Dispatches
Serotonin: Waiting but Not Rewarding
A new study in mice demonstrates that stimulating dorsal raphe serotonin
boosts patient waiting but stimulation itself is not rewarding. Dorsal raphe
serotonin’s unique contribution provides a neural locus for impulsivity and
related failures of patience.
Michael A. McDannald
Stopping by the cafe´ on your way to
work you find an unusually long queue.
Today’s coffee is going to require more
than just a few dollars, it’s going to
require patience. Are you able to wait?
If yes, you may have your dorsal raphe
serotonergic neurons to thank. In this
issue of Current Biology, Fonseca,
Murakami and Mainen
[1]
report that
stimulating dorsal raphe serotonin in
mice boosts patient waiting for a
reward, even though this stimulation
itself is not rewarding.
There has been recent interest in
elucidating the role of dorsal raphe
serotonin in patience
[2]
and reward
[3]
.
This has been driven in part by
advances permitting the selective
excitation of serotonergic neurons in
awake-behaving mice
[4]
. It also
reflects an appreciation for the
long-standing role of serotonin as a
neuromodulator with widespread
projections to the midbrain, forebrain
and prefrontal cortices
[5]
. To date, the
precise role of dorsal raphe serotonin in
patience and reward has been unclear.
Single unit recording has demonstrated
signals for both patience
[6]
and reward
[7]
. One recent study
[2]
found
stimulation of dorsal raphe serotonin
neurons to selectively increase patient
waiting, while another
[3]
found it to be
intrinsically rewarding.
So is dorsal raphe serotonin critical
to waiting or is it a signal for reward?
In the laboratory, as in life, waiting
patiently to receive a reward is
intimately linked to the reward itself.
With this in mind Fonseca et al.
[1]
devised a series of tasks that
separately assessed the contribution of
dorsal raphe serotonin stimulation to
patience and reward. To do this, a
blue-light sensitive ion channel that
permits rapid neural excitation,
channelrhodopsin, was selectively
expressed in serotonergic neurons of
SERT-Cre (SERT) mice — in which
CRE recombinase is expressed under
control of the serotonin transport
(SERT) promoter — so that blue-light
simulation would rapidly excite dorsal
raphe serotonin neurons in the SERT,
but not wild-type, mice.
The first task for the mice examined
patient waiting using a particularly
elegant design. Mice were required
to hold in a waiting port until a tone
was delivered, at which time they
responded to a reward port below.
The wait time was adjusted so that
mice succeeded roughly half the time,
allowing for increases or decreases in
patient waiting to be observed. SERT
and wild-type mice were given trials in
which the amplitude and frequency
of blue-light stimulation were varied.
The results were clear: blue-light
stimulation during the waiting period
facilitated patient waiting in SERT mice,
but not wild-type mice, in a
dose-dependent manner. That is,
increasing amplitude and frequency of
blue-light, thereby increasing the firing
of dorsal raphe neurons, boosted
patient waiting. Analysis of other task
periods found this enhancement in
patient waiting was not simply due to
motor effects. Of course, this result
would also be expected if stimulation
of dorsal raphe serotonin was itself
rewarding.
To rule out this possibility, mice were
tested in two place-preference
procedures. The place-preference
apparatus was composed of two
distinct compartments: one was paired
with blue-light stimulation, while the
other was not. If stimulation of
serotonergic neurons was rewarding,
SERT mice should have come to
prefer the stimulated compartment.
When tested no such preference was
found. An identical result was obtained
when the place preference was
assessed in ‘real time’, meaning that
entering one compartment produced
serotonin stimulation whereas entering
the other compartment did not. The
choice of which compartment to enter
was indifferent to serotonin
stimulation.
OFC
mPFC
NAcc
VTA
DR
Non-serotonergic
(Reward)
Serotonergic
(Patience)
Current Biology
Figure 1. Separate dorsal raphe circuits for waiting and reward.
A sagittal view of the rodent brain is shown. Dorsal raphe (DR) serotonergic projections (red) to
the orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC) and/or nucleus accumbens
(NAcc) are candidate brain regions to integrate the serotonin signal with patient waiting. Dorsal
raphe non-serotonergic projections (blue) to the ventral tegmental area (VTA) mediate reward.
Dispatch
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It is possible that dorsal raphe
serotonin is not rewarding outright,
but may serve to influence processing
of real-world rewards. To assess
this possibility, the mice performed a
task in which they chose to enter one
of two wells. Each well was associated
with different probabilities of reward
as well as different probabilities of
serotonin stimulation. These
probabilities were varied across
blocks’ allowing the authors to track
choice behavior as a function of
reward probability and/or stimulation
probability. Only reward probability
influenced choice behavior.
Dorsal raphe serotonin stimulation did
not bias choice behavior in any
direction.
Stimulation of dorsal raphe
serotonergic neurons that is sufficient
to boost patient waiting is insufficient
to be rewarding. The finding of a
selective role for serotonin in
boosting patience is strengthened
by recent findings that stimulation of
non-serotonergic dorsal raphe neurons
is rewarding
[8,9]
. Taken together,
the results suggest there are separate
circuits for patience and reward in
the dorsal raphe (
Figure 1
).
Non-serotonergic signals for reward
are mediated through projections to
ventral tegmental area
[8,9]
. Candidate
regions to implement serotonergic
signals for patience are the nucleus
accumbens, prefrontal and
orbitofrontal cortices
[10]
. These
regions are integral to goal-directed
actions
[11–13]
and receive strong
serotonergic input
[5]
.
The need for patience extends well
beyond getting your morning coffee.
An inability to exercise patience
(impulsivity) is a prominent component
of attention-deficit/hyperactivity
disorder and addiction
[14]
. By
identifying dorsal raphe serotonin
neurons as a central node, future
studies may rapidly identify a more
complete neural circuit for patient
waiting.
References
1. Fonseca, M.S., Murakami, M., and Mainen, Z.F.
(2015). Activation of dorsal raphe
serotonergic neurons promotes waiting
but is not reinforcing. Curr. Biol. 25,
306–315.
2. Miyazaki, K.W., Miyazaki, K., Tanaka, K.F.,
Yamanaka, A., Takahashi, A., Tabuchi, S., and
Doya, K. (2014). Optogenetic activation of
dorsal raphe serotonin neurons enhances
patience for future rewards. Curr. Biol. 24,
2033–2040.
3. Liu, Z., Zhou, J., Li, Y., Hu, F., Lu, Y., Ma, M.,
Feng, Q., Zhang, J.E., Wang, D., Zeng, J., et al.
(2014). Dorsal raphe neurons signal reward
through 5-HT and glutamate. Neuron 81,
1360–1374.
4. Zhuang, X., Masson, J., Gingrich, J.A., Rayport,
S., and Hen, R. (2005). Targeted gene
expression in dopamine and serotonin neurons
of the mouse brain. J. Neurosci. Meth. 143,
27–32.
5. Vertes, R.P., and Linley, S.B. (2007).
Comparison of projections of the dorsal and
median raphe nuclei, with some functional
considerations. In The Interdisciplinary
Conference on Tryptophan and Related
Substances: Chemistry, Biology, and Medicine.
Proceedings of the Eleventh Triennial Meeting
of International Study Group for Tryptophan
Research, Volume 1304. (Sanjyo-Kaikan
Conference Hall, The University of Tokyo), pp.
98-120.
6. Miyazaki, K., Miyazaki, K.W., and Doya, K.
(2011). Activation of dorsal raphe serotonin
neurons underlies waiting for delayed rewards.
J. Neurosci. 31, 469–479.
7. Nakamura, K., Matsumoto, M., and Hikosaka,
O. (2008). Reward-dependent modulation
of neuronal activity in the primate dorsal
raphe nucleus. J. Neurosci. 28,
5331–5343.
8. McDevitt, R.A., Tiran-Cappello, A., Shen, H.,
Balderas, I., Britt, J.P., Marino, R.A., Chung,
S.L., Richie, C.T., Harvey, B.K., and Bonci, A.
(2014). Serotonergic versus nonserotonergic
dorsal raphe projection neurons: differential
participation in reward circuitry. Cell Rep. 8,
1857–1869.
9. Qi, J., Zhang, S., Wang, H.L., Wang, H., de
Jesus Aceves Buendia, J., Hoffman, A.F.,
Lupica, C.R., Seal, R.P., and Morales, M. (2014).
A glutamatergic reward input from the dorsal
raphe to ventral tegmental area dopamine
neurons. Nat. Commun. 5, 5390.
10. Miyazaki, K., Miyazaki, K.W., and Doya, K.
(2012). The role of serotonin in the regulation of
patience and impulsivity. Mol. Neurobiol. 45,
213–224.
11. Gallagher, M., McMahan, R.W., and
Schoenbaum, G. (1999). Orbitofrontal cortex
and representation of incentive value in
associative learning. J. Neurosci. 19,
6610–6614.
12. Coutureau, E., and Killcross, S. (2003).
Inactivation of the infralimbic prefrontal cortex
reinstates goal-directed responding in
overtrained rats. Behav. Brain Res. 146,
167–174.
13. Corbit, L.H., and Balleine, B.W. (2011). The
general and outcome-specific forms of
pavlovian-instrumental transfer are
differentially mediated by the nucleus
accumbens core and shell. J. Neurosci. 31,
11786–11794.
14. Urcelay, G.P., and Dalley, J.W. (2012). Linking
ADHD, impulsivity, and drug abuse: a
neuropsychological perspective. Curr. Top.
Behav. Neurosci. 9, 173–197.
Department of Psychology, Boston College,
140 Commonwealth Avenue, Chestnut Hill,
MA 02467, USA.
E-mail:
michael.mcdannald@bc.edu
http://dx.doi.org/10.1016/j.cub.2014.12.019
Animal Navigation: Memories
of Home
Sea turtles memorize the magnetic coordinates of their natal beach, returning
to that combination of parameters to lay eggs decades later. The intervening
secular (year-to-year) variation in field intensity and inclination can lead the
nesting females to a series of predictably different beaches.
James L. Gould
Most long-distance migrants make
their initial journey from home flying or
swimming solo, often at night
[1]
. Many
return later to their natal area with
considerable precision. To accomplish
this feat, the young animal is
hypothesized to ‘imprint’ on the nest
site, storing navigational information
for later use. The subsequent return
must depend on some combination of
wide-area information and local cues.
The basis of the larger-scale ability is
that mystery of mysteries in animal
navigation, the map sense. In at least
the case of loggerhead sea turtles,
the global cues for homing after
displacement, as well as juvenile
orientation to the initial feeding area,
are unambiguously magnetic
[2,3]
. In
this issue of Current Biology, Brothers
and Lohmann
[4]
now show that the
return to the natal area is also based on
the precise intensity and inclination
of the magnetic field. Remarkably
enough, they demonstrated the reality
of this long-term navigational memory
without tracking a single turtle.
The initial proposal that the animal
map is based on magnetic parameters
arose from a series of anomalies in the
results of homing pigeon research
[5]
.
The earth’s magnetic field is aligned
with the magnetic poles. At present,
the magnetic north pole is displaced
by about 500 km from the geographic
North Pole. The total intensity of the
field increases by about a factor of two
from the magnetic equator to the poles.
Current Biology Vol 25 No 3
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