海马脑区去甲肾上腺素β-受体在学习和记忆中的作用
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摘要
第一部分 大鼠海马CA1区β-受体参与长时程增强和空间 学习
在离体海马脑片上，激活CA1区(-肾上腺素能受体（β-受体）易化这一区域突触传递的长时程增强（LTP）。然而，在体情况下，CA1区β-受体是否参与LTP，是否参与海马依赖性的学习和记忆，尚无实验证据。为此，我们观察了β-受体激动剂异丙肾上腺素（isoproterenol）或拮抗剂心得安(propranolol)对在体CA1区LTP的调控作用以及对大鼠在Morris水迷宫中空间学习的影响。正常情况下对突触传递效能仅有微小调制作用的10Hz的(节律刺激（每串150个脉冲，1串），在CA1区局部给予L-异丙肾上腺素后，显著地诱导出LTP，这一效应可被DL-心得安所阻断；相反，正常情况下对突触传递强度有显著调制作用的5Hz的(节律刺激（每串150个脉冲，3串），在CA1区局部给予DL-心得安后，所诱导出的LTP被显著压抑。对应的，训练前20分钟在CA1 区注射DL-心得安，大鼠在水迷宫中的学习速度显著慢于对照组，训练后24小时的空间记忆保持也相应地差。以上结果提示，β-受体参与对在体海马CA1区突触可塑性的调控，且对空间学习重要。本工作首次在在体条件下，通过(节律刺激诱导出了CA1区的LTP，并对其β-受体的调控作用进行了观察，为海马CA1区β-受体参与空间学习首次提供了行为学证据。
关键词：β-受体, 长时程增强, CA1区, 海马, 空间学习，大鼠
Part I Involvement of (β-adrenoceptors in hippocampal CA1 region in in vivo long-term potentiation and spatial learning in rats
Activation of (β-adrenoceptors in area CA1 of the hippocampus facilitates in vitro long-term potentiation (LTP) in this region. However, it is unclear if in vivo LTP in area CA1 and hippocampus-dependent learning are subjected to (-adrenergic regulation. To address this question, we investigated the effects of the (-adrenergic agonist L-isoproterenol or antagonist DL-propranolol on in vivo LTP of area CA1 and spatial learning in Morris water maze. In the presence of L-isoproterenol (through local infusion into area CA1), the theta-pulse stimulation with the parameter of 10 Hz, 150 pulses/train, 1 train, a frequency weakly modifying synaptic strength, induced a robust LTP, and this effect was blocked when DL-propranolol was co-administered. By contrast, the theta-pulse stimulation with the parameter of 5 Hz, 150 pulses/train, 3 train, a frequency strongly modifying synaptic strength, induced a significantly smaller LTP when DL-propranolol was administered into area CA1. Accordingly, DL-propranolol impaired rat's spatial learning in the water maze when infused into area CA1 20min pretraining. Compared with control rats, the DL-propranolol-treated rats showed significantly slower learning in the water maze and subsequently exhibited poor memory retention at 24-hr
test. These results suggest that β-adrenoceptors in area CA1 are involved in regulating in vivo synaptic plasticity of this area and are important for spatial learning. The present study was the first work where theta-pulse-stimulation-induced LTP was recorded in area CA1 in vivo and its (-adrenergic regulation was examined, and provided the first behavioral evidence that (-adreneoceptors in area CA1 plays an important role in spatial learning.
Key words: β-adrenoceptors, long-term potentiation, CA1, hippocampus, spatial learning, rat
在离体海马脑片上，激活CA1区(-肾上腺素能受体（β-受体）易化这一区域突触传递的长时程增强（LTP）。然而，在体情况下，CA1区β-受体是否参与LTP，是否参与海马依赖性的学习和记忆，尚无实验证据。为此，我们观察了β-受体激动剂异丙肾上腺素（isoproterenol）或拮抗剂心得安(propranolol)对在体CA1区LTP的调控作用以及对大鼠在Morris水迷宫中空间学习的影响。正常情况下对突触传递效能仅有微小调制作用的10Hz的(节律刺激（每串150个脉冲，1串），在CA1区局部给予L-异丙肾上腺素后，显著地诱导出LTP，这一效应可被DL-心得安所阻断；相反，正常情况下对突触传递强度有显著调制作用的5Hz的(节律刺激（每串150个脉冲，3串），在CA1区局部给予DL-心得安后，所诱导出的LTP被显著压抑。对应的，训练前20分钟在CA1 区注射DL-心得安，大鼠在水迷宫中的学习速度显著慢于对照组，训练后24小时的空间记忆保持也相应地差。以上结果提示，β-受体参与对在体海马CA1区突触可塑性的调控，且对空间学习重要。本工作首次在在体条件下，通过(节律刺激诱导出了CA1区的LTP，并对其β-受体的调控作用进行了观察，为海马CA1区β-受体参与空间学习首次提供了行为学证据。
关键词：β-受体, 长时程增强, CA1区, 海马, 空间学习，大鼠
Part I Involvement of (β-adrenoceptors in hippocampal CA1 region in in vivo long-term potentiation and spatial learning in rats
Activation of (β-adrenoceptors in area CA1 of the hippocampus facilitates in vitro long-term potentiation (LTP) in this region. However, it is unclear if in vivo LTP in area CA1 and hippocampus-dependent learning are subjected to (-adrenergic regulation. To address this question, we investigated the effects of the (-adrenergic agonist L-isoproterenol or antagonist DL-propranolol on in vivo LTP of area CA1 and spatial learning in Morris water maze. In the presence of L-isoproterenol (through local infusion into area CA1), the theta-pulse stimulation with the parameter of 10 Hz, 150 pulses/train, 1 train, a frequency weakly modifying synaptic strength, induced a robust LTP, and this effect was blocked when DL-propranolol was co-administered. By contrast, the theta-pulse stimulation with the parameter of 5 Hz, 150 pulses/train, 3 train, a frequency strongly modifying synaptic strength, induced a significantly smaller LTP when DL-propranolol was administered into area CA1. Accordingly, DL-propranolol impaired rat's spatial learning in the water maze when infused into area CA1 20min pretraining. Compared with control rats, the DL-propranolol-treated rats showed significantly slower learning in the water maze and subsequently exhibited poor memory retention at 24-hr
test. These results suggest that β-adrenoceptors in area CA1 are involved in regulating in vivo synaptic plasticity of this area and are important for spatial learning. The present study was the first work where theta-pulse-stimulation-induced LTP was recorded in area CA1 in vivo and its (-adrenergic regulation was examined, and provided the first behavioral evidence that (-adreneoceptors in area CA1 plays an important role in spatial learning.
Key words: β-adrenoceptors, long-term potentiation, CA1, hippocampus, spatial learning, rat
引文
1. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates (2nd edition). 1986, Academic Press. San Diego, California, USA.
2. Morris R G M, Garrud P, Rawlins J N, et al. Place navigation impaired in rats with hippocampal lesions. Nature1982, 297: 681-683.
3. Morris R G M, Anderson, E, Lynch, G S, et al. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 1986, 319: 774-776.
4. Sandin J, Nylander I, Georgieva J, et al. Hippocampal dynorphin B injections impair spatial learning in rats: a kappa-opioid receptor-mediated effect. Neuroscience 1998, 85: 375-382.
5. Blum S, Moore AN, Adams F, et al. A mitogen-activated protein kinase cascade in the CA1/CA2 subfield of the dorsal hippocampus is essential for long-term spatial memory. J Neurosci 1999, 19: 3535(3544.
6. Cahill L, Prins B, Weber M, McGaugh JL. Beta-adrenergic activation and memory for emotional events. Nature 1994, 371:702-704.
7. McGaugh J L, Cahill L, Roozendaal B. Involvement of the amygdala in memory storage: interaction with other brain systems. Proc Natl Acad Sci USA 1996, 93: 13508-13514.
8. Ferry B, Roozendaal B, McGaugh J L. Role of norepinephrine in mediating stress hormone regulation of long-term memory storage: a critical involvement of the amygdala. Biol Psychiatry 1999, 46: 1140-1152.
9. Mabry TR, Gold PE, McCarty R. Age-related changes in plasma catecholamine responses to acute swim stress. Neurobiol Learn Mem 1995, 63: 260-268.
10. Abel T, Nguyen P V, Barad M, et al. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell 1997, 88: 615-626.
11. Blum S, Moore AN, Adams F, et al. A mitogen-activated protein kinase cascade in the CA1/CA2 subfield of the dorsal hippocampus is essential for long-term spatial memory. J Neurosci 1999, 19: 3535-3544.
12. Schafe G E, Nadel N V, Sullivan G M, et al. Memory consolidation for contextual and autitory fear conditioning is dependent on protein synthesis, PKA, and MAP Kinase. Learn Mem 1999, 6: 97-110.
13. Selcher J C, Atikins C M, Trzaskos J M, et al. A necessity for MAP kinase activation in mammalian spatial learning. Learn Mem 1999, 6: 478-490.
14. Silva A J, Kogan J H, Frankland P W, et al. CREB and memory. Annu Rev Neurosci 1998, 21: 127-148.
15. Impey S, Obrietan K, Storm D R. Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity. Neuron 1999, 23: 11-14.
16. Kandel E R. The molecular biology of memory storage: A dialogue between genes and synapses. Science 2001, 294: 1030-1038.
2. Morris R G M, Garrud P, Rawlins J N, et al. Place navigation impaired in rats with hippocampal lesions. Nature1982, 297: 681-683.
3. Morris R G M, Anderson, E, Lynch, G S, et al. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 1986, 319: 774-776.
4. Sandin J, Nylander I, Georgieva J, et al. Hippocampal dynorphin B injections impair spatial learning in rats: a kappa-opioid receptor-mediated effect. Neuroscience 1998, 85: 375-382.
5. Blum S, Moore AN, Adams F, et al. A mitogen-activated protein kinase cascade in the CA1/CA2 subfield of the dorsal hippocampus is essential for long-term spatial memory. J Neurosci 1999, 19: 3535(3544.
6. Cahill L, Prins B, Weber M, McGaugh JL. Beta-adrenergic activation and memory for emotional events. Nature 1994, 371:702-704.
7. McGaugh J L, Cahill L, Roozendaal B. Involvement of the amygdala in memory storage: interaction with other brain systems. Proc Natl Acad Sci USA 1996, 93: 13508-13514.
8. Ferry B, Roozendaal B, McGaugh J L. Role of norepinephrine in mediating stress hormone regulation of long-term memory storage: a critical involvement of the amygdala. Biol Psychiatry 1999, 46: 1140-1152.
9. Mabry TR, Gold PE, McCarty R. Age-related changes in plasma catecholamine responses to acute swim stress. Neurobiol Learn Mem 1995, 63: 260-268.
10. Abel T, Nguyen P V, Barad M, et al. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell 1997, 88: 615-626.
11. Blum S, Moore AN, Adams F, et al. A mitogen-activated protein kinase cascade in the CA1/CA2 subfield of the dorsal hippocampus is essential for long-term spatial memory. J Neurosci 1999, 19: 3535-3544.
12. Schafe G E, Nadel N V, Sullivan G M, et al. Memory consolidation for contextual and autitory fear conditioning is dependent on protein synthesis, PKA, and MAP Kinase. Learn Mem 1999, 6: 97-110.
13. Selcher J C, Atikins C M, Trzaskos J M, et al. A necessity for MAP kinase activation in mammalian spatial learning. Learn Mem 1999, 6: 478-490.
14. Silva A J, Kogan J H, Frankland P W, et al. CREB and memory. Annu Rev Neurosci 1998, 21: 127-148.
15. Impey S, Obrietan K, Storm D R. Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity. Neuron 1999, 23: 11-14.
16. Kandel E R. The molecular biology of memory storage: A dialogue between genes and synapses. Science 2001, 294: 1030-1038.