It has been known that there are a lot of differences in how prefrontal
neurons respond to stimuli, but nobody has really been able to map these
differences onto the intrinsic wiring of the brain.
The prefrontal cortex, a large and recently evolved structure that
wraps the front of the brain, has powerful "executive" control over
behavior, particularly in humans. The details of how it exerts that
control have been elusive, but UNC School of Medicine scientists,
publishing in Nature
, have now uncovered some of those
details, using sophisticated techniques for recording and controlling
the activity of neurons in live mice.
‘The newly discovered details about the prefontal neurons has major implications for the study of motivation, decision making, as well as addiction and other disorders.’
The UNC scientists, led by Garret Stuber, associate professor
in UNC's departments of psychiatry and cell biology & physiology,
examined two distinct populations of prefrontal neurons, each of which
project to a different brain region outside the cortex.
found that as mice learn to associate a particular sound with a
rewarding sugary drink, one set of prefrontal neurons becomes more
active and promotes what researchers call reward-seeking behavior - a
sign of greater motivation. By contrast, other prefrontal neurons are
silenced in response to the tone, and those neurons act like a brake on
Stuber, senior author of the study and member of the UNC Neuroscience Center, and colleagues obtained their findings with the use of three
sophisticated and relatively new neuroscience tools: deep-brain
two-photon imaging, optogenetics, and genetic techniques for labeling
neurons by their projection targets in the brain. The successful
combination of these tools heralds their future common use in defining
the pathways and functions of many other brain networks to help uncover
the roots of both normal and abnormal behavior.
The study, conducted by first authors and UNC postdoctoral fellows
James Otis and Vijay Namboodiri focused on the dorsomedial
(upper-middle) prefrontal cortex, or dmPFC.
"This region is critical for reward processing, decision making, and
cognitive flexibility among other things, but how distinct populations
of neurons within dmPFC orchestrate such phenomena were unclear," Stuber
Stuber and colleagues examined how the activity of dmPFC neurons
changes during a Pavlovian reward-conditioning process. In this process,
mice learn to associate an auditory tone with a taste of sugary liquid
until the tone itself is enough to make the animals start licking around
their mouths in anticipation.
"This simple experiment models a learning phenomenon that occurs in
lots of different brain regions," Stuber said. "It is critical for
motivation and decision making, and of course it can go awry in drug and
food addiction, depression, and other neuropsychiatric disorders."
As the mice in the experiment learned to associate the tone with the
sweet drink, the researchers found that a subset of the mouse dmPFC
neurons became increasingly excited when the tone sounded, whereas
another subset went increasingly silent. The researchers were able to
observe this phenomenon by using a deep-brain version of two-photon
imaging, a technique in which a microscope visualizes hundreds of brain
cells simultaneously in mice that are awake and able to perform some
The dmPFC is known to output many of its chemical signals to two
other brain regions, the nucleus accumbens (NAc) and the paraventricular
nucleus of the thalamus (PVT), both of which are considered important
for reward-directed behavior. Stuber's team found that the
NAc-projecting neurons in the dmPFC were the ones that became
increasingly excited by the tone, and the PVT-projecting neurons were
the ones that became increasingly suppressed. The two sets of neurons
turned out to be physically separate within the dmPFC only by a few
The team then used optogenetic techniques to artificially drive the
activities of these neurons. Optogenetics allows researchers to use
beams of light to activate specific populations of neurons. Driving the
NAc-projecting neurons caused the mice to anticipate their sweet reward
more intensely, with more licks after the tone. By contrast, driving the
PVT-projecting neurons muted that anticipatory, reward-seeking
The findings represent a basic demonstration of how the dmPFC has
evolved anatomically distinct neuronal populations that have
functionally distinct control over behavior, Stuber said. And the
discovery points to the existence of similar combinations of control
mechanisms elsewhere in the brain.
He and his colleagues are now following up with studies of dmPFC neurons that project to other brain regions.