Abstract
The periaqueductal gray (PAG) is a midbrain structure directly involved in the modulation of defensive behaviors. It has direct projections to several central nuclei that are involved in cardiorespiratory control. Although PAG stimulation is known to elicit respiratory responses, the role of the PAG in the CO2-drive to breathe is still unknown. The present study assessed the effect of chemical lesion of the dorsolateral and dorsomedial and ventrolateral/lateral PAG (dlPAG, dmPAG, and vPAG, respectively) on cardiorespiratory and thermal responses to hypercapnia. Ibotenic acid (IBO) or vehicle (PBS, Sham group) was injected into the dlPAG, dmPAG, or vPAG of male Wistar rats. Rats with lesions outside the dlPAG, dmPAG, or vPAG were considered as negative controls (NC). Pulmonary ventilation (Ve), mean arterial pressure (MAP), heart rate (HR), and body temperature (Tb) were measured in unanesthetized rats during normocapnia and hypercapnic exposure (5, 15, 30 min, 7 % CO2). IBO lesioning of the dlPAG/dmPAG caused 31 % and 26.5 % reductions of the respiratory response to CO2 (1,094.3 ± 115 mL/kg/min) compared with Sham (1,589.5 ± 88.1 mL/kg/min) and NC groups (1,488.2 ± 47.7 mL/kg/min), respectively. IBO lesioning of the vPAG caused 26.6 % and 21 % reductions of CO2 hyperpnea (1,215.3 ± 108.6 mL/kg/min) compared with Sham (1,657.3 ± 173.9 mL/kg/min) and NC groups (1,537.6 ± 59.3). Basal Ve, MAP, HR, and Tb were not affected by dlPAG, dmPAG, or vPAG lesioning. The results suggest that dlPAG, dmPAG, and vPAG modulate hypercapnic ventilatory responses in rats but do not affect MAP, HR, or Tb regulation in resting conditions or during hypercapnia.
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References
Ballantyne D, Scheid P (2001) Central chemosensitivity of respiration: a brief overview. Respir Physiol 129(1–2):5–12
Bandler R, Keay KA (1996) Columnar organization in the midbrain periaqueductal gray and integration of emotional expression. Prog Brain Res 107:285–300
Bandler R, Shipley MT (1994) Columnar organization in the midbrain periaqueductal gray: modules for emotional expression? Trends Neurosci 17(11):379–389
Bandler R, Tork I (1987) Midbrain periaqueductal grey region in the cat has afferent and efferent connections with solitary tract nuclei. Neurosci Lett 74(1):1–6
Bandler R, Carrive P, Zhang SP (1991) Integration of somatic and autonomic reactions within the midbrain periaqueductal grey: viscerotopic, somatotopic and functional organization. Prog Brain Res 87:269–305
Bandler R, Keay KA, Floyd N, Price J (2000) Central circuits mediating patterned autonomic activity during active vs. passive emotional coping. Brain Res Bull 53(1):95–104
Barros RC, Abe AS, Cárnio EC, Branco LG (2004) Regulation of breathing and body temperature of a burrowing rodent during hypoxic-hypercapnia. Comp Biochem Physiol A Mol Integr Physiol 138(1):97–104
Bassal M, Bianchi AL (1982) Inspiratory onset or termination induced by electrical stimulation of the brain. Respir Physiol 50(1):23–40
Behbehani MM (1995) Functional characteristics of the midbrain periaqueductal gray. Prog Neurobiol 46(6):575–605
Beitz AJ (1990) Central gray. In: Paxinos G, Mai JK (eds) The human nervous system, 1st edn. Academic Press, San Diego, pp 307–320
Biancardi V, Bícego KC, Almeida MC, Gargaglioni LH (2008) Locus coeruleus noradrenergic neurons and CO2 drive to breathing. Pflügers Arch 455(6):1119–1128
Canteras NS, Swanson LW (1992) The dorsal premammillary nucleus: an unusual component of the mammillary body. Proc Nalt Acad Sci USA 89:10089–10093
Carrive P (1993) The periaqueductal gray and defensive behavior: functional representation and neuronal organization. Behav Brain Res 58(1–2):27–47
Carrive P (2000) Conditioned fear to environmental context: cardiovascular and behavioral components in the rat. Brain Res 858(2):440–445
Carrive P, Bandler R (1991) Viscerotopic organization of neurons subserving hypotensive reactions within the midbrain periaqueductal grey: a correlative functional and anatomical study. Brain Res 541(2):206–215
Chen XM, Nishia M, Taniguchia A, Nagashima K, Shibatab M, Kanosue K (2002) The caudal periaqueductal gray participates in the activation of brown adipose tissue in rats. Neurosci Lett 331(1):17–20
Coates EL, Li A, Nattie EE (1993) Widespread sites of brain stem ventilatory chemoreceptors. J Appl Physiol 75(1):5–14
Coles SK, Dick TE (1996) Neurones in the ventrolateral pons are required for post-hypoxic frequency decline in rats. J Physiol 497:79–94
Cunha C, Monfils MH, Ledoux JE (2010) GABA(C) receptors in the lateral amygdala: a possible novel target for the treatment of fear and anxiety disorders? Front Behav Neurosci 4:6
Cunha JM, Zanoveli JM, Ledvinka-Filho E, Brandão ML (2010) l-allylglycine dissociates the neural substrates of fear in the periaqueductal gray of rats. Brain Res Bull 81(4–5):416–423
Da Silva LG, Menezes RC, Santos RA, Campagnole-Santos MJ, Fontes MA (2006) Role of periaqueductal gray on the cardiovascular response evoked by disinhibition of the dorsomedial hypothalamus. Brain Res 984(1–2):206–214
De Carvalho D, Bícego KC, de Castro OW, da Silva GS, Garcia-Cairasco N, Gargaglioni LH (2010) Role of neurokinin-1 expressing neurons in the locus coeruleus on ventilatory and cardiovascular responses to hypercapnia. Respir Physiol Neurobiol 172(1–2):24–31
De Luca MC, Brandão ML, Motta VA, Landeira-Fernandez J (2003) Antinociception induced by stimulation of ventrolateral periaqueductal gray at the freezing threshold is regulated by opioid and 5-HT2A receptors as assessed by the tail-flick and formalin tests. Pharmacol Biochem Behav 75(2):459–466
De Luca-Vinhas MC, Macedo CE, Brandão ML (2006) Pharmacological assessment of the freezing, antinociception, and exploratory behavior organized in the ventrolateral periaqueductal gray. Pain 121(1–2):94–104
De Oliveira ST, de Bortoli VC, Zangrossi H Jr (2011) Serotonin-2A receptor regulation of panic-like behavior in the rat dorsal periaqueductal gray matter: the role of GABA. Psychopharmacology 218(4):725–732
Dean JB, Lawing WL, Millhorn DE (1989) CO2 decreases membrane conductance and depolarizes neurons in the nucleus tractus solitarii. Exp Brain Res 76(3):656–661
Dean P, Redgrave P, Westby GW (1989) Event or emergency? Two response systems in the mammalian superior colliculus. Trends Neurosci 12(4):137–147
Dean JB, Bayliss DA, Erickson JT, Lawing WL, Millhorn DE (1990) Depolarization and stimulation of neurons in nucleus tractus solitarii by carbon dioxide does not require chemical synaptic input. Neuroscience 36(1):207–216
Del-Ben CM, Graeff FG (2009) Panic disorder: is the PAG involved? Neural Plast 108135
Dias MB, Nucci TB, Margatho LO, Antunes-Rodrigues J, Gargaglioni LH, Branco LG (2007) Raphe magnus nucleus is involved in ventilatory but not hypothermic response to CO2. J Appl Physiol 103(5):1780–1788
Feldman JL, Mitchell GS, Nattie EE (2003) Breathing: rhythmicity, plasticity, chemosensitivity. Annu Rev Neurosci 26:239–266
Gargaglioni LH, Coimbra NC, Branco LGS (2002) Chemical lesions of the nucleus isthmi increase the hypoxic and hypercarbic drive to breathing of toads. Respir Physiol Neurobiol 132(3):289–299
Gorman JM, Goetz RR, Fyer M, King DL, Fyer AJ, Liebowitz MR, Klein DF (1988) The mitral valve prolapse–panic disorder connection. Psychosom Med 50(2):114–122
Gorman JM, Kent JM, Sullivan GM, Coplan JD (2000) Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry 157(4):493–505
Graeff FG (2002) On serotonin and experimental anxiety. Psychopharmacology (Berl) 163(3–4):467–476
Graeff FG, Audi EA, Almeida SS, Graeff EO, Hunziker MH (1990) Behavioral effects of 5-HT receptor ligands in the aversive brain stimulation, elevated plus-maze and learned helplessness tests. Neurosci Biobehav Rev 14(4):501–506
Hayward LF, Swartz CL, Davenport PW (2003) Respiratory response to activation or disinhibition of the dorsal periaqueductal gray in rats. J Appl Physiol 94(3):913–922
Heymans C, Bouckaert JJ (1930) Sinus caroticus and respiratory reflexes: I. Cerebral blood flow and respiration. Adrenaline apnoea. J Physiol 69(2):254–266
Hodges MR, Richerson GB (2008) Contributions of 5-HT neurons to respiratory control: neuromodulatory and trophic effects. Respir Physiol Neurobiol 164(1–2):222–232
Hodges MR, Martino P, Davis S, Opansky C, Pan LG, Forster HV (2004) Effects on breathing of focal acidosis at multiple medullary raphe sites in awake goats. J Appl Physiol 97(6):2303–2309
Holstege G (1989) Anatomical study of the final common pathway for vocalization in the cat. J Comp Neurol 284(2):242–252
Holstege G (1991) Descending motor pathways and the spinal motor system: limbic and non-limbic components. Prog Brain Res 87:307–421
Huang ZG, Subramanian SH, Balnave RJ, Turman AB, Chow CM (2000) Roles of periaqueductal gray and nucleus tractus solitaries in cardiorespiratory function in the rat brainstem. Resp Physiol 120(3):185–195
Jenck F, Moreau JL, Martin JR (1995) Dorsal periaqueductal gray-induced aversion as a simulation of panic anxiety: elements of face and predictive validity. Psychiatry Res 57(2):181–191
Keay KA, Redgrave P, Dean P (1988) Cardiovascular and respiratory changes elicited by stimulation of rat superior colliculus. Brain Res Bull 20(1):13–26
Klein DF (1993) Panic disorder with agoraphobia. Br J Psychiatry 163:835–837
Kobayashi Y, Katada A, Myoga H, Sakamoto T (1994) A PHA-L study on the descending pathway for vocalization from the periaqueductal gray to the lower brainstem in cats. Soc Neurosci Abstr 20:1407
Leman S, Dielenberg RA, Carrive P (2003) Effect of dorsal periaqueductal gray lesion on cardiovascular and behavioural responses to contextual conditioned fear in rats. Behav Brain Res 143(2):169–176
Loeschcke HH (1982) Central chemosensitivity and the reaction theory. J Physiol 332:1–24
Lovick TA, Parry DM, Stezhka VV, Lumb BM (2000) Serotoninergic transmission in the periaqueductal gray matter in relation to aversive behaviour: morphological evidence for direct modulatory effects on identified output neurons. Neuroscience 95(3):763–772
Malan A (1973) Ventilation measured by body plethysmography in hibernating mammals and in poikilotherms. Respir Physiol 17(1):32–44
Martino PF, Hodges MR, Davis S, Opansky C, Pan LG, Krause K, Qian B, Forster HV (2006) CO2/H+ chemoreceptors in the cerebellar fastigial nucleus do not uniformly affect breathing of awake goats. J Appl Physiol 101(1):241–248
Menezes RC, Zaretsky DV, Fontes MA, DiMicco JA (2009) Cardiovascular and thermal responses evoked from the periaqueductal grey require neuronal activity in the hypothalamus. J Physiol 587:1201–1215
Mulkey DK, Stornetta RL, Weston MC, Simmons JR, Parker A, Bayliss DA, Guyenet PG (2004) Respiratory control by ventral surface chemoreceptor neurons in rats. Nat Neurosci 7(12):1360–1369
Nakamura K, Morrison SF (2007) Central efferent pathways mediating skin cooling-evoked sympathetic thermogenesis in brown adipose tissue. Am J Physiol Regul Integr Comp Physiol 292(1):R127–R136
Nardi AE, Freire RC, Zin WA (2009) Panic disorder and control of breathing. Respir Physiol Neurobiol 167(1):133–143
Nashold BS Jr, Wilson WP, Slaughter DG (1969) Sensations evoked by stimulation in the midbrain of man. J Neurosurg 30(1):14–24
Nattie E, Li A (2009) Central chemoreception is a complex system function that involves multiple brain stem sites. J Appl Physiol 106(4):1464–1466
Oikawa S, Hirakawa H, Kusakabe T, Nakashima Y, Hayashida Y (2005) Autonomic cardiovascular responses to hypercapnia in conscious rats: the roles of the chemo- and baroreceptors. Auton Neurosci 117(2):105–114
Paxinos G, Watson C (2004) The rat brain in stereotaxic coordinates. Elsevier, New York
Pelosi GG, Tavaresa RF, Fernandesb KBP, Corrêa FMA (2009) Cardiovascular effects of noradrenaline microinjection into the medial part of the superior colliculus of unanesthetized rats. Brain Res 1290:21–27
Pierre D (1981) Principles of comparative respiratory physiology. Elsevier/North-Holland Biomedical Press, New York
Putnam RW, Filosa JA, Ritucci NA (2004) Cellular mechanisms involved in CO2 and acid signaling in chemosensitive neurons. Am J Physiol Cell Physiol 287(6):C1493–C1526
Sakamoto T, Nonaka S, Katada A (1996) Control of respiratory muscles during speech and vocalization. In: Miller AD, Bianchi AL, Bishop BP (eds) Neural control of respiratory muscles, 3rd edn. Boca Raton, Florida, pp 249–258
Sawchenko PE, Swanson LW, Steinbusch HW, Verhofstad AA (1983) The distribution and cells of origin of serotonergic inputs to the paraventricular and supraoptic nuclei of the rat. Brain Res 277(2):355–360
Schenberg LC, Bittencourt AS, Sudré EC, Vargas LC (2001) Modeling panic attacks. Neurosci Biobehav Rev 25(7–8):647–659
Schimitel FG, de Almeida GM, Pitol DN, Armini RS, Tufik S, Schenberg LC (2012) Evidence of a suffocation alarm system within the periaqueductal gray matter of the rat. Neurosci 200:59–73
Sewards TV, Sewards MA (2002) Fear and power-dominance drive motivation neural representations and pathways mediating sensory and mnemonic inputs, and outputs to premotor structures. Neurosci Biobehav Rev 26(5):553–579
Subramanian HH, Holstege G (2009) The nucleus retroambiguus control of respiration. J Neurosci 29(12):3824–3832
Subramanian HH, Chow CM, Balnave RJ (2007) Identification of different types of respiratory neurones in the dorsal brainstem nucleus tractus solitarius of the rat. Brain Res 1141:119–132
Subramanian HH, Balnave RJ, Holstege G (2008) The midbrain periaqueductal gray control of respiration. J Neurosci 28(47):12274–12283
Xin L, Geller EB, Liu-Chen LY, Chen C, Adler MW (1997) Substance P release in the rat periaqueductal gray and preoptic anterior hypothalamus after noxious cold stimulation: effect of selective Mu and Kappa opioid agonists. J Pharmacol Exp Ther 282(2):1055–1063
Zhang W, Hayward LF, Davenport PW (2005) Respiratory muscle responses elicited by dorsal periaqueductal gray stimulation in rats. Am J Physiol Regul Integr Comp Physiol 289(5):R1338–R1347
Zhang W, Hayward LF, Davenport PW (2007) Respiratory responses elicited by rostral versus caudal dorsal periaqueductal gray stimulation in rats. Auton Neurosci 134(1–2):45–54
Acknowledgments
This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), INCT-Fisiologia Comparada. Luana Tenorio Lopes was the recipient of a FAPESP scholarship. We would like to thank Aretuza Capalbo Carregari, Euclides R. Seccato, and Daoud Hibraim Elias Filho for excellent technical assistance.
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Lopes, L.T., Patrone, L.G.A., Bícego, K.C. et al. Periaqueductal gray matter modulates the hypercapnic ventilatory response. Pflugers Arch - Eur J Physiol 464, 155–166 (2012). https://doi.org/10.1007/s00424-012-1119-6
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DOI: https://doi.org/10.1007/s00424-012-1119-6