小脑在豚鼠延迟性和痕迹性条件眨眼反应习得和表达过程中的作用研究
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摘要
目的和方法
长期以来人们一直认为小脑只具有运动调节功能,但实验和临床研究的结果表明小脑可能还参与了多种复杂的认知和学习过程,如运动性学习。
经典眨眼条件反射是研究小脑参与运动性学习机制的极好模型。该类条件反射的建立依赖于条件刺激和非条件刺激的配对出现。根据条件刺激与非条件刺激出现时间的不同,经典眨眼条件反射可以分成延迟性和痕迹性两种模式。在前者中,条件刺激先于非条件刺激开始,并与非条件刺激同时结束。而在后者中,条件刺激结束与非条件刺激开始之间存在一个时间间隔。
大量实验研究(包括损毁、神经元单位放电记录、刺激、可逆性失活和脑功能性成像技术等)的结果均提示小脑是延迟性眨眼条件反射建立所必需的神经结构。但是,对小脑皮层和小脑中位核在此过程中的相对重要性仍存在较大的争议。此外,近期的研究发现,小脑皮层和小脑中位核在痕迹性眨眼条件反射过程中均有不同程度的活化,但它们在此过程中的作用仍不清楚。
本研究的目的就是:(1)利用化学性可逆性失活的方法,在延迟性和痕迹性条件反射训练过程中失活小脑的中位核,观察失活作用对眨眼条件反射习得的影响,近而判断小脑中位核在延迟性和痕迹性眨眼条件反射建立过程中的作用;(2)利用透射电镜技术,检测延迟性和痕迹性眨眼条件反射建立后小脑中位核内突触超微结构的变化,初步探讨小脑中位核参与两类眨眼条件反射建立的机制(;3)利用化学性受体阻断法,阻断小脑皮层对小脑中位核神经元活动的影响,近而判断小脑皮层在痕迹性条件眨眼反应表达控制过程中的作用。研究小脑在延迟性和痕迹性条件眨眼反应习得和表达过程中的作用,既能全面确定小脑的运动性学习功能,又能为深入地研究相关机制提供新思路,具有重要的理论意义。
结果
1.单侧小脑中位核在延迟性条件眨眼反应习得过程中的作用
1)豚鼠经典眨眼条件反射建立的关键期为条件反射训练第2-4天;
2) 2.50μg/kg剂量的蝇蕈醇可以完全抑制一侧的豚鼠小脑中位核;
3)训练前向左侧小脑中部定量微注射GABAA受体激动剂蝇蕈醇,可逆性失活左侧小脑中位核,可以完全抑制豚鼠左侧延迟性眨眼条件反射的习得;
4)训练前向右侧小脑中部定量微注射GABAA受体激动剂蝇蕈醇,可逆性失活右侧小脑中位核,对豚鼠左侧延迟性眨眼条件反射习得的早期阶段具有显著的迟滞效应,但这种迟滞效应在豚鼠左侧延迟性眨眼条件反射习得的后期不再显著;
5)向小脑中部微注射无论是蝇蕈醇还是人工脑脊液均不会显著影响非条件眨眼反应的表达。
2.小脑中位核在痕迹性条件眨眼反应习得过程中的作用
1)在痕迹性眨眼条件反射训练期间,可逆性失活一侧小脑中位核,可以阻止豚鼠对刺激间隔期为50 ms的同侧痕迹性眨眼条件反射习得,但却不能阻止豚鼠对刺激间隔期为250 ms的同侧痕迹性眨眼条件反射习得;
2)当痕迹性眨眼条件反应已经习得后,无论刺激间隔期的长度如何,可逆性失活一侧小脑中位核,均可以显著抑制已习得的同侧痕迹性条件眨眼反应表达;
3.经典眨眼条件反射习得后豚鼠小脑中位核内突触超微结构的变化
1)延迟性模式配对训练组豚鼠小脑中位核内兴奋性和抑制性突触后膜致密物均显著增厚;
2)痕迹性模式配对和非配对训练都未显著改变豚鼠训练侧小脑中位核内突触的超微结构;
4.小脑皮层在痕迹性条件眨眼反应表达过程中的作用
1)当建立稳定的痕迹性眨眼条件反射后,向小脑中部微注射GABAA受体拮抗剂甲酰荷包牡丹碱,封闭小脑中位核神经元表面GABAA受体,可以显著地改变豚鼠已习得的痕迹性条件眨眼反应的拓扑学特征;
2)当建立稳定的痕迹性眨眼条件反射后,向小脑中部微注射GABAA受体激动剂蝇蕈醇使小脑中位核神经元细胞膜电位超极化,抑制中位核神经元活动,可以完全地抑制豚鼠对已习得痕迹性条件眨眼反应的表达。
结论
1.同侧小脑中位核在延迟性眨眼条件反射的建立过程中起到了至关重要的作用,而对侧小脑中位核仅参与了该类眨眼条件反射习得的早期过程;
2.小脑中位核是否参与痕迹性眨眼条件反射的建立,取决于条件刺激与非条件刺激之间的时间间隔。随着时间间隔长度的增加,小脑中位核在痕迹性眨眼条件反射建立过程中的重要性就越小。但是,无论刺激间隔的长短,小脑中位核均是痕迹性条件眨眼反应表达所必需的神经结构;
3.延迟性眨眼条件反射训练可以改变训练同侧小脑中位核内突触的超微结构,但相同刺激参数的痕迹性眨眼条件反射训练并不引起训练同侧小脑中位核内突触的超微结构发生类似改变,提示小脑中位核可能并不参与痕迹性眨眼条件反射的建立过程;
4.小脑皮层可能参与了对痕迹性条件眨眼反应拓扑学特征的控制过程。
Aims and methods:
Numerous lines of evidence ranging from purely theoretical considerations to human functional imaging studies have consistently implicated the cerebellum as being critically involved in a number of learning related tasks. Among the tasks in which the cerebellum is critically involved, a number of studies from several laboratories have demonstrated that the cerebellum is essentially involved in acquisition and expression of classically conditioned discrete skeletal movements, in particular, the classically conditioned eyeblink response.
Classical conditioning of eyeblink reflex is a widely-used model system for elucidating the mechanisms of cerebellar involvement in motor learning, which involves paired presentation of a behaviorally neutral conditioned stimulus (CS, e.g., a tone) and an aversive unconditioned stimulus (US, e.g., a corneal airpuff in the eye). Initially, the organism produces only a reflexive unconditioned response (UR) to the US. However, after repeated pairings of the CS and US, the alone CS begins to elicit anticipatory conditioned eyeblink response (CR), suggesting that an association between the CS and US has been learned. There are two paradigms of eyeblink conditioning that differ in the temporal relationship between the CS and US. In the delay paradigm, the CS precedes, overlaps, and coterminates with the US. On the other hand, in the trace paradigm, the CS and the US are separated by a stimulus-free time gap (called trace interval, TI).
Cumulative evidence from the lesion, recording, stimulation, reversible inactivation and neuroimaging studies has proved the cerebellum to be the basic locus of delay eyeblink conditioning. However, the relative contributions of the cerebellar cortex and interpositus nucleus to the acquisition of delay eyeblink conditioning are far to be determined. On the other hand, significant activations of the cerebellar cortex and interpositus nucleus during trace eyeblink conditioning have recently been observed. At this time, it is unclear what role does the cerebellar cortex and interpositus nucleus play during trace eyeblink conditioning.
Consequently, the present study was undertaken to (1) investigate the role of cerebellar interpositus nucleus during the acquisition of delay and trace eyeblink conditioning in guinea pigs; (2) investigate changes of the synaptic ultrastrure in the guinea pig interpositus nucleus after delay and trace eyeblink conditioning; (3) investigate the cerebellar cortical function duting the expression of acquired trace-conditioned eyeblink responses in guinea pigs.
Results:
(1) Role of the unilateral cerebellar interpositus nucleus during the acquisition of delay eyeblink conditioning.
1) The CR acquisition increased sharply during the sessions 2 to 4;
2) A dose of 2.5 ug/kg muscimol had a sufficient inactivation effect;
3) Microinjections of muscimol, a GABAA receptor agonist, into the left intermediate cerebellum before training completely prevented acquisition of the left CRs in guinea pigs;
4) Microinjections of muscimol into the right intermediate cerebellum before training retarded acquisition of the left CRs at the early stage of training, whereas the CR acquisition was not affected at the later stage of traning relative to that of the Control animals;
5) Microinjections of either aCSF or muscimol into the intermediate cerebellum did not affect the performance of tone-airpuff evoked UR;
(2) Role of the unilateral cerebellar interpositus nucleus during the acquisition of trace eyeblink conditioning.
1) Inactivations of the left cerebellar interpositus nuelceus with the GABAA receptor agonist muscimol during training prevent the acquisition of left TEBC using a relatively short (50 ms) TI, instead of the acquisition of left TEBC using a relatively long (250 ms) TI;
2) Inactivations of the left cerebellar interpositus nucleus abolished the established left trace CRs regardless of the time length of TI;
(3) Changes of synaptic ultrastructure in the cerebellar interpositus nucleus after delay and trace eyeblink conditioning.
1) The PSD thickness of the excitatory and inhibitory synapses in the guinea pig interpositus nucleus increased after 10 daily sessions of delay eyeblink conditioning;
2) However, the PSD thickness of the excitatory and inhibitory synapses in the guinea pig interpositus nucleus did not significantly change after 10 daily sessions of trace eyeblink conditioning;
(4) Role of the cerebellar cortex during the expression of acquired trace-conditioned eyeblink responses in guinea pigs.
1) Topography of the acquired trace-conditioned eyeblink responses was disrupted after blockade of cerebellar cortical input to the interpositus nucleus with bicuculline methiodide;
2) Expression of the acquired trace-conditioned eyeblink response was totally abolished after microinjections of the GABAA agonist muscimol into the intermediate cerebellum;
Conclusions:
1) In contrast to the essential role of the ipsilateral cerebellar interpositus nucleus, the contralateral cerebellar interpositus nucleus is potentially involved in the acquisition of unilaterally classical eyeblink conditioning during the early stage of training.
2) While the ipsilateral cerebellar interpositus nucleus is essential for the expression of trace CRs, its contribution to the acquisition of trace CRs appears to mainly depend on the length of trace interval.
3) Delay, but not trace eyeblink conditioning is associated with significant changes of synaptic ultrastructure in the guinea pig interpositus nucleus.
4) Blockade of cerebellar cortical input to the cerebellar interpositus nucleus disrupts the topography of acquired trace-conditioned eyeblink responses in guinea pigs.
长期以来人们一直认为小脑只具有运动调节功能,但实验和临床研究的结果表明小脑可能还参与了多种复杂的认知和学习过程,如运动性学习。
经典眨眼条件反射是研究小脑参与运动性学习机制的极好模型。该类条件反射的建立依赖于条件刺激和非条件刺激的配对出现。根据条件刺激与非条件刺激出现时间的不同,经典眨眼条件反射可以分成延迟性和痕迹性两种模式。在前者中,条件刺激先于非条件刺激开始,并与非条件刺激同时结束。而在后者中,条件刺激结束与非条件刺激开始之间存在一个时间间隔。
大量实验研究(包括损毁、神经元单位放电记录、刺激、可逆性失活和脑功能性成像技术等)的结果均提示小脑是延迟性眨眼条件反射建立所必需的神经结构。但是,对小脑皮层和小脑中位核在此过程中的相对重要性仍存在较大的争议。此外,近期的研究发现,小脑皮层和小脑中位核在痕迹性眨眼条件反射过程中均有不同程度的活化,但它们在此过程中的作用仍不清楚。
本研究的目的就是:(1)利用化学性可逆性失活的方法,在延迟性和痕迹性条件反射训练过程中失活小脑的中位核,观察失活作用对眨眼条件反射习得的影响,近而判断小脑中位核在延迟性和痕迹性眨眼条件反射建立过程中的作用;(2)利用透射电镜技术,检测延迟性和痕迹性眨眼条件反射建立后小脑中位核内突触超微结构的变化,初步探讨小脑中位核参与两类眨眼条件反射建立的机制(;3)利用化学性受体阻断法,阻断小脑皮层对小脑中位核神经元活动的影响,近而判断小脑皮层在痕迹性条件眨眼反应表达控制过程中的作用。研究小脑在延迟性和痕迹性条件眨眼反应习得和表达过程中的作用,既能全面确定小脑的运动性学习功能,又能为深入地研究相关机制提供新思路,具有重要的理论意义。
结果
1.单侧小脑中位核在延迟性条件眨眼反应习得过程中的作用
1)豚鼠经典眨眼条件反射建立的关键期为条件反射训练第2-4天;
2) 2.50μg/kg剂量的蝇蕈醇可以完全抑制一侧的豚鼠小脑中位核;
3)训练前向左侧小脑中部定量微注射GABAA受体激动剂蝇蕈醇,可逆性失活左侧小脑中位核,可以完全抑制豚鼠左侧延迟性眨眼条件反射的习得;
4)训练前向右侧小脑中部定量微注射GABAA受体激动剂蝇蕈醇,可逆性失活右侧小脑中位核,对豚鼠左侧延迟性眨眼条件反射习得的早期阶段具有显著的迟滞效应,但这种迟滞效应在豚鼠左侧延迟性眨眼条件反射习得的后期不再显著;
5)向小脑中部微注射无论是蝇蕈醇还是人工脑脊液均不会显著影响非条件眨眼反应的表达。
2.小脑中位核在痕迹性条件眨眼反应习得过程中的作用
1)在痕迹性眨眼条件反射训练期间,可逆性失活一侧小脑中位核,可以阻止豚鼠对刺激间隔期为50 ms的同侧痕迹性眨眼条件反射习得,但却不能阻止豚鼠对刺激间隔期为250 ms的同侧痕迹性眨眼条件反射习得;
2)当痕迹性眨眼条件反应已经习得后,无论刺激间隔期的长度如何,可逆性失活一侧小脑中位核,均可以显著抑制已习得的同侧痕迹性条件眨眼反应表达;
3.经典眨眼条件反射习得后豚鼠小脑中位核内突触超微结构的变化
1)延迟性模式配对训练组豚鼠小脑中位核内兴奋性和抑制性突触后膜致密物均显著增厚;
2)痕迹性模式配对和非配对训练都未显著改变豚鼠训练侧小脑中位核内突触的超微结构;
4.小脑皮层在痕迹性条件眨眼反应表达过程中的作用
1)当建立稳定的痕迹性眨眼条件反射后,向小脑中部微注射GABAA受体拮抗剂甲酰荷包牡丹碱,封闭小脑中位核神经元表面GABAA受体,可以显著地改变豚鼠已习得的痕迹性条件眨眼反应的拓扑学特征;
2)当建立稳定的痕迹性眨眼条件反射后,向小脑中部微注射GABAA受体激动剂蝇蕈醇使小脑中位核神经元细胞膜电位超极化,抑制中位核神经元活动,可以完全地抑制豚鼠对已习得痕迹性条件眨眼反应的表达。
结论
1.同侧小脑中位核在延迟性眨眼条件反射的建立过程中起到了至关重要的作用,而对侧小脑中位核仅参与了该类眨眼条件反射习得的早期过程;
2.小脑中位核是否参与痕迹性眨眼条件反射的建立,取决于条件刺激与非条件刺激之间的时间间隔。随着时间间隔长度的增加,小脑中位核在痕迹性眨眼条件反射建立过程中的重要性就越小。但是,无论刺激间隔的长短,小脑中位核均是痕迹性条件眨眼反应表达所必需的神经结构;
3.延迟性眨眼条件反射训练可以改变训练同侧小脑中位核内突触的超微结构,但相同刺激参数的痕迹性眨眼条件反射训练并不引起训练同侧小脑中位核内突触的超微结构发生类似改变,提示小脑中位核可能并不参与痕迹性眨眼条件反射的建立过程;
4.小脑皮层可能参与了对痕迹性条件眨眼反应拓扑学特征的控制过程。
Aims and methods:
Numerous lines of evidence ranging from purely theoretical considerations to human functional imaging studies have consistently implicated the cerebellum as being critically involved in a number of learning related tasks. Among the tasks in which the cerebellum is critically involved, a number of studies from several laboratories have demonstrated that the cerebellum is essentially involved in acquisition and expression of classically conditioned discrete skeletal movements, in particular, the classically conditioned eyeblink response.
Classical conditioning of eyeblink reflex is a widely-used model system for elucidating the mechanisms of cerebellar involvement in motor learning, which involves paired presentation of a behaviorally neutral conditioned stimulus (CS, e.g., a tone) and an aversive unconditioned stimulus (US, e.g., a corneal airpuff in the eye). Initially, the organism produces only a reflexive unconditioned response (UR) to the US. However, after repeated pairings of the CS and US, the alone CS begins to elicit anticipatory conditioned eyeblink response (CR), suggesting that an association between the CS and US has been learned. There are two paradigms of eyeblink conditioning that differ in the temporal relationship between the CS and US. In the delay paradigm, the CS precedes, overlaps, and coterminates with the US. On the other hand, in the trace paradigm, the CS and the US are separated by a stimulus-free time gap (called trace interval, TI).
Cumulative evidence from the lesion, recording, stimulation, reversible inactivation and neuroimaging studies has proved the cerebellum to be the basic locus of delay eyeblink conditioning. However, the relative contributions of the cerebellar cortex and interpositus nucleus to the acquisition of delay eyeblink conditioning are far to be determined. On the other hand, significant activations of the cerebellar cortex and interpositus nucleus during trace eyeblink conditioning have recently been observed. At this time, it is unclear what role does the cerebellar cortex and interpositus nucleus play during trace eyeblink conditioning.
Consequently, the present study was undertaken to (1) investigate the role of cerebellar interpositus nucleus during the acquisition of delay and trace eyeblink conditioning in guinea pigs; (2) investigate changes of the synaptic ultrastrure in the guinea pig interpositus nucleus after delay and trace eyeblink conditioning; (3) investigate the cerebellar cortical function duting the expression of acquired trace-conditioned eyeblink responses in guinea pigs.
Results:
(1) Role of the unilateral cerebellar interpositus nucleus during the acquisition of delay eyeblink conditioning.
1) The CR acquisition increased sharply during the sessions 2 to 4;
2) A dose of 2.5 ug/kg muscimol had a sufficient inactivation effect;
3) Microinjections of muscimol, a GABAA receptor agonist, into the left intermediate cerebellum before training completely prevented acquisition of the left CRs in guinea pigs;
4) Microinjections of muscimol into the right intermediate cerebellum before training retarded acquisition of the left CRs at the early stage of training, whereas the CR acquisition was not affected at the later stage of traning relative to that of the Control animals;
5) Microinjections of either aCSF or muscimol into the intermediate cerebellum did not affect the performance of tone-airpuff evoked UR;
(2) Role of the unilateral cerebellar interpositus nucleus during the acquisition of trace eyeblink conditioning.
1) Inactivations of the left cerebellar interpositus nuelceus with the GABAA receptor agonist muscimol during training prevent the acquisition of left TEBC using a relatively short (50 ms) TI, instead of the acquisition of left TEBC using a relatively long (250 ms) TI;
2) Inactivations of the left cerebellar interpositus nucleus abolished the established left trace CRs regardless of the time length of TI;
(3) Changes of synaptic ultrastructure in the cerebellar interpositus nucleus after delay and trace eyeblink conditioning.
1) The PSD thickness of the excitatory and inhibitory synapses in the guinea pig interpositus nucleus increased after 10 daily sessions of delay eyeblink conditioning;
2) However, the PSD thickness of the excitatory and inhibitory synapses in the guinea pig interpositus nucleus did not significantly change after 10 daily sessions of trace eyeblink conditioning;
(4) Role of the cerebellar cortex during the expression of acquired trace-conditioned eyeblink responses in guinea pigs.
1) Topography of the acquired trace-conditioned eyeblink responses was disrupted after blockade of cerebellar cortical input to the interpositus nucleus with bicuculline methiodide;
2) Expression of the acquired trace-conditioned eyeblink response was totally abolished after microinjections of the GABAA agonist muscimol into the intermediate cerebellum;
Conclusions:
1) In contrast to the essential role of the ipsilateral cerebellar interpositus nucleus, the contralateral cerebellar interpositus nucleus is potentially involved in the acquisition of unilaterally classical eyeblink conditioning during the early stage of training.
2) While the ipsilateral cerebellar interpositus nucleus is essential for the expression of trace CRs, its contribution to the acquisition of trace CRs appears to mainly depend on the length of trace interval.
3) Delay, but not trace eyeblink conditioning is associated with significant changes of synaptic ultrastructure in the guinea pig interpositus nucleus.
4) Blockade of cerebellar cortical input to the cerebellar interpositus nucleus disrupts the topography of acquired trace-conditioned eyeblink responses in guinea pigs.
引文
[1] Christian KM, Thompson RF. Neural substrates of eyeblink conditioning: acquisition and retention. Learn Mem 2003; 11: 427-455.
[2] Rogers RF, Britton GB, Steinmetz JE. Learning-related interpositus activity is conserved across species as studied during eyeblink conditioning in the rat. Brain Res 2001; 905: 171-177.
[3] Green JT, Arenos JD. Hippocampal and cerebellar single-unit activity during delay and trace eyeblink conditioning in the rat. Neurobiol Learn Mem 2007; 87: 269-284.
[4] Lincoln JS, McCormick DA, Thompson RF. Ipsilateral cerebellar lesions prevent learning of the classically conditioned nictitating membrane/eyelid response. Brain Res 1982; 323: 190-193.
[5] Lavond DG, Hembree TL, Thompson RF. Effect of kainic acid lesions of the cerebellar interpositus nucleus on eyelid conditioning in the rabbit. Brain Res. 1985; 326: 179-182.
[6] Welsh JP, Harvey JA. Pavlovian conditioning in the rabbit during inactivation of the interpositus, J Physiol (London) 1991; 444: 459-480.
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