Strengthening of horizontal cortical connections following skill learning Rioult-Pedotti, M. S., et al. (1998) Commentary by: Brian Prinzen Emine Duygu Nangir Zachary SaadonAnteneh 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

Results Anteneh Kassa Cohen, J. D. et al. J Neurophysiol 93: , 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 Implications Article 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 H 2 O 2, respectively, on LTP forms of synaptic plasticity during aging. observations suggest that both O 2 and H 2 O 2 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 LTP  Affect synaptogenesis, learning & memory (learning motor skills are symptoms of disorders) Duygu Nangir

Conclusion Relating 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

References Rioult Pedotti, M.S., Friedman, D., Hess, G., Donoghue, J.P., (1998). Strengthening of horizontal coritcal connections folowing skill learning. Nature, 1(2), Martin, S.J., Morris, R.G.M. (2001). Cortical Plasticity: It’s All the Range! Current Biology, 11, R57-R59 Rioult-Pedotti, M. S., Friedman, D., & Donoghue, J. P. (2000). Learning-induced LTP in neocortex. Science (New York, N.Y.), 290 (5491), 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, Goldschmith, et al. (2005). Interference of chronically ingested copper in long-term potentiation (LTP) of rat hippocampus. Brain Research, 1056 (2), Watson, et al. (2006). Age-dependant modulation of hippocampal long-term potentiation by antioxidant enzymes. Journal of Neuroscience Research, 84, Frantseva, et al. (2008). Evidence for impaired long-term potentiation in schizophrenia and its relationship to motor skill learning. Cerebral Cortex, 18 (5), Sanes, J.N., Donoghue, J.P. (2000). Plasticity and Primary Motor Cortex. Annual Review of Neuroscience, 23, Hikosaka, O., Nakamura, K., Sakai, K., Nakahara, H. (2002) Central Mechanisms of Motor Skill Learning. Current Opinion in Neuroscience

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