Strengthening of horizontal cortical connections following skill learning

Rioult-Pedotti, M. S., et al. (1998)

Commentary by:

Brian Prinzen Emine Duygu Nangir

Zachary Saadon Anteneh Kassa

Outline

Summary Pros Methodological Critique

Synaptic Changes Contradicting Evidence Future Implications Conclusion

Zach Saadon

Summary - Hypothesis

Motor skill learning strengthens horizontal connections in rat M1 using an LTP-like mechanism

Zach Saadon

Summary - Methods

Training condition Paired controls Unpaired controls Ipsilateral control Forelimb vs. hindlimb Field potentials recorded using glass

micropipettes placed in layer II/III of M1 slice

Zach Saadon

Summary – Results

Field Potentials: Trained M1 > Untrained Trained > Control Hindlimb region showed

no amplitude difference

Zach Saadon

Summary - Conclusions

The learning of a motor skill engages an LTP-like process – thus mediating the strengthening of horizontal cortical connections

Zach Saadon

Pros

Right handed rats Use of multiple controls Testing for electrically induced LTP

Zach Saadon

Synaptic Changes

Brian Prinzen

Pyramidal arrangement of motor skills

A combination of previously known motor skills

A complex motor skill is often composed of a fixed sequence of movements

Hikosaka et al.

Synaptic Changes METHODOLOGY

Brian Prinzen

Synaptic Changes METHODOLOGY

Changes represent a new motor skill or an adaptation and combination of previously learned motor skills?

“These tasks may be considered forms of motor-skill learning because the motor actions appear to have required the acquisition of novel spatiotemporal muscle activity patterns, but they also include forms of adaptation. It remains a challenge to evaluate whether modifications following this type of learning reflect the process of learning or altered motor actions” Sanes and Donoghue (2000)

Brian Prinzen

Synaptic Changes IMPLICATIONS

No denying the change in synaptic efficacy

Too quick to interpret data “we currently have no idea how increases in

synaptic efficacy among the horizontal connections of the forelimb region of M1 can encode a complex spatiotemporal sequence of movements”

Martin and Morris, 2001

Do changes represent actual motor program engram or some auxiliary information processing purpose?

Brian Prinzen

Synaptic Changes IMPLICATIONS

If novel motor action produced changed in synaptic efficacy in left brain, why do we not see any changes in right brain?

Left forelimb performed “new motor skill”, but no change in right M1 “The difference between untrained M1 and left and right M1 of

controls was not significant.” Rioult-Pedotti et al.

Evidence for lack of novelty and synaptic change representing information processing Whether the precise pattern of changes in synaptic strengths

constitutes and engram of the motor program for the execution of the task, or whether such changes have some ancillary information processing role.”

Martin and Morris, 2001

Brian Prinzen

Contradictory Evidence

Anteneh Kassa

Contradictory Evidence

Skilled motor learning does not enhance long-term depression in the motor cortex in vivo

(Castro & Cohen, 2004)

AIM- Investigate how learning a reaching task affects excitability, short-term, & long-term plasticity

Anteneh Kassa

Contradictory evidence

RATIONAL

learning is expected to produce bi-directional changes while stress produces uni-directional changes

METHOD

compare food deprived trained rats with food deprived untrained rats and naïve controls

Anteneh Kassa

ResultsAnteneh Kassa

Cohen, J. D. et al. J Neurophysiol 93: 1486-1497, 2005

Results

LFS to induce LTD Controls had

significantly lower levels of LTD

Food deprivation resulted in increased LTD in the other groups

Anteneh Kassa

What’s going on?

Why was there no difference in excitability between trained and untrained hemispheres?

Why did the slice studies not reveal an effect of food deprivation and handling on LTD?

Anteneh Kassa

Look for LTP in spinal cord neurons Central pattern

generators Neurons in the spinal

cord receive projections from the motor cortex

Measure field potentials

Anteneh Kassa

Suggestions for methodology

Compare the effects of food deprivation

Look for LTP in spinal cord neurons

Include a group that was administered NMDA antagonists and measure learning ability

Anteneh Kassa

Further Implications

Duygu Nangir

Further Implications

LTP processes have been correlated to symptoms of Schizophrenia, Parkinson’s and Alzheimer's and may be involved in these neurodegenerative disorders.Are related to disrupted plasticity in the cortex

There has been many studies that relate LTP to these neurodegenerative disorders, including those that are involved in motor learning and other processes

Duygu Nangir

Further Implications

Direct evidence of LTP motor learning in Schizophrenia

Concludes that: SCZ patients revealed a correlation between LTP with motor

skill learning; the deficit in learning & memory in SCZ may be acting through or dependent of a disconnected LTP

Association between LTP-like plasticity & motor skill learning suggestion that a disruption of neural plasticity may underlie the deficits in learning & memory and in the actual disorder of Schizophrenia

Frantseva et. al, 2007

Duygu Nangir

Further ImplicationsArticle topic: What they set to

prove (purpose)Conclusion Relation to LTP and

motor learning

Age-Dependent Modulation of Hippocampal Long-Term Potentiation by Antioxidant Enzymes (Journal of Neuroscience Research, 2006)

examine the effects of the antioxidant enzymes, which produce and remove

H2O2, respectively, on

LTP forms of synaptic plasticity during aging.

observations suggest

that both O2 and H2O2

also play a positive facilitatory role in LTP forms of synaptic plasticity in the mammalian hippocampus

oxidative stress is associated with aging & neurodegenerative disorders [Alzheimer's, Parkinson’s]since LTP has age related deficits, factors all link to LTP & symptoms are motor deficits

Interference of chronically ingested copper in long-term potentiation (LTP)of rat hippocampus (Brain Research, 2005)

find the evidence of copper interaction in LTP, stimulated by copper involvement in neurodegenerative illness, like Parkinson, & Alzheimer.

results show that copper reduces synaptic sensibility. These effects represent a significant disturbance in the plasticity phenomenon associated with learning and memory

copper suppresses LTP, maintaining the function of synaptic traffic – copper blocks the receptors in LTPAffect synaptogenesis, learning & memory (learning motor skills are symptoms of disorders)

Duygu Nangir

ConclusionRelating to the Article

Pros(good, correlating parts of the study)

1. Use right-handed rats (creates a good control)2. Use multiple controls (ipsilateral vs. contraleral; trained vs.

paired; trained vs. naïve; hind-limb vs. fore-limb)3. Testing for electrically induced LTP

Cons(what could have been done better)

1. We can't deny the presence of changes in synaptic pathways, but we need to evaluate if they are due to the learning of a new motor skill or just the adaptation of old skills

2. LTP is bi-directional (not uni-) in LTP & LTD; no LTD+rats show LTP from stress & food deprivation

Suggestions(what can be changed to improve the study)

1. Use NMDA antagonists & measure ability to induce LTP ex vivo (M1 relies on NMDA for LTP)

2. Since M1 neurons are connected to neurons in spinal cord, they can measure LTP in spinal cord

Discussion(how this study has affected future studies)

Motor learning deficits have been correlated to neurodegenerative disorders that involved LTP-like plasticity in the brain

Neurodegenerative disorders: Schizophrenia, Alzeihemer’s & Parkinsons

Duygu Nangir

ReferencesRioult Pedotti, M.S., Friedman, D., Hess, G., Donoghue, J.P., (1998). Strengthening of

horizontal coritcal connections folowing skill learning. Nature, 1(2), 230-234Martin, S.J., Morris, R.G.M. (2001). Cortical Plasticity: It’s All the Range! Current Biology,

11, R57-R59Rioult-Pedotti, M. S., Friedman, D., & Donoghue, J. P. (2000). Learning-induced LTP in

neocortex. Science (New York, N.Y.), 290 (5491), 533-536. Cohen, J.D., & Castro, M.A. (2004). Skilled motor learning does not enhance long-term

depression in the motor cortex in vivo. Journal of Neurophysiology. (Bethesda MD), 93, 1486-1497

Goldschmith, et al. (2005). Interference of chronically ingested copper in long-term potentiation (LTP) of rat hippocampus. Brain Research, 1056 (2), 176-82

Watson, et al. (2006). Age-dependant modulation of hippocampal long-term potentiation by antioxidant enzymes. Journal of Neuroscience Research, 84, 1564-1574

Frantseva, et al. (2008). Evidence for impaired long-term potentiation in schizophrenia and its relationship to motor skill learning. Cerebral Cortex, 18 (5), 990-6

Sanes, J.N., Donoghue, J.P. (2000). Plasticity and Primary Motor Cortex. Annual Review of Neuroscience, 23, 393-415

Hikosaka, O., Nakamura, K., Sakai, K., Nakahara, H. (2002) Central Mechanisms of Motor Skill Learning. Current Opinion in Neuroscience.12 217-222

Questions?Questions?