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Hibernators survive repeated cycles of torpor and arousal during the hibernation season. During torpor, hibernating animals drastically reduce their heart rate, respiratory rate, body temperature, blood flow and oxygen consumption; however, during periodic arousal, this suppressed physiological state rapidly surges and returns to euthermy (Daan, 1991; Waßmer et al., 1997; Fukuhara et al., 2003; 2004).

Exposure of the neonate to episodes of acute hypoxia during birth results in a variety of adaptive changes that include fluid re-absorption and secretion of surfactant in the lungs to promote air breathing (Slotkin and Seidler 1988). These physiological responses depend critically on catecholamine secretion from adrenomedullary chromaffin cells (AMC), which express a direct, developmentally-regulated hypoxia sensing mechanism, independent of the nervous system (Slotkin and Seidler 1988, 1986; Thompson et al., 1997). The hypoxic response in neonatal AMC, as well as their immortalized counterparts (i.e. MAH cells), appears to be mediated via inhibition of O-sensitive K channels, though the signaling pathway is not completely understood (Fearon et al 2002; Thompson et al., 1997). These O2 -sensitive K channels include large conductance Ca-dependent K, i.e. BK or maxi-K, and delayed rectifier K channels (Thompson and Nurse 1998; Thompson et al., 2002). Inhibition of these channels is thought to facilitate membrane depolarization, voltage-gated Ca entry and catecholamine secretion (Thompson et al., 1997; Thompson and Nurse, 1998, 2000).

Control of cellular functions by extracellular signal-induced elevation of intracellular Ca is a common theme in excitable biosystems including the carotid body chemoreception. The Ca-signal is delivered to appropriate intracellular target proteins via phosphorylation catalyzed by multifunctional Ca/calmodulindependent protein kinases (CaM kinases), which are composed of types I, II and IV (Hanson and Schulman, 1992; Sakagami and Kondo, 1998). In order to see how CaM kinases are involved in the chemoreception, the present study examined the localization of CaM kinase I in immuno-light and electron microscopy in the rat carotid body as well as its adjacent superior cervical ganglion. The latter contains SIF (small intensely fluorescent) cells, at least some of which exhibit cytological features including the innervation similar to those of the carotid body chief cells (Kondo, 1977).

The carotid body is the main arterial chemoreceptor that senses oxygen levels in the blood. In mammalian species, the carotid body is localized in the carotid bifurcation and innervated by the carotid sinus nerve consisting of sensory fibers from the glossopharyngeal nerve. The organ also receives the ganglioglomerular nerve issuing from the superior cervical ganglion of sympathetic trunk (Verna, 1979). In the mouse, especially, the carotid body joins with the superior cervical ganglion and is penetrated by nerve bundles derived from the ganglion (Kameda et al., 2002). In contrast to mammalian species, the carotid body of chickens is situated in the cervico-thoracic region together with the thyroid, parathyroid and ultimobranchial glands, which form a continuous series along the common carotid artery. The organ is located between the distal (nodose) ganglion of the vagus nerve and the recurrent laryngeal nerve and supplied richly with their branches (see Kameda, 2002 for references).

The role of the carotid body (CB) in response to hypoxia is very well defined (Fitzgerald and Shirahata, 1997). The hypoxic ventilatory response (HVR) is characterized by an increase in ventilation, but this response remains variable among individuals (Eisele et al., 1992; Vizek et al., 1987; Weil 1970). Genetics may play a critical role in explaining this variability. Indeed, longitudinal and twin studies do demonstrate the role of genetics in the HVR (Collins et al., 1978; Kawakami et al., 1982). Studies utilizing inbred strains of mice have also demonstrated the effect of genetics on the response to hypoxia (Tankersley et al., 1994 & 2000). Two strains of mice in these studies were identified as having extreme responses to hypoxia.

The carotid body is a major chemosensory organ for hypoxia, hypercapnia and acidosis in the arterial blood (Fitzgerald and Shirahata 1997; Gonzalez et al., 1994). During hypoxia, the neural output from the carotid body increases and reflexly modifies several variables in the respiratory system. A prominent response is an increase in ventilation, but the hypoxic ventilatory response (HVR) among individuals varies widely (Eisele et al., 1992; Vizek et al., 1987). Studies in humans (Collins et al., 1978; Kawakami et al., 1982; Nishimura et al., 1991; Thomas et al., 1993) suggest that genetic factors significantly contribute to those differences. Similarly, studies in mice (Tankersley et al., 1994) and rats (Weil et al., 1998) clearly indicate that genetic determinants robustly influenced HVR. Among several inbred strains of mice the DBA/2J mice demonstrated the highest HVR and the A/J mice the lowest HVR (Tankersley et al., 1994). The differences in HVR between these two strains of mice may be closely related to the structural differences of the carotid body (Yamaguchi et al., 2003). The size of the carotid body and the quantity of glomus cells in the DBA/2J mice are significantly larger than those in the A/J mice. Those differences were clearly segregated between the strains, suggesting that genetic factors strongly influence the observed phenotypic differences between the DBA/2J and A/J mice. The purpose of the current study was to confirm that the morphological characteristic differences in the carotid body between the DBA/2J and A/J mice are controlled by genetic factors. Thus, we generated the first-filial progeny (F1) by a crossing the DBA/2J (female) and A/J (male) strains of mice, and examined the morphological differences of the carotid body in the DBA/2J, A/J and their F1 mice.

Peripheral arterial chemoreceptors, within the carotid body (CB), are critical in maintaining respiratory and cardiac hemostasis by uniquely sensing changes in O tension. The components of the peripheral arterial chemoreceptors are found within the CB, but the physiologic effects of activation of these chemoreceptors are widespread and significant (Gonzalez et al., 1994). The CB is located in the bifurcation of the carotid artery and consists of three major neuronal components that include: 1) type I chemosensory cells, also known as glomus cells, which contain neurotransmitters and autoreceptors; 2) type II cells, which are similar to supportive glial cells; and 3) chemoafferent nerve fibers from the carotid sinus nerve, a branch of the IX cranial nerve, with cell bodies in the petrosal ganglion (PG) (Verna 1997).

The development of oxygen chemosensitivity in carotid chemoreceptor cells, i.e. type I cell (glomus cell), is reported to continue postnatally (Wasicko et al., 1999), and it has been suggested that environmental experiences such as episode of hypoxia and chronic hypoxia during critical period of maturation may result in long-term alterations in the structure or function of the respiratory control neural network (Carroll, 2003). In the previous studies, we have observed no apparent effect on the hypoxic ventilatory response (HVR) in the day 7 newborn rats, which had daily episode of anoxia from day 1 to day 6 (day 0 = day of birth) (Saiki and Mortola, 1994), but significantly higher HVR in the 3-weeks-old rats, which had an episode of anoxia on day 3-4 after birth (Saiki and Matsumoto, 1999). These results suggest that the severity of anoxia and the timing of the anoxic episode as well as the assessment of HVR may be important factors, and that an episode of anoxia during the neonatal period has long-lasting effects on the control of ventilation in rats. Because no further information is available on the effects, including carotid body chemoreceptors, we examined whether or not an episode of anoxia in neonatal period induces changes in the carotid body and glomus cell structures in the three-weeks-old rats.

The peripheral arterial chemoreceptors in the carotid body (CB) are the first step in a closed–loop feedback control system that acts to normalize arterial oxygen and carbon dioxide levels by rapidly modulating ventilation. Type I cells in the CB are excitable and contain O - sensitive K channels (Gonzalez et al., 1995; Montoro et al., 1996; Wyatt et al., 1995). Reduction of K conductance in response to hypoxia is the signal that triggers Type I cell depolarization, Ca entry, and secretion of neurotransmitters that bind to receptors on the first order sensory nerve endings of the carotid sinus nerve with cell bodies in the petrosal ganglion {(Gonzalez et al., 1994;Gonzalez et al., 1992). These first order sensory neurons (chemoafferents) project to second order neurons within the nucleus tractus solitarii (nTS), which send projections to the muscles of respiration. While the cascade of molecular and cellular events occurs in multiple CB preparations from multiple mammalian species, key aspects of the cascade are still unknown, particularly identification of the specific oxygen sensor within the Type I cell that initiates the cascade and the specific excitatory neurotransmitter systems that are involved in chemoexcitation. Furthermore, in multiple immature mammalian species, including human infants, hypoxic chemosensitivity matures during the first several weeks of postnatal life. Specific mechanisms mediating that maturation are unknown.

Perinatal adrenal medulla responds to hypoxia by increasing the release of catecholamine (CA) that are responsible for metabolic, cardio-circulatory and respiratory mechanisms crucial to the adaptation to the extrauterine life (3, 11). In neonatal rat, hypoxia elicits directly this secretory response since splachnic innervation of AM is not mature until the second week of postnatal life (10).