Lesions of the Basal Forebrain Cholinergic System Impair Task Acquisition and Abolish Cortical Plasticity Associated with Motor Skill Learning

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Lesions of the Basal Forebrain Cholinergic System
Impair Task Acquisition and Abolish Cortical
Plasticity Associated with Motor Skill Learning

• James M. Conner, Andrew Culberson,
• Christine Packowski, Andrea A. Chiba,
• and Mark H. Tuszynski

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Plasticity and learning

• Molecular modifications
• Synaptic modifications
• Cellular modifications
• System/Circuit modifications

Learning
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Reorganization of Cortical Representations

• Plasticity of adult motor representations
  following both peripheral (Cohen et al., 1991
  Donoghue et al., 1990 Sanes, et al., 1988
  Schieber and Deuet, 1997 Wu and Kaas, 1999) and
  central (Chen et al., 2002 Hallett, 2001 Nudo
  et al., 1996) lesions and following motor skill
  learning (Kleim et al., 1998 Pascual-Leone et
  al., 1995).
• Reorganization of motor maps may therefore be a
  substrate enabling normal motor learning and
  functional recovery following a lesion.
• But, is it required?

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The basal forebrain

• The basal forebrain cholinergic system may play a
  role in mediating lesion-induced plasticity of
  sensory representations.
• Excitotoxic lesions of the nucleus basalis
  magnocellularis (NBM) in rats (Juliano et al.,
  1991 Webster et al., 1991).
• Immunotoxin specific for cholinergic neurons in
  basal forebrain (Baskerville et al., 1997
  Sachdev et al., 1998 Zhu and Waite, 1998) and
  selective blockade of cholinergic signaling
  within barrel cortex (Maalouf et al., 1998).
• Selective removal of cholinergic projections to
  olfactory bulb (Linster et al., 2001).

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More from the basal forebrain

• The basal forebrain and learning
• Nonspecific NBM lesions and learning deficits
  (Olton and Wenk, 1987, review).
• Highly selective lesions of cholinergic neurons
  in basal forebrain and no (or modest) deficits
  (Baxter and Chiba 1999 Wrenn and Wiley, 1998,
  reviews).

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Now, for this study

• Postulated that a key physiological role of the
  basal forebrain cholinergic (BFC) system is to
  modulate plasticity associated with cortical
  representations
• Learning paradigms relying on cortical
  reorganizations will be especially susceptible to
  alterations to BFC function.
• What are the behavioral consequences of BFC
  lesions on learning a skilled motor task?

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• Group 1 Behavioral Consequences of NBM lesions
• Bilateral NBM lesions (11) or sham (17) prior to
  learning skilled reaching task.
• Group 2 NBM lesions and memory retention
• Trained on skilled reaching task for 3 weeks
  prior to receiving bilateral NBM lesions (12),
  bilateral injections of vehicle (3) or sham (9).
• Group 3 NBM medial septum lesions
• Bilateral lesions of both NBM and medial septum
  (6), bilateral injections of vehicle in NBM and
  medial septum (3) and sham (3).

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• Lesions induced by intraparenchymal injections of
  192-IgG-saporin (SAP) in artificial cerebrospinal
  fluid.
• 2 sites for NBM and 2 sites for medial septum
• Vehicle was artificial cerebrospinal fluid.

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http//www.bol.ucla.edu/nwoolf/
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http//www.bol.ucla.edu/nwoolf/
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Miranda and Bernudez-Rattoni, 1999. http//www.pub
medcentral.nih.gov/articlerender.fcgi?artid26907
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Skilled Reach Training and Histology

• Single-pellet retrieval task
• 15 days (first 3-4 days as shaping)
• 60 trials or 10 minutes
• 2 cm distance by d5
• Animals reached with preferred limb
• Histology
• Sections processed for AChE, receptor p75 and
  parvalbumin

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Average reaching accuracy Intact47.43.7 NBM
lesion21.24.1
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Group 3

• Is residual learning in NBM animals a result of
  unlesioned BFC neurons from the medial septum?
• Combined lesions of NBM and medial septum
  resulted in impaired acquisition of the
  single-pellet retrieval task relative to vehicle
  treated animals and intact animals (plt.05), but
  were not found to result in significant
  differences in reaching performance compared to
  NBM lesions alone (pgt.05).

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Motor Learning Impairments

• Were motor learning impairments in NBM and
  NBMmedial septum lesioned animals a result of
  attention deficits?

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Are NMB lesions specific to motor learning?
No differences were observed between groups in
activity level during training or testing. Both
groups had significant reductions in activity
level during testing relative to baseline.
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NBM lesions and overall sensorimotor deficits
No difference between groups on footfalls per
trial with either the hindpaw or forepaw.
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Group 2
Pgt.05 for prelesion performance between
groups, postlesion performance between groups and
from pre- to post-lesion in SAP lesioned animals.
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50µm
AChE fibers in primary motor cortex
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Control
SAP
250µm
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Control
SAP
250µm
SAP lesions did not damage GABAergic neurons
within the basal forebrain
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Godde et al., 2002
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Conclusions

• BFC system is necessary for mediating cortical
  plasticity associated with skilled motor learning
• Cortical map reorganization is a key substrate
  for enabling an animal to effectively learn a
  skilled motor behavior
• What do the cortical maps look like in the
  animals with NBM medial septum lesions after
  learning?

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More Conclusions

• Rats with NBM lesions had impaired, but not
  eliminated, learning of the skilled motor task
• Forelimb area was not totally abolished, but
  plasticity of the motor maps was blocked
• Some cortical control of movement
• BFC system increases efficiency of learning