Corticostriatal mechanisms of action learning and habit formation

动作学习和习惯形成的皮质纹状体机制

• 批准号: 8148179
• 负责人: David M Lovinger
• 金额: $ 64.94万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8148179
• 关键词: habit learning

Neural activity signaling the initiation and termination of action sequences emerges in nigrostriatal circuits during sequence learning We investigated simultaneous changes in behavioral microstructure and neural activity in nigrostriatal circuits as mice learned a self-paced operant task in which eight lever presses would earn a reward. The average lever press rate increased with training, while the behavior of the mice became organized into discrete sequences of about eight presses. As training progressed there was faster performance of more accurate sequences and less behavioral variability, suggesting that a robust action sequence structure emerged with training. We recorded neural activity in nigrostriatal circuits with electrode arrays in the dorsal striatum (DS) and substantia nigra (SN) during the emergence of action sequences. Many medium spiny neurons (MSNs) displayed increased firing rate preceding the first press in a series, which was higher than the rate increase preceding other presses. Sequence initiation specific activity was also found in putative SN GABAergic and dopaminergic neurons. Neurons in all three areas showed modulated activity selectively before the final press of a sequence. Few neurons signaled both sequence initiation and termination. The proportion of neurons showing start/stop related activity was much higher than that showing activity selectively related to middle presses within a sequence. The proportion of press-related neurons did not change during training, but the percentage of neurons with sequence start/stop related neural activity increased with learning. We next attempted to disrupt striatal circuit function using mice with a striatal-specific deletion of NMDAR1 (striatal NR1-KO). Behavior and striatal neuronal activity was examined after 6 days of training on the FR8 schedule in KO mice and littermate controls. Striatal NR1-KO mice learned to lever press for reward, although KOs showed larger inter-sequence-interval (ISI) but not inter-press interval. The proportion of MSNs displaying lever press-related activity was similar in striatal NR1-KO mice and littermate controls, and this proportion did not change with training. However, the percentage of neurons with start/stop activity was decreased in striatal NR1-KO mice compared to controls, and this did not change with training in the KO mice. Striatal NR1-KO mice exhibited little evidence of sequence learning compared with controls. The sequence length after training was different from eight presses in striatal NR1-KO. The impairment in sequence learning did not stem from any obvious motor impairment in striatal NR1-KO mice, as within-sequence press rate was similar between KOs and controls, and the ISI decreased with training in KO mice. Importantly, the variability of sequence behavior for each animal was generally higher in KO and did not diminish as much with training as in controls. In summary, neurons in nigrostriatal circuits can signal the boundaries of self-paced action sequences. This sequence boundary selective neural activity emerges during training to perform a specific action sequence. Striatal-specific loss of NMDA receptors selectively impairs sequence learning, indicating that striatal circuits are necessary to learn and crystallize specific action sequences. Dissociable roles of DA on striatal firing rate and synchrony during akinesia The basal ganglia and DA are involved in action selection and movement initiation. Loss of SN DA projections and decreased striatal DA levels are the characteristic features of Parkinsons disease (PD). Decreased DA levels lead to changes in striatal neuron firing rate, and it is generally believed that DA depletion increases activity in the indirect pathway MSNs (striatopallidal MSNs, expressing mainly D2 receptors) and decreased activity of direct pathway MSNs (striatonigral MSNs, expressing mainly D1 receptors), ultimately resulting in decreased motor cortex activity. However, several recent studies failed to observe decreased overall firing rate in motor cortex after DA depletion. DA loss can result in abnormal oscillatory activity and increased synchrony in the basal ganglia, possibly contributing to Parkinsonian motor deficits. Although DA depletion changes both firing rate and synchrony in striatum, it is not known if these changes are mechanistically related. It is also not known if D1 or D2 type DA receptors have similar effects on rate and synchrony. There may also be more interactions between the direct and indirect pathways than initially thought. It is therefore important to investigate if changes in firing rate and synchrony upon DA disruption are related. Acute blockade of DA receptors (D1, D2, and D1+D2) produced altered the firing rate of striatal neurons, with the majority of neurons showing changes after D1+D2 antagonism. Blockade of D2 type receptors alone also caused a significant proportion of neurons to change firing rate, while blockade of D1-type receptors did not. D1+D2 blockade decreased firing rate in the majority of neurons, and similar effects were observed with blockade of either receptor alone. Thus, the difference in the number of neurons changing rate after D1 or D2 blockade cannot be attributed to differences in the sign of the changes. These data suggest that D2 blockade produces similar changes in neuronal firing rate in the dorsal striatum to those caused by D1+D2 blockade, while blockade of D1-receptors produces smaller changes. D1 blockade produces rate changes similar to those produced by D2 blockade, but in a smaller population of neurons. Acute DA-blockade also changed the entrainment of MSNs to local field potential (LFP) oscillations. Entrainment was low in the baseline condition, but increased after D1+D2 blockade or D1 blockade, while D2 blockade had no such effect. Interestingly, MSNs showing entrainment to the LFP tended to fire near the trough of the LFP oscillation after DA-blockade, corresponding to the point of highest intracellular depolarization. In contrast, fast-spiking interneurons fired preferentially at the peak of the LFP, when intracellular potentials should be more hyperpolarized, while putative cholinergic interneurons tended to fire after the trough of the LFP oscillation. These data confirm that acute D1+D2 blockade leads to increased entrainment of striatal MSNs to the LFP as observed after DA depletion. The effects of the different dopaminergic manipulations suggest that the influences DA signaling on striatal firing rate and synchrony are dissociable. However, this evidence is indirect and based solely on the different magnitudes of the effects of D1 and D2 blockade. We thus determined if there was any relation between the probability of a neuron changing firing rate and changing entrainment to the LFP after DA-blockade. No differences were found in the probability of an entrainment change between rate-changing neurons and non-rate-changing neurons, indicating no consistent relationship between firing rate and entrainment changes after DA-blockade. We conclude: 1) the majority of MSNs show decreased firing frequency, 2) the relative power of the LFP oscillations changes in striatum, and 3) MSNs are entrained to the LFP after acute DA-blockade. Although blockade of D1 or D2 receptors alone produced similar akinesia, the effects of D1 or D2 antagonism on striatal firing rate and synchrony were different. D2 blockade altered MSN firing rate and LFP oscillation power, but did not affect synchrony, while D1 blockade strongly altered synchrony. There was no consistent relationship between firing rate changes and LFP entrainment changes after DA-blockade. Thus, lack of D1 and D2 type receptor activation can exert independent yet interactive effects, which may contribute to PD.

神经活动信号传达作用序列的启动和终止在序列学习过程中出现在斑纹纹状体电路中 当小鼠学会了一项自定进度的操作任务时，我们研究了黑纹理电路中行为微观结构和神经活动的同时变化，其中八个杠杆按压将获得回报。随着训练的平均杠杆新闻速率增加，而小鼠的行为被组织成大约八个按压的离散序列。随着训练的进行，更准确的序列和行为变异性的性能更快，这表明随着训练出现了强大的动作序列结构。 我们记录了在动作序列出现期间，在背纹状体（DS）和底底（SN）中具有电极阵列的骨纹状体电路中的神经活动。许多中刺神经元（MSN）在系列第一压力机之前显示出发射速率提高，该发射速率高于其他压力机之前的速率。在推定的SN GABA能和多巴胺能神经元中还发现了序列起始特异性活性。在序列的最终压力上，所有三个区域的神经元在选择性的调制活动中均有选择性。很少有神经元可以发出序列起始和终止。显示起始/停止相关活动的神经元的比例远高于序列中与中间压力相关的活动的比例。在训练过程中，与新闻相关的神经元的比例没有变化，但是与学习相关的神经活动的神经元百分比随着学习而增加。 接下来，我们尝试使用具有NMDAR1（纹状体NR1-KO）的纹状体特异性缺失的小鼠破坏纹状体电路函数。在KO小鼠和同窝控制的FR8时间表进行了6天的训练后，检查了行为和纹状体神经元活动。纹状体NR1-KO小鼠学会了杠杆奖励以获得奖励，尽管KOS表现出较大的序列间间隔（ISI），但没有压力间的间隔。在纹状体NR1-KO小鼠和同窝式对照中，显示杠杆压力相关活性的MSN的比例相似，并且该比例并未随训练而变化。然而，与对照组相比，纹状体NR1-KO小鼠的神经元的百分比降低了，并且随着KO小鼠的训练不会改变。 与对照组相比，纹状体NR1-KO小鼠几乎没有序列学习的证据。训练后的序列长度与纹状体NR1-KO中的八个压机不同。序列学习的损害并不源于纹状体NR1-KO小鼠中任何明显的运动障碍，因为KOS和对照组之间的序列新闻率相似，并且随着KO小鼠的训练，ISI降低。重要的是，在KO中，每只动物的序列行为的变异性通常都更高，并且在训练中的降低不如对照。 总而言之，黑质纹状体电路中的神经元可以表明自定进定作用序列的边界。该序列边界选择性神经活动在训练期间出现以执行特定的动作序列。 NMDA受体的纹状体特异性丧失选择性损害序列学习，这表明纹状体回路对于学习和结晶特定的作用序列是必要的。 DA在Akinesia期间DA上的可分离作用在纹状体触发速率和同步 基底神经节和DA参与了行动选择和运动启动。帕金森病（PD）的特征是SN DA投影和纹状体DA水平降低的丧失。 DA水平降低会导致纹状体神经元的发射率的变化，并且通常认为DA耗竭会增加间接途径MSN的活性（纹状体金属MSN，主要表达D2受体）和直接途径MSN的活性降低（层状MSN）（纹状体MSN，表达D1受体的主要表达D1受体），最终的活性。但是，最近的一些研究未能观察到DA耗竭后运动皮层的总体发射率降低。 DA损失可能导致振荡活性异常，并增加基底神经节的同步性，可能导致帕金森氏运动不足。 尽管DA耗竭会改变纹状体的点火速率和同步，但尚不清楚这些变化是否与机械上有关。尚不清楚D1或D2型DA受体是否对速率和同步具有相似的影响。 直接和间接途径之间的相互作用也可能比最初想象的要多。因此，重要的是研究发射速率的变化和DA中断时同步的变化是否相关。 DA受体（D1，D2和D1+D2）的急性阻断产生了纹状体神经元的发射速率，大多数神经元在D1+D2拮抗后显示出变化。 仅D2型受体的阻断也导致很大比例的神经元改变发射速率，而D1​​型受体的阻断没有。 D1+D2阻断降低了大多数神经元的发射速率，并且仅通过两种受体的封锁就观察到了类似的作用。因此，D1或D2阻滞后神经元变化率的差异不能归因于变化符号的差异。 这些数据表明，D2阻滞在背纹状体中与D1+D2封锁引起的神经元发射率相似，而D1受体受体的阻断会产生较小的变化。 D1封锁产生的速率变化类似于D2封锁产生的变化，但在较小的神经元中。 急性DA-Blockade还将MSN的夹带更改为局部场电位（LFP）振荡。在基线条件下，夹带较低，但在D1+D2阻断或D1封锁后增加，而D2封锁没有这种影响。有趣的是，显示出LFP夹带的MSN倾向于在DA块后LFP振荡的槽附近发射​​，对应于最高的细胞内去极化点。相反，当细胞内电位应更加极化时，在LFP的峰值上优先触发快速刺激的中间神经元，而假定的胆碱能中间神经元在LFP振荡后倾向于发射。 这些数据证实，急性D1+D2阻断导致纹状体MSN夹带到LFP，如DA耗竭后观察到的那样。 不同多巴胺能操纵的影响表明，影响DA信号对纹状体发射速率和同步的影响是可以解散的。但是，该证据是间接的，仅基于D1和D2阻滞作用的不同幅度。因此，我们确定神经元变化的发射率的概率与DA阻滞后变化夹带的夹带之间是否存在任何关系。在改变速率的神经元与非率变化的神经元之间夹带变化的可能性中没有发现差异，这表明发射速率与DA锁骨后的夹带变化之间没有一致的关系。 我们得出的结论是：1）大多数MSN显示出​​降低频率，2）纹状体的LFP振荡变化的相对功率，以及3）MSN在急性DA-Blockade后夹住LFP。尽管单独的D1或D2受体的阻断产生了类似的运动，但D1或D2拮抗对纹状体放电速率和同步的影响却不同。 D2封锁改变了MSN的发射速率和LFP振荡能力，但不会影响同步，而D1封锁强烈改变了同步。 DA阻滞后发射速率变化与LFP夹带变化之间没有一致的关系。因此，缺乏D1和D2型受体激活可以发挥独立但相互作用的作用，这可能有助于PD。