Transcript ppt5

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
Plasticity and learning
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Molecular modifications
Synaptic modifications
Cellular modifications
System/Circuit modifications
Learning
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,
and central (Chen et al., 2002; Hallett, 2001; Nudo et al.,
1996) lesions and following motor skill learning
1999)
(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?
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).
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).
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?
• 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).
• 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.
http://www.bol.ucla.edu/~nwoolf/
http://www.bol.ucla.edu/~nwoolf/
Miranda and Bernudez-Rattoni, 1999.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=26907
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
Average reaching accuracy: Intact=47.4%±3.7%; NBM lesion=21.2%±4.1%
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 singlepellet retrieval task relative to vehicle treated
animals and intact animals (p<.05), but were
not found to result in significant differences in
reaching performance compared to NBM
lesions alone (p>.05).
Motor Learning Impairments
• Were motor learning impairments in NBM and
NBM+medial septum lesioned animals a result of
attention deficits?
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.
NBM lesions and overall sensorimotor deficits
No difference
between groups
on footfalls per trial
with either the
hindpaw or forepaw.
Group 2
P>.05 for
prelesion
performance
between
groups,
postlesion
performance
between
groups and
from pre- to
post-lesion
in SAP
lesioned
animals.
50μm
AChE fibers in primary motor cortex
Control
SAP
250μm
Control
SAP
250μm
SAP lesions did not damage GABAergic neurons within the basal forebrain
Godde et al., 2002
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?
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