Department of Environmental Health, Life Science and Human Technology, Nara Women s University, Kita-Uoya Nishimachi, Nara , Japan

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1 56 Exp Physiol 95.1 pp Experimental Physiology Symposium Reports Role of differential changes in sympathetic nerve activity in the preparatory adjustments of cardiovascular functions during freezing behaviour in rats Kenju Miki and Misa Yoshimoto Department of Environmental Health, Life Science and Human Technology, Nara Women s University, Kita-Uoya Nishimachi, Nara , Japan Freezing behaviour is associated with a distinct pattern of changes in cardiovascular function, which has been considered as a preparatory reflex for fight or flight behaviour. However, the detailed mechanisms underlying preparatory cardiovascular adjustments and their physiological implications have received less attention. We studied responses in renal and lumbar sympathetic nerve activity and cardiovascular function during freezing behaviour in conscious rats, which was induced by exposure to loud white noise. Freezing behaviour was associated with regionally specific alterations in sympathetic nerve activity, in that renal sympathetic nerve activity increased while lumbar sympathetic nerve activity did not change. Moreover, freezing behaviour was associated with differential shifts in baroreflex control of sympathetic outflows, which could help to explain the selective responses in renal and lumbar sympathetic nerve activity during freezing behaviour. These differential changes in sympathetic outflows would result in a visceral vasoconstriction without having any impact on the skeletal muscle vasculature. These cardiovascular adjustments during freezing behaviour may help to explain the immediate and massive increase in muscular blood flow that occurs at the onset of fight or flight behaviour. It is hypothesized that central command originating from the defence area could somehow modulate separate baroreflex pathways, causing differential changes in sympathetic nerve activity to generate the preparatory cardiovascular adjustments during the freezing behaviour. (Received 11 August 2009; accepted after revision 21 August 2009; first published online 21 August 2009) Corresponding author K. Miki: Department of Environmental Health, Life Science and Human Technology, Nara Women s University, Kita-Uoya Nishimachi, Nara , Japan. k.miki@cc.nara-wu.ac.jp Defensive behaviour is an essential mechanism in the survival process in animals and humans (Hilton, 1982; Schenberg et al. 2005). Survival depends on the ability to make an immediate response to a threatening or dangerous situation which has to be successful and is critically important to animals because the cost of an inadequate defence may be injury or death. Defensive behaviour can be divided into two classes depending on the nature of the stress. The first class is where an animal has information about a threat or predator and has previous experience of dealing with the stress, in which case an animal shows the fight or flight response. The second class is where an animal has no information or previous experience of the stress, or faces a predator which the animal recognizes that it cannot overcome, and the animal would rather take negative behaviour. In this case, the animal remains motionless in an apparent attempt to escape detection by the predator, which is so-called freezing behaviour (Schadt & Hasser, 2004). The freezing action also functions as a prolonged alerting response to a novel situation in the environment and contributes towards saving energy. These defensive behavioural actions are associated with a distinct change in the pattern of cardiovascular function (Hilton, 1982). The sympathetic nerves play an important role in mediating the rapid cardiovascular responses to stress, and their involvement in fight or flight behaviour has been extensively studied. The fight or flight response has generally been considered to result in increases in sympathetic outflows in a uniform and global fashion, leading to elevations in heart rate and systemic arterial pressure (Hilton, 1982). However, the way in which sympathetic nerve outflow is organized during freezing behaviour has received less attention, and the aim of this DOI: /expphysiol

2 Exp Physiol 95.1 pp Sympathetic nerve activity during freezing behaviour 57 article is to review the neural mechanisms underlying cardiovascular adjustments during freezing behaviour. Differential changes in sympathetic outflows during freezing behaviour Freezing behaviour alters almost the entire range of cardiovascular function. Thus, while systemic arterial pressure remains unchanged, there have been consistent reports of a decrease or no change in heart rate and cardiac output (Schadt & Hasser, 1998, 2004), accompanied by visceral vasoconstriction (Hilton, 1982). These data suggest that visceral vasoconstriction may cause an increase in total peripheral resistance, which may be offset by a reduction in cardiac output, with the end result that systemic arterial pressure remains unchanged during the freezing period. The cardiovascular responses observed during freezing behaviour could well be explained by a differential change in sympathetic outflows. Renal sympathetic nerve activity increases immediately after the onset of freezing behaviour in conscious rats, and this increase is sustained throughout the period of freezing (Miki et al. 2009). The step increase in renal sympathetic nerve activity would lead to an increase in renal vascular resistance, since we had previously reported that there was a significant inverse linear relationship between renal sympathetic nerve activity and renal vascular conductance (Yoshimoto et al. 2004). We would speculate that the response observed in renal vascular resistance during the freezing behaviour might be extrapolated to that of the visceral vasculature and resistance, although there are no data reporting changes in splanchnic sympathetic nerve activity during freezing behaviour at present. It is therefore likely that freezing behaviour evokes an immediate and sustained increase in renal and possibly splanchnic sympathetic nerve activity, resulting in an increase in renal and splanchnic vascular resistance. By contrast, we have also observed that lumbar sympathetic nerve activity remained unchanged during freezing behaviour (Miki et al. 2009). A significant inverse relationship has been reported between lumbar sympathetic nerve activity and iliac vascular conductance in conscious rats (Miki et al. 2004). These findings are supported by the report of Halliwill et al. (1997) in humans, showing that there was a significant inverse linear relationship between muscle sympathetic nerve activity from the radial nerve and forearm vascular conductance during mental stress. These data suggest that sympathetic nerve activity exerts relatively little influence on the muscle vasculature during freezing behaviour because lumbar sympathetic nerve activity remained unchanged during freezing behaviour. Bradycardia has been consistently reported during freezing (Schadt & Hasser, 1998, 2004) and indeed, we also observed that freezing behaviour was associated with an immediate and sustained reduction in heart rate, suggesting that cardiac output may decrease during freezing. No direct recordings of cardiac sympathetic and vagal activity during freezing behaviour are available at present. However, Carrive (2006) has provided indirect evidence showing that both cardiac sympathetic and vagal activity are strongly activated during freezing behaviour in rats. Together, these pieces of evidence would suggest that sympathetic nerve activity is regulated in a regionally different manner during freezing behaviour. This would allow selective vasoconstriction in the visceral organs with little influence on the muscle vascular resistance. Moreover, heart rate seems to be modulated differently during freezing behaviour. Thus, the pattern of changes in sympathetic nerve activity appears to act in concert to regulate the visceral organs, the muscles and the heart, in a regionally directed manner, which could orchestrate the preparatory cardiovascular adjustments for the whole body during freezing behaviour. The cardiovascular changes may represent readiness for fight or flight behaviour Freezing behaviour has been recognized as a preparatory reflex for active defence actions, i.e. fight or flight. The following discussion considers how the sympathetic nervous system contributes to generating preparatory adjustments of cardiovascular functions. We should begin by evaluating the responses of the cardiovascular and sympathetic nervous systems during fight or flight (Hilton, 1982; Squire, 2003; Schenberg et al. 2005). To fight or take flight, almost the entire skeletal muscle mass should be recruited, causing an abrupt and massive increase in metabolic rate as a consequence of the contracting muscle. To meet the oxygen demand for the rapid increase in muscle metabolic rate, there will be an increase in muscle blood flow caused by a vasodilatation of the muscular vasculature. Two major adjustments will take place to maintain systemic arterial pressure in the face of such a massive vasodilatation at the onset of fight or flight, namely: (1) an increase in cardiac output; and (2) redistribution of blood flow from visceral organs to the actively contracting muscle. The global increase in sympathetic nerve activity may play a critical role in the increase in cardiac output, owing to its chronotropic and inotropic effects on the heart, and vasoconstriction of the visceral organs and non-contracting muscle. In this way, systemic arterial pressure may be maintained at a higher level during the fight or flight response. Freezing behaviour is associated with well-organized cardiovascular adjustments to prepare for fight or flight. Immediate behavioural and cardiovascular responses are essential to either fight against or escape from

3 58 K. Miki and M. Yoshimoto Exp Physiol 95.1 pp the threat or danger. The cardiovascular responses during freezing behaviour have two significant features. Firstly, sympathetic outflows innervating the kidney and the splanchnic organs are likely to be selectively activated during freezing behaviour, resulting in visceral vasoconstriction without any influence on the muscular vasculature. Thus, the preparatory vasoconstriction in the visceral organs could minimize the time lag for redistribution of blood flow from the visceral organs to the actively contracting muscle during the transition from freezing to fight or flight. Secondly, the reduction in heart rate induced by freezing behaviour could offset the increase in total peripheral resistance caused by visceral vasoconstriction. Indeed, the hypokinetic state of the heart may result in conserving energy in the heart muscle, which could be used for the immediate increase in cardiac function required at the transition from freezing to the active state. It is therefore likely that the haemodynamic alterations during freezing may represent readiness for an active action but at a minimal energy cost to the animal. Acute shifts in baroreflex control of sympathetic outflows The baroreflex is a negative feedback loop that controls systemic arterial pressure by modulating the degree of sympathetic nerve activity. During fight or flight, systemic arterial pressure, heart rate and sympathetic nerve activity are all increased simultaneously, which could not be explained by a single baroreflex curve. Early studies indicated that the arterial baroreflex was inhibited during fight or flight, allowing simultaneous increases in systemic arterial pressure and sympathetic nerve activity (Coote et al. 1979). However, there has been accumulating data showing that the arterial baroreflex is reset/shifted acutely (Miki et al. 2003; Nagura et al. 2004). Indeed, stimulation of the hypothalamic defence area has been shown to reset baroreflex control of renal sympathetic nerve activity and heart rate (McDowall et al. 2006). Unfortunately, we are not aware of any attempts to generate baroreflex function curves during fight or flight behaviour in conscious states. However, in a somewhat different state, i.e. during exercise, similar concomitant increases in systemic arterial pressure, heart rate and sympathetic nerve activity have been observed. We have shown previously that the baroreflex response curve for renal sympathetic nerve activity is shifted acutely to right and upwards after the onset of treadmill exercise in rats (Miki et al. 2003). It is therefore likely that acute shifts in baroreflex control of sympathetic nerve activity and heart rate might occur during fight or flight behaviour, allowing concomitant increases in systemic arterial pressure, sympathetic nerve activity and heart rate during active defensive reactions. Figure 1. Hypothesis explaining differential regulation by sympathetic outflows by central command during freezing behaviour Baroreflex pathways may be somehow discretely separated in the brain. Central command originated from the activation of the defence area could modulate the baroreflex pathways in a regionally different manner, allowing differential changes in sympathetic nerve activity during freezing behaviour. Abbreviations: RSNA, renal sympathetic nerve activity; LSNA, lumbar sympathetic nerve activity; and HR, heart rate.

4 Exp Physiol 95.1 pp Sympathetic nerve activity during freezing behaviour 59 Could the arterial baroreflex explain the differential changes in sympathetic nerve activity observed during freezing behaviour? We attempted to generate baroreflex curves for renal and lumbar sympathetic nerve activity and heart rate when conscious animals exhibited this frozen state (Miki et al. 2009). We found that freezing behaviour was associated with differential shifts in baroreflex control of renal and lumbar sympathetic nerve activity; the baroreflex curve for renal sympathetic nerve activity was shifted upwards, while there was no change in the baroreflex curve for lumbar sympathetic nerve activity. It has been suggested that there may exist discrete subgroups of neuronal networks within the baroreflex pathway, allowing differential modification of the baroreflex control of selected sympathetic nerve outputs (Polson et al. 2007). This view agrees well with the reports that microinjection of angiotensin II (Polson et al. 2007) and adenosine (Scislo et al. 2008) modulated sympathetic nerve activity in a regionally specific manner in acutely prepared rats. Role of central command in generating differential changes in sympathetic outflows during freezing behaviour It has been suggested that central command and afferent inputs originating from the mechano- and chemoreceptors in muscle play a dominant role in regulating sympathetic outflows during daily activity, including exercise (Rowell, 1986). Since the electromyogram remained unchanged during freezing behaviour (M. Yoshimoto, K. Nagata & K. Miki, unpublished observation), the contribution of afferent inputs originating from the muscle to regulate sympathetic nerve activity during freeing may be small, possibly negligible. Thus, central command is most likely to play a major role in generating differential changes in sympathetic nerve activity during freezing behaviour. Figure 1 illustrates our hypothesis on the differential regulation of sympathetic outflows. Central command originating from activation of the defence area could modulate baroreflex pathways in a regionally specific manner. This could result in acute shifts in the baroreflex curve for renal sympathetic nerve activity, while exerting no influence on the baroreflex curve for lumbar sympathetic nerve activity. If this occurred, it could help explain the fact that renal sympathetic nerve activity increased while lumbar sympathetic nerve activity remained constant with no changes in arterial pressure during freezing behaviour, as shown in Fig. 1. In this way, cardiovascular function seems to be tactically organized by central command during freezing behaviour to prepare for the active actions required to deal with the threatening fight or flight situation. The behavioural and cardiovascular responses displayed during freezing behaviour have been thought to possess a high degree of comparability with those occurring in man reflecting normal human fear and apprehension (De Boer & Koolhaas, 2003). It is possible to speculate that central activation caused by fear and anxiety might initiate the preparatory reflexes in cardiovascular function for active avoidance, which may be related to the pathogenesis of cardiovascular reactivity and disorders associated with prolonged exposure to fear and anxiety (Vitaliano et al. 1993) in humans. References Carrive P (2006). Dual activation of cardiac sympathetic and parasympathetic components during conditioned fear to context in the rat. 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