The ability to perform a sequence of movements is a key component of motor skills, such as typing and playing a musical instrument. How the brain binds elementary movements together into meaningful actions has been a topic of much interest. The preparation for and generation of sequential movements is classically thought to depend on the supplementary motor area (SMA) and the pre-SMA (Roland et al., 1980; Tanji and Shima, 1994; Gerloff et al., 1997; Shima and Tanji, 1998; Nakamura et al., 1998; Nakamura et al., 1999; Hikosaka et al., 2002; Picard and Strick, 2001; Dayan and Cohen, 2011). According to this view, the primary motor cortex (M1) is thought to produce the patterns of muscle activity that are necessary to implement the motor plans generated by the premotor areas. There is growing evidence, however, that M1 of humans and non-human primates is involved in the acquisition and maintenance of sequential movements. For example, the activity of some M1 neurons appears to reflect the serial order of potential target stimuli (Pellizzer et al., 1995; Carpenter et al., 1999). Similarly, a large number of M1 neurons (~40%) and metabolic activity reflected aspects of learned movement sequences (Lu and Ashe, 2005; Matsuzaka et al., 2007; Picard et al., 2013). In addition, the functional connectivity of M1 neurons was suggested to be associated with sequential planning of movements (Hatsopoulos et al., 2003). These observations and others imply a more active role for M1 in the acquisition and maintenance of skilled movement sequences than previously thought (Karni et al., 1995; Dayan and Cohen, 2011). In fact, the results of imaging studies in humans underscore the importance of practice history and skill level for the activation of the motor areas (Krings et al., 2000; Meister et al., 2005).

However, causal experiments to test M1's involvement in the acquisition or maintenance of motor sequences have been challenging. M1 is critical for implementing motor output. Lesion or inactivation of M1 will abolish the motor commands to the spinal cord that generate muscle activity. Instead, we manipulated protein synthesis in M1 to selectively disrupt information storage in this cortical area. This approach has been successful in the experimental dissection and analysis of other memory systems in rodents (Davis and Squire, 1984; Nader et al., 2000a; Kleim et al., 2003; Luft et al., 2004). In these studies, local injection of an inhibitor for protein synthesis, anisomycin, was shown to interfere with learning and maintenance of memory (Davis and Squire, 1984; Nader et al., 2000a; Nader et al., 2000b; Kandel, 2001; Kleim et al., 2003; Dudai, 2004a; Luft et al., 2004; Dudai, 2012; Rudy, 2013).

We trained two monkeys (Cebus apella) on two tasks. In one task, the monkeys performed sequential movements guided by memory (Repeating task) (Figure 1a,b). As a control task, the monkeys also were trained to perform reaching movements guided by visual cues (Random task, for details see Materials and methods). After the monkeys practiced each sequence for more than 100 training days and became proficient with performing the two tasks, we made injections of the protein synthesis inhibitor, anisomycin, in M1 to test M1's involvement in maintenance of sequential movements after the extensive practice. The injections of aniomycin solution (100 mg/ml) were placed at sites in which intracortical stimulation evoked shoulder or elbow movements (Figure 1c–f, for details see Materials and methods). We analyzed the monkeys' behavior before and after the injection separately for each movement in each task. A movement from one target to the next is defined as a trial.

Figure 1

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The anisomycin injections had a significant effect on the performance of the movements during the Repeating task (Figures 2 and 3a,b). The injections resulted in a significant increase in the number of errors (Figures 2 and 3; χ² test, p<0.05) and a significant decrease in the number of predictive responses, an indication of sequence learning, (Figure 3c; χ² test, p<0.05) during the Repeating task. In contrast, performance of visually guided movements during the Random task was not significantly disrupted (χ² test, p>0.05).

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The incorrect responses during the Repeating task can be categorized as two types: errors of accuracy and errors in direction. An accuracy error is a reach performed in the correct direction (e.g., to the right in move 1–5), but to an endpoint outside of the correct target (e.g., short of target 5). As shown in Figure 2a, before the injection, the monkey made correct contact to target 5 on 96% of the trials in the Repeating task (sequence 5-3-1). After the anisomycin injection, the number of incorrect responses increased dramatically. The monkey then made accuracy errors on 45% of the trials (Figure 2a).

A direction error was considered to be a reach performed in the direction opposite to the correct target (Figure 2b, E_D). For example, movement 2–4 requires a rightward movement from target 2 to target 4. As shown in Figure 2b, the monkey made a correct movement to target 4 on 93% of the trials in the Repeating task (sequence 1-2-4) before the injection. After the anisomycin injection, the animal moved his arm to the left from target 2 and made direction errors on 18% of the trials in the Repeating task (Figure 2b). This type of error suggests a deficit in selecting the movement component in the sequence. For the injection session illustrated in Figures 2 and 3, the error rate increased significantly for five of the six movements performed during the Repeating task.

Overall, we observed a significant increase in error rate during the Repeating task for all of six injection sessions (χ² test, p<0.05; monkey N, n = 4; monkey R, n = 2). The effect of anisomycin was more pronounced for certain moves of the learned sequences (Figures 3 and 4). The affected moves varied between sessions. The error rate increased by an average of 42% for the most affected movements during the Repeating task (Figure 4b; paired t-test; p=0.002). The effect of anisomycin injections were consistent between monkeys (Figure 4—figure supplement 1). Given that performance of the Random task was unaffected, we attribute the performance changes observed in the Repeating task to the effect of anisomycin injection on memory. Overall, the effect of injections on the error rates was strong and consistent for the Repeating task and was consistently nonexistent for the Random task.

Figure 4 with 2 supplements see all

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During the Repeating task, there were trials when the monkey stopped the arm movement during midflight, redirected the arm and made a correct response within 800 msec after the presentation of the visual cue. These correct responses with longer RT were categorized as non-predictive responses (RT >150 msec) (see Materials and methods). We used the ratio of predictive/non-predictive trials as one of the indicators to assess the effect of injections on animal’s task performance (Figures 3 and 4). As shown in Figure 3c, the ratio of predictive trials decreased from 92.4% to 35.3% for the most affected movement, from target 5 to 3, during the Repeating task (χ² test, p<0.001). Overall, we observed a significant decrease in the number of predictive movements during the Repeating task for all of six injection sessions (χ² test, p<0.05). The ratio of predictive responses decreased by an average of 55.7% for the most affected movements during the Repeating task (Figure 4c; paired t-test, p=0.002). A decrease in the number of predictive responses suggests an increase in the time for movement selection. In the non-predictive trials, it is possible that the monkey used the visual cue information to make a correct response since the animal’s performance in the Random task was not affected by the injections.

After the injections, during the Repeating task, MTs significantly increased in 73.3% of the movements and RTs significantly increased for all the movements (two monkeys, six injections, t-test, p<0.05; averaged increase of MT: 45.82 msec, averaged increase of RT: 140.23 msec). The increase of RT and MT may reflect the monkeys’ hesitation, uncertainty about the next target or change of the strategy. On the other hand, during the Random task, the injections did not cause a significant change in movement times for most of the movements in 5 of 6 injections (t-test, p>0.05). In three sessions, a small, but significant increase in movement time occurred only for one movement (t-test, p<0.05). Overall, during the Random task, RTs increased in sixty percent of the movements (t-test, p<0.05, averaged increase of RT: 84.61 msec; averaged increase of MT: 38.73 msec). In summary, the effects on RT and MT were strong and consistent within the Repeating task, but were weak and variable within the Random task. Anisomycin injection in M1 impaired performance of the Repeating task for 1–2 days after the injection (χ² test, p<0.05). The task performance returned to the baseline after 1–2 days of training (Figure 4—figure supplement 2).

As control experiments, we inactivated M1 by injecting muscimol, a GABA agonist, into the shoulder representation of M1 in two sessions. We examined the performance of the animal on the Random and Repeating tasks as we did for anisomycin injections into M1. We found that M1 inactivations impaired performance on both the Random and Repeating tasks (χ² test, p<0.05). The results indicate that M1 inactivation caused an indiscriminate deficit of motor production. Injection of saline into M1 did not have any significant effects on performance of both the Random and Repeating tasks (χ² test, p<0.05).

In the present study, localized inhibition of protein synthesis in M1 resulted in a selective deficit in the performance of internally generated sequential movements during the Repeating task. This observation emphasizes the importance of M1 for the generation of sequential movements that are memory guided. Our results suggest that, although M1 is critical for movement production, it also is involved in the maintenance of skilled sequential movements.

Growing evidence showed that M1 is reorganized after extensive practice of sequential movements, yet our understanding of its neural basis after extensive practice is still limited. Human imaging studies reported that the volume of M1 is larger in professional musicians compared to amateurs or non-musicians suggesting that there is an effect of extensive practice on M1 structure (Amunts et al., 1997; Gaser and Schlaug, 2003; Zatorre et al., 2012; Draganski and May, 2008; Herholz and Zatorre, 2012; Sampaio-Baptista and Johansen-Berg, 2017; Wenger et al., 2017). Non-human primate studies also showed the effect of extensive practice of sequential movements on the neural and metabolic activity in M1 (Matsuzaka et al., 2007; Picard et al., 2013). After years of training, 40% of M1 neurons were differentially active during the performance of visually guided and memory guided sequential reaching (Matsuzaka et al., 2007). Uptake of 2DG in arm M1 was shown to be low in monkeys that performed highly practiced, internally generated sequences of movements (Picard et al., 2013). These observations imply a more active role for M1 in the planning and generation of sequential movements than previously thought. Our current observations also suggest that M1 is involved in sequential movements after extensive practice.

In rodent studies, the role of motor cortex in learning and maintenance of a skilled forelimb reaching task was tested by injecting an inhibitor for protein synthesis (Kleim et al., 2003; Luft et al., 2004). In these studies, the rats were trained to reach and grasp for a food pellet placed outside the cage (Kleim et al., 2003; Luft et al., 2004). Kleim and his colleagues reported that an injection of anisomycin into the motor cortex after 14 days of the task training disrupted the performance of the skilled forelimb task (Kleim et al., 2003). The injection of anisomycin not only disrupted the performance of the motor skill task, but also caused a significant reduction in synapse number and synapse size in M1 in vivo (Kleim et al., 2003). Luft and his colleagues reported that injection of anisomycin into the motor cortex after the 1^st and 2^nd days of training on the task disrupted the learning of the task (Luft et al., 2004). These studies suggested that the anisomycin injection interfered with the learning or maintenance of the forelimb motor skills such as reaching and grasping. In these studies, the effects of protein synthesis inhibition on the task performance were compared with motor production in well-established behaviors such as eating and walking. In addition, the rodents were trained for only 1–14 days prior to the injections in the previous studies (Kleim et al., 2003; Luft et al., 2004). On the other hand, in our study, we trained monkeys to perform sequential movements guided by memory (i.e. a complex motor skill) more than 100 days prior to the injection. In addition, the effect of anisomycin injection on the performance of the memory guided sequence was compared with the effect on a visually guided reaching task. Our results suggest that M1 is involved in maintenance of complex motor skills such as sequential movements after extensive practice.

The role of protein synthesis in learning and memory has been extensively studied especially in the context of fear conditioning of rodents (Davis and Squire, 1984; Nader et al., 2000a; Nader et al., 2000b; Kandel, 2001; Dudai, 2004a; Dudai and Eisenberg, 2004b; Rudy, 2013). De novo protein synthesis, during or shortly after initial training, is shown to be an essential step in consolidation of long-term memory (Davis and Squire, 1984). Moreover, the studies using anisomycin suggested the neural trace of memory may become labile upon retrieval, after which it may be reconsolidated (Nader et al., 2000a; reviewed in Dudai, 2012 and Rudy, 2013). These studies using anisomycin suggested that the neural trace may be destabilized through protein degradation and rebounded through protein synthesis during the reconsolidation (Nader et al., 2000a; Nader, 2003; Sara, 2000; Lee et al., 2008; Rudy, 2008; Rudy, 2013). The destabilized trace is proposed to be bi-directionally modified (i.e. weakened or strengthened), so that the memory can be 'updated' (Rudy, 2008; Sara, 2000; Dudai, 2012). Thus, when the protein synthesis inhibitor, anisomycin, was given during retrieval, the retrieved memory trace was lost as anisomycin prevents synthesis of the proteins needed to reconsolidate the memory trace (Nader et al., 2000a; Lee et al., 2008; Dudai, 2012). On the other hand, it is unclear how much these results can be generalized to other forms of memory. Our results showed that performance of well-trained sequential movements was impaired by injections of the protein synthesis inhibitor into M1 of monkeys during the repetitive training. These observations suggest that the neural traces for sequential movements may be repetitively strengthened over multiple sessions of practice through lingering protein synthesis in M1, which may lead to an increase of synaptic efficacy in M1 and slow improvement of the task performance. Further studies will expand our understanding of the mechanisms that support memory strengthening.

Furthermore, studies using brain slices showed that protein synthesis is required for long-lasting synaptic plasticity (late long-term potentiation) (reviewed in Kelleher et al., 2004) and spine-head enlargement and growth during learning (Steward and Levy, 1982; Steward and Fass, 1983; Steward and Schuman, 2003; Tanaka et al., 2008). Several observations indicate that the effects of protein synthesis inhibitors on long-lasting synaptic plasticity are likely to be a specific consequence of their translational blockade (Linden, 1996; Huber et al., 2000; Beaumont et al., 2001; Kelleher et al., 2004). These studies in rodents support our finding that inhibition of protein synthesis in M1 of monkeys interfered with performance of sequential movements guided by memory.

M1 is densely interconnected with the dorsal premotor cortex proper (PMd) (Dum and Strick, 2005). We recently demonstrated that inactivation of the PMd resulted in a selective deficit in the performance of internally generated sequences (Ohbayashi et al., 2016). We proposed that the PMd contributes to the internal generation of sequential movements through maintaining motor-motor associations. Our current results are consistent with the PMd functioning as a major source of input to M1 to guide the performance of internally generated sequences. Previous studies reported that extended practice on a sequence of movements resulted in dramatic alterations in the functional activation and neural responses of M1 (Matsuzaka et al., 2007; Picard et al., 2013). In addition, human imaging studies found a functional and structural change in M1 of professional musicians (Elbert et al., 1995; Amunts et al., 1997; Gaser and Schlaug, 2003; Schwenkreis et al., 2007; Draganski and May, 2008; Herholz and Zatorre, 2012; Zatorre et al., 2012; Sampaio-Baptista and Johansen-Berg, 2017; Wenger et al., 2017). These studies, along with our current results, suggest that M1 is involved in the maintenance of sequential movements after extensive practice. M1's specific contribution to the acquisition and maintenance of sequential movements needs to be further explored in future experiments.

The care of the monkeys and the experimental protocols adhered to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the U.S. Public Health Service Policy on Humane Care and Use of Laboratory Animals. All procedures used followed institutional guidelines and were approved by the Institutional Animal Care and Use Committee.

All data generated or analysed during this study are included in the manuscript. Source data files have been provided for Figures 2, 3, 4 and supplement figures.

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Author details

1. Machiko Ohbayashi

   1. Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, United States
   2. Systems Neuroscience Center, Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Validation, Investigation, Visualization, Methodology

   For correspondence

   machiko@pitt.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2563-9049

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