males responded with a sustained increase in heart-rate during pup exposure. This prolonged increase in heart rate was not explained by novelty, locomotion or thermoregulation. Although heart rate was elevated during pup exposure, respiratory sinus arrhythmia (RSA) did not differ between these males and males exposed to control stimuli indicating that vagal inhibition of the heart was maintained. Blockade of beta-adrenergic receptors with atenolol abolished the pup-induced heart rate increase, implicating sympathetic activity in the pup-induced increase in heart rate. Blockade of vagal input to the heart delayed the males’ approach to the pup. Increased activity in brainstem autonomic regulatory nuclei was also observed in males exposed to pups. Together, these findings suggest that exposure to a pup activates both vagal and sympathetic systems. This unique physiological state (i.e. increased sympathetic excitation of the heart, while maintaining some vagal cardiac tone) associated with male caregiving behavior may allow males to both nurture and protect infants