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要旨

Neural coding in medial prefrontal cortex (mPFC) is thought to underlie various cognitive behaviors
such as rule-guided learning, strategy use, or cognitive flexibility. Specifically, prefrontal
neurons display many behaviorally relevant correlates related to sensory perception,
motor responses, or reward that are believed to contribute to behavioral outcome. The
mPFC is the cortical region that receives exceptionally dense dopaminergic (DA) innervation
arising from the mesopontine Ventral Tegmental Area (VTA). Noradrenergic fibers originating
from the brain stem nucleus Locus Coeruleus (LC) are also dense in mPFC. Previous investigations
indicated that NA and DA systems have common target neurons in mPFC. The
ascending NA and DA projections to mPFC have been implicated in a broad range of cognitive
processes in rodents and primates including modulation of perception, attention, motivation,
or memory. It is still, however, unknown whether and how NA and DA affect the prefrontal
neural codes.
To address this question, we performed simultaneous recordings of unit activity and local
field potentials in mPFC, VTA and LC in the rat. We first studied temporal relations of firing
activity in the three brain regions during spontaneous and evoked activity under anesthesia.
Mild electric shocks were applied to the rat hind paw for somatosensory stimulation. The LC
neurons responded to a single foot shock (1ms, 5mA) with a short latency (~20ms), phasic
burst, followed by brief inhibition. Trains of pulses (100ms, 50Hz, 5mA) elicited much
stronger responses. The mPFC and VTA neurons did not respond to a single foot shock.
Trains elicited sustained (~1s) excitatory responses in a subpopulation of mPFC neurons
with latencies of ~100ms, usually followed by inhibition. Trains elicited both excitatory and
inhibitory responses in a small number of putative dopaminergic, VTA cells, with latencies
always greater than 100ms. Both spontaneous and evoked activity of VTA neurons was highly
synchronized with mPFC activity; cortical activity always led VTA by several milliseconds.
In some cases, sensory stimulation resulted in entrainment of mPFC and VTA neurons in several
cycles of slow oscillation. Next, we inhibited the LC by systemic or local application of
clonidine, an α2-adrenergic receptor agonist. This manipulation dramatically abolished the
excitatory evoked responses in both VTA and mPFC without having much effect on spontaneous
activity.
The results indicate that short-latency responses of LC neurons to somatosensory stimulation
with corresponding release of NA modulate sensory responses in the target regions including
mPFC and VTA. The long-latency responses of the VTA cells suggest that its ascending
projections do not play an important role in modulating mPFC responses to noxious stimuli.
VTA activity is rather driven by mPFC and, possibly, modulated by LC.
We will further investigate NA modulation of mPFC codes in the rat performing a prefrontaldependent
task. To induce release of NA in mPFC, we will apply electrical microstimulation
to the LC just before presentation of discrimination stimuli, mimicking the burst activity of
LC typically observed in response to salient stimuli. We expect to see more robust coding in
the mPFC correlated with better behavioral performance in the presence of LC activation.