許多流行病學統計及研究指出，規律性運動可以降低罹患心血管疾病的風險。下視丘前區的室旁核 ( PVN ) 可以透過神經及賀爾蒙路徑來調控心血管反應，其中在神經路徑的調控上包括興奮性的麩氨酸 ( glutamate ) 以及抑制性的γ-胺基丁酸 ( GABA ) 和一氧化氮 ( NO )。已知大鼠經過長期跑步機運動訓練後，會透過增強下視丘GABA活性來降低心跳與血壓。跑步機及滾輪為現今兩種常用的實驗動物運動模式，而滾輪運動對下視丘調控心血管反應的影響卻是未知的。因此，本實驗欲探討八周自主性滾輪運動訓練對大鼠平靜狀態時及面臨束縛型壓力時心血管反應的影響。五周齡的Wistar大白鼠隨機分成控制組及運動組，利用壓力感測器植入大鼠體內取得即時的心血管參數。除此之外，也分離下視丘前區及後區蛋白質來量化GABA相關蛋白質 ( 一氧化氮合成酶：nNOS、麩胺酸脫羧酵素67：GAD67及抑制性離子通道受器聚合蛋白：gephyrin ) 的表現量。結果顯示自運動滿第二周起運動組平均體重顯著低於控制組，經過八周自主性滾動訓練後，並沒有改善運動組在平靜狀態下的心跳、血壓、自律神經活性及感壓接受器反應活性，除此之外，在面臨束縛型壓力所引起的心血管反應也是無差異的。利用相關係數分析運動組平均跑步距離與心血管參數發現，運動距離與心跳血壓呈現負相關，與脈搏壓則呈現正相關。本篇研究證實，長期自主式滾輪運動並沒有增強大鼠下視丘的GABA系統，且對於平靜及面臨壓力時的心血管表現改善也不大。在下視丘調控心血管方面而言，滾輪運動並不像跑步機運動，對於下視丘調控心血管方面的影響是較小的。

Generally speaking, physical exercise is associated with reduced risk of cardiovascular disease. Hypothalamic paraventricular nucleus (PVN) plays an important role in regulating cardiovascular responses via neuronal and hormonal pathways. The synaptic control of the PVN involves excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) and nitric oxide. Recent results from our laboratory indicated that chronic treadmill running in rats induced hypothalamic adaptations to reset the resting HR/BP to lower levels. Since treadmill running and wheel running are the two most common used animal exercise models, whether and how wheel running exerts similar cardiovascular effects are unknown. In this study, we investigated the effects of eight weeks voluntary wheel running on resting HR/BP and on stress-induced cardiovascular responses in conscious rats. A telemetric probe was inserted into the abdominal aorta of certain animals to monitor their cardiovascular performances real time under resting or immobilization-stressed conditions. In addition, hypothalamic tissues were obtained for quantifying the amount of GABA system-related proteins (such as GAD67, nNOS, and gephyrin). The results showed that since exercise for 2 weeks, exercise group had lower body weight gain than sedentary group. Eight weeks wheel running apparently did not change the resting HR, BP, autonomic nerve activity, baroreceptor reflex sensitivity and hypothalamic GABA system-related protein expression, nor did it ameliorate the immobilization stress-evoked cardiovascular responses. Pearson correlation showed that the running distance were negative correlation with resting HR/BP and positive correlation with pulse pressure. These results indicated that wheel running unlike treadmill running, might exert only minimal effects on the hypothalamic control of cardiovascular performances.

1. Richter, E.A., et al., Muscle glucose metabolism following exercise in the rat: increased sensitivity to insulin. J Clin Invest, 1982. 69(4): p. 785-93.
2. Wannamethee, S.G. and A.G. Shaper, Physical activity in the prevention of cardiovascular disease: an epidemiological perspective. Sports Med, 2001. 31(2): p. 101-14.
3. Metkus, T.S., Jr., K.L. Baughman, and P.D. Thompson, Exercise prescription and primary prevention of cardiovascular disease. Circulation, 2010. 121(23): p. 2601-4.
4. Guyenet, P.G., The sympathetic control of blood pressure. Nat Rev Neurosci, 2006. 7(5): p. 335-46.
5. Manyam, N.V., et al., Levels of gamma-aminobutyric acid in cerebrospinal fluid in various neurologic disorders. Arch Neurol, 1980. 37(6): p. 352-5.
6. Kosel, M., et al., Diminished GABA(A) receptor-binding capacity and a DNA base substitution in a patient with treatment-resistant depression and anxiety. Neuropsychopharmacology, 2004. 29(2): p. 347-50.
7. Bu, D.F., et al., Two human glutamate decarboxylases, 65-kDa GAD and 67-kDa GAD, are each encoded by a single gene. Proc Natl Acad Sci U S A, 1992. 89(6): p. 2115-9.
8. Martin, D.L. and K. Rimvall, Regulation of gamma-aminobutyric acid synthesis in the brain. J Neurochem, 1993. 60(2): p. 395-407.
9. Waagepetersen, H.S., U. Sonnewald, and A. Schousboe, The GABA paradox: multiple roles as metabolite, neurotransmitter, and neurodifferentiative agent. J Neurochem, 1999. 73(4): p. 1335-42.
10. Antonaccio, M.J., L. Kerwin, and D.G. Taylor, Reductions in blood pressure, heart rate and renal sympathetic nerve discharge in cats after the central administration of muscimol, a GABA agonist. Neuropharmacology, 1978. 17(10): p. 783-91.
11. Martin, D.S., T. Segura, and J.R. Haywood, Cardiovascular responses to bicuculline in the paraventricular nucleus of the rat. Hypertension, 1991. 18(1): p. 48-55.
12. Zhang, K. and K.P. Patel, Effect of nitric oxide within the paraventricular nucleus on renal sympathetic nerve discharge: role of GABA. Am J Physiol, 1998. 275(3 Pt 2): p. R728-34.
13. Fritschy, J.M., Epilepsy, E/I Balance and GABA(A) Receptor Plasticity. Front Mol Neurosci, 2008. 1: p. 5.
14. Yu, W., et al., Gephyrin clustering is required for the stability of GABAergic synapses. Mol Cell Neurosci, 2007. 36(4): p. 484-500.
15. Pickering, T.G., Mental stress as a causal factor in the development of hypertension and cardiovascular disease. Curr Hypertens Rep, 2001. 3(3): p. 249-54.
16. Dampney, R.A., et al., Central mechanisms underlying short- and long-term regulation of the cardiovascular system. Clin Exp Pharmacol Physiol, 2002. 29(4): p. 261-8.
17. Bullitt, E., et al., The effect of stimulus duration on noxious-stimulus induced c-fos expression in the rodent spinal cord. Brain Res, 1992. 580(1-2): p. 172-9.
18. Zangenehpour, S. and A. Chaudhuri, Differential induction and decay curves of c-fos and zif268 revealed through dual activity maps. Brain Res Mol Brain Res, 2002. 109(1-2): p. 221-5.
19. Melia, K.R., et al., Induction and habituation of immediate early gene expression in rat brain by acute and repeated restraint stress. J Neurosci, 1994. 14(10): p. 5929-38.
20. Lino-de-Oliveira, C., et al., Effects of acute and chronic fluoxetine treatments on restraint stress-induced Fos expression. Brain Res Bull, 2001. 55(6): p. 747-54.
21. Cullinan, W.E., et al., Pattern and time course of immediate early gene expression in rat brain following acute stress. Neuroscience, 1995. 64(2): p. 477-505.
22. Chowdhury, G.M., T. Fujioka, and S. Nakamura, Induction and adaptation of Fos expression in the rat brain by two types of acute restraint stress. Brain Res Bull, 2000. 52(3): p. 171-82.
23. DiCarlo, S.E., et al., Daily exercise normalizes the number of diaphorase (NOS) positive neurons in the hypothalamus of hypertensive rats. Brain Res, 2002. 955(1-2): p. 153-60.
24. Kramer, J.M., et al., Chronic exercise alters caudal hypothalamic regulation of the cardiovascular system in hypertensive rats. Am J Physiol Regul Integr Comp Physiol, 2001. 280(2): p. R389-97.
25. Beatty, J.A., et al., Physical exercise decreases neuronal activity in the posterior hypothalamic area of spontaneously hypertensive rats. J Appl Physiol, 2005. 98(2): p. 572-8.
26. Zheng, H., et al., Exercise training improves endogenous nitric oxide mechanisms within the paraventricular nucleus in rats with heart failure. Am J Physiol Heart Circ Physiol, 2005. 288(5): p. H2332-41.
27. Nelson, A.J., et al., Neuroplastic adaptations to exercise: neuronal remodeling in cardiorespiratory and locomotor areas. J Appl Physiol, 2005. 99(6): p. 2312-22.
28. Nelson, A.J., et al., Effects of exercise training on dendritic morphology in the cardiorespiratory and locomotor centers of the mature rat brain. J Appl Physiol, 2010. 108(6): p. 1582-90.
29. Nelson, A.J. and G.A. Iwamoto, Reversibility of exercise-induced dendritic attenuation in brain cardiorespiratory and locomotor areas following exercise detraining. J Appl Physiol, 2006. 101(4): p. 1243-51.
30. Liu, Y.F., et al., Differential effects of treadmill running and wheel running on spatial or aversive learning and memory: roles of amygdalar brain-derived neurotrophic factor and synaptotagmin I. J Physiol, 2009. 587(Pt 13): p. 3221-31.
31. Stranahan, A.M., K. Lee, and M.P. Mattson, Central mechanisms of HPA axis regulation by voluntary exercise. Neuromolecular Med, 2008. 10(2): p. 118-27.
32. Kuo, T.B. and S.H. Chan, Continuous, on-line, real-time spectral analysis of systemic arterial pressure signals. Am J Physiol, 1993. 264(6 Pt 2): p. H2208-13.
33. Cerutti, C., et al., Autonomic nervous system and cardiovascular variability in rats: a spectral analysis approach. Am J Physiol, 1991. 261(4 Pt 2): p. H1292-9.
34. Moraska, A., et al., Treadmill running produces both positive and negative physiological adaptations in Sprague-Dawley rats. American Journal of Physiology-Regulatory Integrative and Comparative Physiology, 2000. 279(4): p. R1321-R1329.
35. Maestroni, G.J., A. Conti, and W. Pierpaoli, Role of the pineal gland in immunity. Circadian synthesis and release of melatonin modulates the antibody response and antagonizes the immunosuppressive effect of corticosterone. J Neuroimmunol, 1986. 13(1): p. 19-30.
36. Noble, E.G., et al., Differential expression of stress proteins in rat myocardium after free wheel or treadmill run training. J Appl Physiol, 1999. 86(5): p. 1696-701.
37. Korner, P.I., J.B. Uther, and S.W. White, Circulatory effects of chloralose-urethane and sodium pentobarbitone anaesthesis in the rabbit. J Physiol, 1968. 199(2): p. 253-65.
38. Korner, P.I., et al., The effects of chloralose-urethane and sodium pentobarbitone anaesthesia on the local and autonomic components of the circulatory response to arterial hypoxia. J Physiol, 1968. 199(2): p. 283-302.
39. Morris, C., et al., Anaesthesia in haemodynamically compromised emergency patients: does ketamine represent the best choice of induction agent? Anaesthesia, 2009. 64(5): p. 532-9.
40. Neukirchen, M. and P. Kienbaum, Sympathetic nervous system: evaluation and importance for clinical general anesthesia. Anesthesiology, 2008. 109(6): p. 1113-31.
41. Kienbaum, P., et al., S(+)-ketamine increases muscle sympathetic activity and maintains the neural response to hypotensive challenges in humans. Anesthesiology, 2001. 94(2): p. 252-8.
42. Tucker, B.J., et al., Analysis of adrenergic effects of the anesthetics Inactin and alpha-chloralose. Am J Physiol, 1982. 243(3): p. F253-9.
43. Chen, C.Y., S.E. DiCarlo, and T.J. Scislo, Daily spontaneous running attenuated the central gain of the arterial baroreflex. Am J Physiol, 1995. 268(2 Pt 2): p. H662-9.
44. Collins, H.L. and S.E. DiCarlo, Daily exercise attenuates the sympathetic component of the arterial baroreflex control of heart rate. Am J Physiol, 1997. 273(6 Pt 2): p. H2613-9.
45. Morimoto, K., et al., Spontaneous wheel running attenuates cardiovascular responses to stress in rats. Pflugers Arch, 2000. 440(2): p. 216-22.
46. Ahlgren, J.K. and L.F. Hayward, Daily voluntary exercise alters the cardiovascular response to hemorrhage in conscious male rats. Auton Neurosci, 2011. 160(1-2): p. 42-52.
47. Campeau, S., et al., Hypothalamic pituitary adrenal axis responses to low-intensity stressors are reduced after voluntary wheel running in rats. J Neuroendocrinol, 2010. 22(8): p. 872-88.
48. Fediuc, S., J.E. Campbell, and M.C. Riddell, Effect of voluntary wheel running on circadian corticosterone release and on HPA axis responsiveness to restraint stress in Sprague-Dawley rats. J Appl Physiol, 2006. 100(6): p. 1867-75.
49. Droste, S.K., et al., Voluntary exercise impacts on the rat hypothalamic-pituitary-adrenocortical axis mainly at the adrenal level. Neuroendocrinology, 2007. 86(1): p. 26-37.
50. Droste, S.K., et al., Effects of long-term voluntary exercise on the mouse hypothalamic-pituitary-adrenocortical axis. Endocrinology, 2003. 144(7): p. 3012-23.
51. Dishman, R.K., et al., Activity-Wheel Running Attenuates Suppression of Natural-Killer-Cell Activity after Footshock. Journal of Applied Physiology, 1995. 78(4): p. 1547-1554.
52. Droste, S.K., et al., Effects of long-term voluntary exercise on the mouse hypothalamic-pituitary-adrenocortical axis. Endocrinology, 2003. 144(7): p. 3012-3023.
53. Dishman, R.K., et al., Activity wheel running blunts increased plasma adrenocorticotrophin (ACTH) after footshock and cage-switch stress. Physiology & Behavior, 1998. 63(5): p. 911-917.
54. Neddens, J. and A. Buonanno, Selective populations of hippocampal interneurons express ErbB4 and their number and distribution is altered in ErbB4 knockout mice. Hippocampus, 2010. 20(6): p. 724-44.
55. Doron, G. and K. Rosenblum, c-Fos expression is elevated in GABAergic interneurons of the gustatory cortex following novel taste learning. Neurobiol Learn Mem, 2010. 94(1): p. 21-9.
56. Esclapez, M., et al., Comparative localization of two forms of glutamic acid decarboxylase and their mRNAs in rat brain supports the concept of functional differences between the forms. J Neurosci, 1994. 14(3 Pt 2): p. 1834-55.
57. Wu, L.A., et al., Activation of GABAergic neurons following tooth pulp stimulation. J Dent Res, 2010. 89(5): p. 532-6.
58. Bali, B., et al., Visualization of stress-responsive inhibitory circuits in the GAD65-eGFP transgenic mice. Neurosci Lett, 2005. 380(1-2): p. 60-5.
59. Hentges, S.T., et al., Proopiomelanocortin expression in both GABA and glutamate neurons. J Neurosci, 2009. 29(43): p. 13684-90.
60. Yang, Y., et al., Intrastriatal manganese chloride exposure causes acute locomotor impairment as well as partial activation of substantia nigra GABAergic neurons. Environ Toxicol Pharmacol, 2011. 31(1): p. 171-8.
61. Gardiner, S.M. and T. Bennett, The effects of short-term isolation on systolic blood pressure and heart rate in rats. Med Biol, 1977. 55(6): p. 325-9.
62. Naranjo, J.R. and J.A. Fuentes, Association between hypoalgesia and hypertension in rats after short-term isolation. Neuropharmacology, 1985. 24(2): p. 167-71.
63. Shen, S. and A.J. Ingenito, Comparison of cardiovascular responses to intra-hippocampal mu, delta and kappa opioid agonists in spontaneously hypertensive rats and isolation-induced hypertensive rats. J Hypertens, 1999. 17(4): p. 497-505.
64. Gardiner, S.M., T. Bennett, and P.A. Kemp, Systemic arterial hypertension in rats exposed to short-term isolation; intra-arterial systolic and diastolic blood pressure and baroreflex sensitivity. Med Biol, 1980. 58(4): p. 232-9.
65. Sharp, J.L., et al., Stress-like responses to common procedures in male rats housed alone or with other rats. Contemp Top Lab Anim Sci, 2002. 41(4): p. 8-14.
66. Stranahan, A.M., D. Khalil, and E. Gould, Social isolation delays the positive effects of running on adult neurogenesis. Nat Neurosci, 2006. 9(4): p. 526-33.