HOT TOPICS
Throwing Some Light on Executive Function in Parkinsons Disease
Narayanan NS, Land BB, Solder JE, Deisseroth K, DiLeone RJ. Prefrontal D1 dopamine signaling is
required for temporal control. Proc Natl Acad Sci U S A 2012;109:2072620731.
Other than the core motor disorder of Parkinsons disease
(PD), cognitive impairment is a prominent nonmotor feature of
the disease. In the spectrum of cognitive impairment, the
temporal processing of movements appears to be dramati-
cally impaired. To date, treating this cognitive deficit remains
problematic.
In a recent study, Narayanan et al. elegantly studied the
neural circuitry underlying temporal control. This executive
function is critical for guiding movements in time in order to
achieve behavioral goals. By using a fixed-interval timing
task, rats were submitted to a simple behavioral sequence
comprising responding to a reward after a 20-second unre-
warded interval. Silencing dopaminergic neurons from the
ventral tegmental area resulted in impairments in the behav-
ioral sequence allowing performance of the task. After
showing that the mesolimbic dopaminergic neurons were
involved in temporal control, subsequent investigations
focused on their prefrontal targets. First, inactivating the
prefrontal cortex with muscimol further confirmed the
involvement of this region by impairing the animals perform-
ance. Then, the alternating injection of D1 or D2 receptor
antagonists within the prefrontal cortex allowed the prefer-
ential role of D1-mediated circuitry in temporal control to be
highlighted. Finally, to refine the role of prefrontal D1-related
pathways, an optogenetic-mediated activation or inhibition
of D1 neurons was used. When confronted with the fixed-
interval timing task, the photoinhibition of D1-expressing
neurons transiently reduced the optimal responding behav-
ior. Conversely, photostimulation increased the animals
response to the reward. By impacting upon response effi-
ciency rather than shifting response in time, these observa-
tions argue for a top-down control of behavioral goals
assumed by prefrontal regions. Together, the results pro-
vided by Narayanan et al. increase our understanding of the
involvement of the mesolimbic dopaminergic circuitry and
prefrontal D1 neurons in mediating cognitive function.
Cognitive impairments in PD appear from the early stages
of the disease and dopaminergic treatments can be beneficial
in improving some frontal abnormalities.1 Levodopa has, how-
ever, been proposed to act with an inverted U function2 and
doses usually given to treat motor symptoms may be deleteri-
ous to cognitive tasks.3 D1-D2 agonists provide inconsistent
results by either being ineffective4 or beneficial5 on several
cognitive functions, probably via the same inverted U-shaped
relationship observed for L-dopa.6 An effect of dopamine ago-
nists is found in de novo patients,4,5 but as the disease pro-
gresses, the amount of drug necessary to alleviate motor
symptoms might overdose the relatively spared mesolimbic
pathways7 and be subsequently detrimental. Moreover, as for
motor side effects, chronic dopaminergic stimulation seems
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Relevant conflicts of interest/financial disclosures: Nothing to report.
Published online in Wiley Online Library (wileyonlinelibrary.com).
DOI: 10.1002/mds.25477
1052 Movement Disorders, Vol. 28, No. 8, 2013
to be deleterious to cognitive processing, limiting its thera-
peutic efficacy.8 Together, these findings suggest that the
temporal window during which pharmacological treatment
might improve executive function in PD is narrow and only
select cognitive domains may benefit. Although promising,
the findings from Narayanan et al. should therefore be inter-
preted with caution. Nevertheless, the temporal resolution
offered by optogenetics illustrates a fine control of the pre-
frontal circuitry that might be crucial for efficient cognitive
functioning. Further studies using an nonpharmacological
approach might be helpful to identify new therapeutic
strategies.
Michel Engeln, MS
Institut des Maladies Neurodegeneratives,
CNRS UMR 5293, Bordeaux, France
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