Local increase in cortical ACh signaling during performance of a motor skill learning task.

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ABSTRACT

The basal forebrain cholinergic system has been shown to play a vital role in learning and experience-dependent plasticity in the cortex [1][2][3]. Previous studies with the skilled forelimb reaching task indicate that disruption of cholinergic signaling to the motor cortex impairs skill acquisition and local cortical reorganization associated with training [4]. Additional studies have shown that acetylcholine (Ach) can boost cortical signaling, and may act as a gate of plasticity [5]. One implication of such studies is that, during performance of a behavioral task, cholinergic signaling increases within regions of the brain engaged (and modified) with training. To test this hypothesis, ACh levels were measured in the forelimb region of the motor cortex before, during, and after performance of a skilled forelimb reaching task. ACh levels increased 1.85 fold during task performance compared to levels measured before and after training. These results suggest that cholinergic signaling within the motor cortex expedites motor learning and cortical reorganization when present during skill performance.

Local increase in cortical ACh signaling during performance of a motor skill learning task.
Biane, J. (2010). The OneSci Journal 1(A), e1-e4.

Author(s): Jeremy Biane

Contents

Preface

The following represents something that is all too common in science: the unpublishable project.

We've all had 'em. Those studies where p = 0.08, or you couldn't reproduce someone else's findings, or your really interesting pilot study got lost amongst "more important" research priorities, never to be followed up on again. Perhaps your findings were "negative" and the null hypothesis is actually true. Whatever the case, in their pursuit of an ever-increasing impact factor, journals invaribly eschew such findings, leaving a large, vital chunck of scientfic inquiry uncommunicated. In short, academic journals do not want this data.

We do.

The purpose of this site is to disseminate findings that, despite sound scientific method, do not reach threshold for traditional publication.

The following report is not exhaustive, nor is it meant to be. It is, at best, the beginning of a conversation; at worst, a blip on the science radar. Comments are welcome. If interested, I can upload the raw data as well.


Introduction

The following was a side project I conducted in 2008 while visiting Martin Sarter’s lab at the University of Michigan.

A belief that drives various projects in the Tuszynski lab is that cholinergic signaling facilitates cortical reorganization. We have previously shown that ablation of either global or local cholinergic inputs impairs cortical plasticity and learning associated with such plasticity [6]. Our belief is that connectivity between active neurons is augmented in the presence of acetylcholine. Thus, circuits mediating a particular behavior or cortical response are strengthened by cholinergic signaling. However, it is believed that acetylcholine release is not specific to neurons or circuits, but instead is released via volume transmission. Studies in our lab further suggest that cortical cholinergic innervation (and release) is independent only at the level of modality (e.g., motor cortex, visual cortex, etc), and within each modality, acetylcholine release is global. This scenario presents a potential problem: how can specific circuits within a modality be selectively strengthened during learning? Surely there are extraneous circuits activated around the time of our behavior/event of interest which we would not want to augment.

One plausible answer lies in acetylcholinesterase (AChE), the enzyme responsible for the breakdown of acetylcholine. The action of AChE is one of the fastest known among enzymes, with an ability to break down 5,000 molecules of ACh per second. Consequently, although ACh may flood a particular modality during its release, its temporal characteristics are more important than its spatial properties. For example, although ACh may flood the entire auditory cortex when a behaviorally relevant tone is played, only the neurons active during the brief period of increased ACh will be affected.

Armed with this interpretation, I spent several months in Dr. Sarter’s lab working with amperometric probes designed to measure ACh levels with subsecond resolution (see a very cool paper from his lab using this technique here [7]). My specific hypothesis was that cholinergic signaling would be phase locked to a behaviorally relevant event (in my case, ACh release would coincide with individual forelimb reaches during skilled forelimb reach training). That data will have to wait for another time. However, I took advantage of the microdialysis expertise in the Sarter lab to investigate whether ACh levels increased in the motor cortex during performance of the skilled forelimb reaching task. My sample size was low (9 sessions from 3 animals). But the data were rather nice, and I believe they should be added to our collective knowledge base, preliminary as they may be.


Methods

Three young adult Fischer-344 male rats were used for this study. Each animal was implanted with a cannula targeting the forelimb region of the motor cortex contralateral to the forepaw used for reaching. Animals were acclimated to the reaching chamber for a period of five days. During this time, animals were shaped to reach through an opening in the chamber to retrieve a single sugar pellet located approximately 2 cm away. The single-pellet reaching apparatus has been described previously [8]. Animals were trained for a period of three weeks. On training days 1, 6, and 12, microdiaylsis probes were inserted though the cannula and into the motor cortex. Animals were allowed to acclimate to the probe for a period of 3 hours prior sample collection. Samples were collected in 8-minute bins. Four collections were made prior to task performance, 5 collections were made during training, and 4 additional collections were made post training. Further details of the microdialysis method can be found elsewhere [9]. Animals were allowed to continuously reach for pellets during task-collection bins, with animals averaging between 300-400 reaches over the 40-minute period.


Results

Figure 1: ACh levels are increased throughout task performance vs. pre and post performance

Because the efficacy of individual probes differed between sessions, measurements are relative to either pre-task levels, or pre- and post-task levels combined. Figure 1 shows the ratio of ACh levels by collection bin relative to the averaged pre-task values. Acetylcholine values were greater during reach training compared to pre- (and post-) reaching conditions. The combined average of all reaching bins (standardized to the combined average of both the pre- and post-reaching conditions) showed a 1.85-fold increase in ACh levels during reach training (SD = 0.71).

Summary

Acetylcholine levels showed a marked increase within the forelimb region of the motor cortex throughout forelimb reach training. It should be noted that the increase in ACh signaling was immediate (present during the first bin), enduring (elevated throughout all bins), and confined to bins where reaching was executed (levels dropped off immediately following termination of training). The current results are in agreement with previous findings demonstrating that cholinergic signaling in the motor cortex is important for acquisition of skilled forelimb reaching, as well as the cortical organization accompanying such leaning [10]

Caveats

Several crucial controls are absent, limiting the interpretation of these results. Foremost is the lack of an activity control condition. It’s possible that the increased activity within the motor cortex during reach training, and not skill learning per se, is driving the observed increase in ACh detection during performance. Additionally, ACh levels were exclusively measured within the motor cortex. Thus, the increase seen may not be selective to M1, but may reflect a global increase in cholinergic signaling throughout the cortex during an attentionally demanding behavioral task.


Acknowldegements

Many thanks to Martin Sarter (UMich), Mark Tuszynski (UCSD, VA hospital), and James Conner (UCSD) for their guidance, and Damon Young (UMich) for his technical assistance.


References

  1. ↑ Bakin JS, Weinberger NM. Induction of a physiological memory in the cerebral cortex by stimulation of the nucleus basalis. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11219-24.
  2. ↑ Conner JM, Chiba AA, Tuszynski MH. The basal forebrain cholinergic system is essential for cortical plasticity and functional recovery following brain injury. Neuron. 2005 Apr 21;46(2):173-9.
  3. ↑ Kilgard MP, Merzenich MM. Cortical map reorganization enabled by nucleus basalis activity. Science. 1998 Mar 13;279(5357):1714-8.
  4. ↑ Conner JM, Kulczycki M, Tuszynski MH. Unique contributions of distinct cholinergic projections to motor cortical plasticity and learning. Cereb Cortex. 2010 Nov;20(11):2739-48.
  5. ↑ Rasmusson DD, The role of acetylcholine in cortical synaptic plasticity. Behav Brain Res. 2000 Nov;115(2):205-18.
  6. ↑ Conner JM, Culberson A, Packowski C, Chiba AA, Tuszynski MH. Lesions of the Basal forebrain cholinergic system impair task acquisition and abolish cortical plasticity associated with motor skill learning. Neuron. 2003 Jun 5;38(5):819-29.
  7. ↑ Parikh V, Kozak R, Martinez V, Sarter M. Prefrontal acetylcholine release controls cue detection on multiple timescales. Neuron. 2007 Oct 4;56(1):141-54.
  8. ↑ Conner JM, Culberson A, Packowski C, Chiba AA, Tuszynski MH. Lesions of the Basal forebrain cholinergic system impair task acquisition and abolish cortical plasticity associated with motor skill learning. Neuron. 2003 Jun 5;38(5):819-29.
  9. ↑ Kozak R, Martinez V, Young D, Brown H, Bruno JP, Sarter M. Toward a neuro-cognitive animal model of the cognitive symptoms of schizophrenia: disruption of cortical cholinergic neurotransmission following repeated amphetamine exposure in attentional task-performing, but not non-performing, rats. Neuropsychopharmacology. 2007 Oct;32(10):2074-86.
  10. ↑ Conner JM, Kulczycki M, Tuszynski MH. Unique contributions of distinct cholinergic projections to motor cortical plasticity and learning. Cereb Cortex. 2010 Nov;20(11):2739-48.


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