高血壓好發於老年人，也是引發心臟、血管疾病的重要因子之一。近幾年研究發現，高血壓也與神經退化性疾病和認知功能下降有關。海馬迴腦區中所產生新的神經細胞(神經新生)，被認為與學習記憶有密切的關係。過去已有研究利用自發性高血壓大鼠，來探討高血壓對於神經新生的影響，獲得的結果並不一致。自發性高血壓被認為是基因突變或多型性的結果，且有報告指出，不同實驗室之自發性高血壓大鼠的背景基因並不相同。另外，血壓之調控已知與下視丘密切相關，而下視丘又與海馬迴互相調控，因此自發性高血壓與海馬迴神經新生之因果關係，無法釐清。為了解決此問題，本研究以相同基因背景的小鼠，以窄化其中一條腎動脈的方式誘發高血壓，再研究高血壓對神經新生與學習記憶的影響。結果顯示，手術後7天，血壓明顯上升(約20%)，並至少持續至手術後60天。比起對照組，手術後1個月，神經新生下降；此一現象在2個月後更為明顯。手術1個月後，利用物件探索測驗(Object recognition test) ，發現小鼠之短期記憶、長期記憶，以及NR-1 、p-GSKα/β皆明顯下降，而p-PI3K、p-AKT、p-p38明顯上升；但是對海馬迴中腦血管的密度、星狀膠細胞與微膠細胞的密度、以及VEGF、p-ERK、p-JNK、BDNF、TrkB、RAGE (receptor for advanced glycation end product)、TNF-α、ICAM (intercellular adhesion molecule 1)、SYT1、SNAP25、SYP的量，皆無影響。綜合以上的結果，我們發現高血壓會導致成年小鼠之海馬迴神經新生與記憶力下降，其中可能受到p-p38發炎路徑而影響，但其詳細機制仍需探討。

Hypertension (HTN), a common disease in the elder people, is associated with increased cardiovascular diseases. HTN has also been linked to neurodegenerative diseases and cognitive impairment in humans. Adult hippocampal neurogenesis is involving in the performance of learning and memory. Several studies using spontaneous hypertensive rats (SHRs) to study the effect of HTN on adult hippocampal neurogenesis have reached inconsistent conclusions. SHRs are selected for high blood pressure from Wistar Kyoto rats. However, after many decades of selection, SHRs in different laboratories are known to have different genetic background. Regulation of blood pressure is intimately associated with hypothalamus which received reciprocal connections from hippocampus. Thus, whether the altered neurogenesis is a result of HTN or different genetic background is unclear. The objective of this study is to examine the effect of HTN on adult hippocampal neurogenesis in the same genetic background animals, B6C3 mice. HTN was induced by 2 kidneys, 1 clip method (2K1C) which coarctated one of the two renal arteries. The results showed that blood pressures of the 2K1C mice were higher than the sham group 7 d after the surgery (about 20%) and remained high up to 60 d after the surgery. One month after the 2K1C surgery, neurogenesis, as determined by the 5-bromo-2’-deoxyuridine and doublecortin double-positive cells number, was lower than that of the sham group, and this phenomenon was more pronounced 2 months after the surgery. 2K1C surgery also decreased the learning and memory ability as determined by non-spatial object recognition test, the level of NR-1 and p-GSKα/β 1 month after the surgery, but increased the level of the p-PI3K、p-AKT、p-p38. However, 2K1C surgery did not alter the blood vessel density, glial cells number, the levels of VEGF/p-ERK, BDNF/TrkB, RAGE, TNF-α, SYT1, SNAP25, SYP in the hippocampi of 2K1C and sham groups. Taken together, this study suggests that HTN reduces adult hippocampal neurogenesis and memory performance may through the p-p38-related pathway, but the detailed mechanism is still unclear.

1.Chobanian, A.V., et al., Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension, 2003. 42(6): p. 1206-52.

2.Kearney, P.M., et al., Global burden of hypertension: analysis of worldwide data. The Lancet, 2005. 365(9455): p. 217-223.

3.Sua, T.-C., Evidence for improved control of hypertension in Taiwan: 1993-2002, in J Hypertens.2008 p. 600-6.

4.Carretero, O.A. and S. Oparil, Essential Hypertension : Part I: Definition and Etiology. Circulation, 2000. 101(3): p. 329-335.

5.Kennelly, S.P., B.A. Lawlor, and R.A. Kenny, Blood pressure and the risk for dementia: a double edged sword. Ageing Res Rev, 2009. 8(2): p. 61-70.

6.Rigaud1, A., et al., Cerebral complications of hypertension. Journal of Human Hypertension, 2000. 14(10-11): p. 605-16.

7.Launer LJ, R.G., Petrovitch H, Masaki K, Foley D, White LR, Havlik RJ., Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging. , 2000. 21(1): p. 49-55.

8.Korf, E.S., et al., Midlife blood pressure and the risk of hippocampal atrophy: the Honolulu Asia Aging Study. Hypertension, 2004. 44(1): p. 29-34.

9.Obisesan, T.O., et al., High blood pressure, hypertension, and high pulse pressure are associated with poorer cognitive function in persons aged 60 and older: the Third National Health and Nutrition Examination Survey. J Am Geriatr Soc, 2008. 56(3): p. 501-9.

10.Longstreth, W.T., Jr., et al., Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study. Stroke, 1996. 27(8): p. 1274-82.

11.Togashi, H., et al., Effects of clonidine and guanfacine on drinking and ambulation in spontaneously hypertensive rats. Pharmacol Biochem Behav, 1982. 17(3): p. 519-22.

12.Ueno, K.I., et al., Behavioural and pharmacological relevance of stroke-prone spontaneously hypertensive rats as an animal model of a developmental disorder. Behav Pharmacol, 2002. 13(1): p. 1-13.

13.Russell, V.A., T. Sagvolden, and E.B. Johansen, Animal models of attention-deficit hyperactivity disorder. Behav Brain Funct, 2005. 1: p. 9.

14.The hippocampus in spontaneously hypertensive rats an animal model of vascular dementia. Mech Ageing Dev., 2002 123(5): p. 547-59.

15.Tomassoni, D., et al., Increased expression of glial fibrillary acidic protein in the brain of spontaneously hypertensive rats. Clin Exp Hypertens, 2004. 26(4): p. 335-50.

16.Pietranera, L., et al., Protective effects of estradiol in the brain of rats with genetic or mineralocorticoid-induced hypertension. Psychoneuroendocrinology, 2008. 33(3): p. 270-81.

17.Pietranera, L., et al., Abnormalities of the hippocampus are similar in deoxycorticosterone acetate-salt hypertensive rats and spontaneously hypertensive rats. J Neuroendocrinol, 2006. 18(6): p. 466-74.

18.Van Praag, H., et al., Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci, 2005. 25(38): p. 8680-5.

19.Altman, J. and G.D. Das, Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol, 1965. 124(3): p. 319-35.

20.Eriksson PS, P.E., Björk-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH., Neurogenesis in the adult human hippocampus. Nat Med., 1998. 4(11): p. 1313-7.

21.Trice, B.B.S.a.J.E., Evidence that granule cells generated in the dentate gyrus of adult rats extend axonal projections. Experimental Brain Research, 1988. 72(2): p. 399-406.

22.Michael Nilsson, E.P., Ulf Johansson, Owe Orwar, and P.S. Eriksson1, Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory. J Neurobiol 1999. 39(4): p. 569-78.

23.Wu CW, C.Y., Yu L, Chen HI, Jen CJ, Wu SY, Lo CP, Kuo YM., Exercise enhances the proliferation of neural stem cells and neurite growth and survival of neuronal progenitor cells in dentate gyrus of middle-aged mice. J Appl Physiol, 2008. 105(5): p. 1585-94.

24.Jin, K., et al., Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci U S A, 2002. 99(18): p. 11946-50.
25.Fournier, N.M., et al., Vascular endothelial growth factor regulates adult hippocampal cell proliferation through MEK/ERK- and PI3K/Akt-dependent signaling. Neuropharmacology, 2012. 63(4): p. 642-52.

26.Campuzano, R., et al., Serum basic fibroblast growth factor levels in exercise-induced myocardial ischemia more likely a marker of endothelial dysfunction than a marker of ischemia? Eur J Med Res, 2002. 7(3): p. 93-7.

27.Trejo JL, C.E., Torres-Aleman I., Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J Neurosci, 2001. 21(5): p. 1628-34.
28.Scharfman, H., et al., Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol, 2005. 192(2): p. 348-56.

29.Frielingsdorf, H., et al., Nerve growth factor promotes survival of new neurons in the adult hippocampus. Neurobiol Dis, 2007. 26(1): p. 47-55.

30.Gould, E., et al., Adrenal steroids regulate postnatal development of the rat dentate gyrus: II. Effects of glucocorticoids and mineralocorticoids on cell birth. J Comp Neurol, 1991. 313(3): p. 486-93.

31.Kempermann, G., L. Wiskott, and F.H. Gage, Functional significance of adult neurogenesis. Curr Opin Neurobiol, 2004. 14(2): p. 186-91.

32.In Koo HWANG, Y.S.Y., Jung Hoon CHOI, Ki-Yeon YOO, Sun Shin YI, Dae Won CHUNG, and C.-S.K. Hyun-Jin KIM, Seon-Gil DO, Je Kyung SEONG, In Se LEE and Moo-Ho WON, Doublecortin-Immunoreactive Neuronal Precursors in the Dentate Gyrus of Spontaneously Hypertensive Rats at Various Age Stages- Comparison with Sprague-Dawley Rats. J Vet Med Sci, 2008. 70(4): p. 373-7.

33.Okamoto, K. and K. Aoki, Development of a strain of spontaneously hypertensive rats. Jpn Circ J, 1963. 27: p. 282-93.

34.Kronenberg, G., A. Lippoldt, and G. Kempermann, Two genetic rat models of arterial hypertension show different mechanisms by which adult hippocampal neurogenesis is increased. Dev Neurosci, 2007. 29(1-2): p. 124-33.

35.Ekaterina Perfilieva, A.R., Jenny Nyberg, Barbro B. Johansson, and and P.S. Eriksson, Gender and Strain Influence on Neurogenesis in Dentate Gyrus. J Cereb Blood Flow Metab., 2001. 21(3): p. 211-7.

36.Pietranera, L., et al., Involvement of brain-derived neurotrophic factor and neurogenesis in oestradiol neuroprotection of the hippocampus of hypertensive rats. J Neuroendocrinol, 2010. 22(10): p. 1082-92.

37.Wiesel, P., et al., Two-kidney, one clip and one-kidney, one clip hypertension in mice. Hypertension, 1997. 29(4): p. 1025-30.

38.John N. Lorenz, V.M.L., Michelle L. Nieman, Thomas Damhoff, Vikram Prasad, and a.J.B.L. William H. Beierwaltes, Renovascular hypertension using a modified two-kidney, one-clip approach. Am J Physiol Renal Physiol, 2011. 301(3): p. F615-21.

39.Intengan, H.D. and E.L. Schiffrin, Vascular Remodeling in Hypertension: Roles of Apoptosis, Inflammation, and Fibrosis. Hypertension, 2001. 38(3): p. 581-587.

40.Carnevale, D., et al., Role of neuroinflammation in hypertension-induced brain amyloid pathology. Neurobiol Aging, 2012. 33(1): p. 205 e19-29.

41.Lu, B., BDNF and activity-dependent synaptic modulation. Learn Mem, 2003. 10(2): p. 86-98.

42.Yamada K, N.T., Brain-Derived Neurotrophic Factor TrkB Signaling in Memory Processes. J Pharmacol Sci., 2003. 91(4): p. 267-70.

43.Voloboueva, L.A. and R.G. Giffard, Inflammation, mitochondria, and the inhibition of adult neurogenesis. J Neurosci Res, 2011. 89(12): p. 1989-96.

44.Haller H, P.J., Dragun D, Lippoldt A, Luft FC., Leukocyte infiltration and ICAM-1 expression in two-kidney one-clip hypertension. Nephrol Dial Transplant, 1997. 12(5): p. 899-903.

45.Carnevale, D., et al., Hypertension induces brain beta-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature. Hypertension, 2012. 60(1): p. 188-97.

46.Soderling, T.R. and V.A. Derkach, Postsynaptic protein phosphorylation and LTP. Trends Neurosci, 2000. 23(2): p. 75-80.

47.Charchar, F.J., M.K. Kapuscinski, and S.B. Harrap, Nerve Growth Factor Gene Locus Explains Elevated Renal Nerve Growth Factor mRNA in Young Spontaneously Hypertensive Rats. Hypertension, 1998. 32(4): p. 705-709.

48.Diez, J., et al., Altered regulation of smooth muscle cell proliferation and apoptosis in small arteries of spontaneously hypertensive rats. Eur Heart J, 1998. 19 Suppl G: p. G29-33.

49.Meyer, J.S., et al., Risk factors accelerating cerebral degenerative changes, cognitive decline and dementia. Int J Geriatr Psychiatry, 1999. 14(12): p. 1050-61.

50.Clements, K.M. and P.E. Wainwright, Spontaneously hypertensive, Wistar Kyoto and Sprague-Dawley rats differ in performance on a win-stay task and a conditioned cue preference task in the water radial arm maze. Behav Brain Res, 2007. 183(2): p. 169-77.

51.Wells, A.M., et al., Medial temporal lobe functioning and structure in the spontaneously hypertensive rat: comparison with Wistar-Kyoto normotensive and Wistar-Kyoto hypertensive strains. Hippocampus, 2010. 20(6): p. 787-97.

52.Li, Q., et al., The usefulness of the spontaneously hypertensive rat to model attention-deficit/hyperactivity disorder (ADHD) may be explained by the differential expression of dopamine-related genes in the brain. Neurochem Int, 2007. 50(6): p. 848-57.

53.Ferguson, S.A. and A.M. Cada, Spatial learning/memory and social and nonsocial behaviors in the spontaneously hypertensive, Wistar-Kyoto and Sprague-Dawley rat strains. Pharmacol Biochem Behav, 2004. 77(3): p. 583-94.

54.Shen, Q., et al., Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell, 2008. 3(3): p. 289-300.