ESSAY
EPPENDORF
Brains Don’t Play Dice—or Do They?
Associative brain centers are able to account
for an infinite amount of possible associations
through randomized sensory input.
L
ife is often unpredictable. The brain
thus needs to draw on past experience to prepare for future events.
It does so by associating sensory stimuli,
such as an odor, with desirable or undesirable outcomes. The smell of burning wood,
for example, can evoke the soothing recollection of a cozy campfire or the traumatic
memory of a burning house. It is through
such associations that sensory stimuli that
are a priori neutral become endowed with
meaning. But life is full of possibilities. So
how are associative brain centers able to
account for an infinite number of possible
associations?
Using the olfactory system of the fruit
fly Drosophila melanogaster, I tackled this
question in the laboratory of Richard Axel
at Columbia University (1). The Drosophila
olfactory circuit is similar to that of vertebrates in terms of its design logic, but consists of far fewer neurons. Fruit flies can
learn to associate an odor with
an electric shock or a sugar
reward. On the basis of these
associations, they will adjust
their behavior when encountering that odor again. Such
olfactory associative memories are formed in the mushroom body, a brain center
comprising about 2000 neurons (known as Kenyon cells)
and receiving mainly olfactory input (2, 3).
Fruit flies detect odors by
means of olfactory sensory
neurons located on their antennae and maxillary palps. Most
of these neurons express only
one of about 50 odorant receptor proteins (4–7). The olfactory sensory neurons project to
the antennal lobe, where they
are sorted such that neurons
expressing the same receptor converge onto one of the
51 glomeruli (6, 7). This wir-
Eppendorf and Science are pleased to present the
essay by Sophie Caron, a 2013 finalist for the Eppendorf and Science Prize for Neurobiology.
ing diagram (see the figure), in which each
odorant receptor is mapped onto one glomerulus, prefigures how odors are represented
in the antennal lobe. When an odorant molecule binds to its cognate receptors, the sensory neurons expressing these receptors fire,
and an odor-specific pattern of glomerular
activity emerges, a so-called “odor-evoked
map” (8). Projection neurons dedicated to
each glomerulus then relay olfactory information to two higher brain centers: the lateral
Mapping mushroom body connections.
(A) Schematic of the D. melanogaster olfactory circuit. All olfactory sensory neurons
expressing the same odorant receptor (like
colors) converge in one of the 51 antennal
lobe glomeruli (dotted circles). One or more
projection neurons connect each glomerulus to the lateral horn (not shown) and the
mushroom body, where associative memories are formed. How projection neurons are
wired to Kenyon cells was unknown. (B and
C) Mapping Kenyon cell inputs (Scale bars,
10 µm). (C) Starting with a single photolabeled Kenyon cell (white arrowhead), a projection neuron (red) connected to one of the
dendritic endings of that Kenyon cell (red
arrowhead) was filled with dye. (B) The innervation pattern of the red-labeled projection
neuron in the antennal lobe allows for the
identification of the corresponding glomerulus (arrowhead). (D) Matrix of 654 connections between 51 glomeruli and 200 Kenyon
cells. Each row corresponds to the glomerular inputs of a single Kenyon cell, and each
column represents one of the antennal lobe
glomeruli. Red bars indicate a connection
between a Kenyon cell and a glomerulus.
Yellow bars indicate two connections to the
same glomerulus. Differences in the number
of connections per glomerulus are a function of the number of synaptic endings of
their projection neurons. Statistical analyses
revealed a random pattern of connectivity.
Department of Neuroscience, Columbia University, 701 West 168th
Street, New York, NY 10032, USA.
E-mail: [email protected]
1 NOVEMBER 2013
horn, which mediates innate behaviors, and
the mushroom body, where associative olfactory memories are formed (9, 10).
How does the mushroom body represent odors such that olfactory associations
can emerge? We reasoned that, much like in
the antennal lobe, the wiring diagram might
hold the key. Together with my colleagues
at Columbia University, I developed a technique to identify the input of individual Kenyon cells. Kenyon cells were labeled in order
to visualize their synaptic endings, revealing
that each Kenyon cell is connected to, on average, seven projection neurons. Subsequently,
between two to seven of the connected projection neurons were marked with a neural
tracer such that their cognate glomeruli could
be identified. We charted 654 connections of
200 Kenyon cells and assigned them to the
51 antennal lobe glomeruli (11). Some glomeruli are represented more often than others,
but this skewed frequency is simply a conse-
VOL 342
SCIENCE
Published by AAAS
www.sciencemag.org
574b
Downloaded from www.sciencemag.org on August 19, 2015
Sophie J. C. Caron
ESSAY
Finalist
Sophie Caron is currently a postdoctoral fellow in the Department of Neuroscience at Columbia University. Sophie grew up
in St-Blaise-sur-Richelieu in Canada and earned a B.Sc. in Biochemistry at the Université de Montréal. She moved to New York
City to study the developmental mechanisms behind the diversification of sensory neurons in the laboratory of Dr. Alexander
Schier at New York University and, later, Harvard. Having completed her Ph.D., Sophie joined the laboratory of Dr. Richard
Axel at Columbia University, where she studies how the information gathered through the senses is represented in higher brain
centers, in particular those involved in memory.
For the full text of finalist essays and for information about applying for next year’s awards,
see Science Online at http://scim.ag/eppendorf.
overlap minimally between different odors.
In fact, as soon as any order is imposed on
the connections between projection neurons
and Kenyon cells, the resulting activity patterns begin to overlap and render the system
less able to form odor-specific associations.
Counterintuitive as it may seem, randomization appears to be an advantageous strategy
for forming associations, because it minimizes the similarity between different sensory representations.
The randomization of inputs we discovered in the Drosophila mushroom body
may be a general principle of neural circuit
architecture in associative brain centers. In
the vertebrate cerebellum, which processes
sensorimotor information, granule cells, like
Kenyon cells, also receive a limited number
of inputs. David Marr and James Albus postulated that, owing to their limited inputs,
the granule cells encode different motor
patterns as sparse representations; and to
accommodate more representations in the
coding space defined by granule cells, they
proposed that granule cell input would have
to be randomly organized (14).
Our characterization of Kenyon cell connections in Drosophila provides the first anatomical evidence for randomized sensory
input in an associative brain center. Randomization may be a fundamental strategy to
represent the vast number of possible associations with a limited number of neurons, it
might be the very embodiment of the unpredictability of life.
References and Notes
1. L. B. Vosshall, R. F. Stocker, Annu. Rev. Neurosci. 30, 505
(2007).
2. M. Heisenberg, Nat. Rev. Neurosci. 4, 266 (2003).
3. Y. Aso et al., J. Neurogenet. 23, 156 (2009).
4. P. J. Clyne et al., Neuron 22, 327 (1999).
5. L. B. Vosshall, H. Amrein, P. S. Morozov, A. Rzhetsky, R.
Axel, Cell 96, 725 (1999).
6. A. Couto, M. Alenius, B. J. Dickson, Curr. Biol. 15, 1535
(2005).
7. E. Fishilevich, L. B. Vosshall, Curr. Biol. 15, 1548 (2005).
8. J. W. Wang, A. M. Wong, J. Flores, L. B. Vosshall, R. Axel,
Cell 112, 271 (2003).
9. A. M. Wong, J. W. Wang, R. Axel, Cell 109, 229 (2002).
10. E. C. Marin, G. S. Jefferis, T. Komiyama, H. Zhu, L. Luo,
Cell 109, 243 (2002).
11. S. J. Caron, V. Ruta, L. F. Abbott, R. Axel, Nature 497, 113
(2013).
12. M. Murthy, I. Fiete, G. Laurent, Neuron 59, 1009 (2008).
13. K. S. Honegger, R. A. Campbell, G. C. Turner, J. Neurosci.
31, 11772 (2011).
14. D. Marr, J. Physiol. 202, 437 (1969).
Acknowledgments: I thank V. Ruta, L. F. Abbott, and R. Axel
for our collaboration.
10.1126/science.1245982
CREDIT: GEORDIE WOOD
quence of the number of presynaptic endings
specific to the different projection neurons.
Within this set of connections, we then
searched for any discernible pattern that
might predict how glomeruli connect to the
Kenyon cells. We first tested whether there
are certain pairs of glomeruli that preferentially converge on a Kenyon cell, but could
not find any preferred pairings. Likewise,
there are no Kenyon cells dedicated to a specific glomerulus. Next, we searched for any
biological criteria, such as glomerulus position, odor-response profile, or developmental origin, by which one input on a Kenyon
cell would predict its other inputs. We statistically tested more than 10 different criteria
but could not detect any such predictive pattern. Instead, the connections appeared to be
completely random (11).
To confirm this notion, we created a data
set in which the relative frequency of glomerular connections remained the same,
but the Kenyon cells that they connect to
were randomly shuffled. This shuffled data
set behaved the same as our observational
data set in all statistical tests. The lack of
any discernable pattern in the connections
between glomeruli and Kenyon cells means
that each Kenyon cell receives its input from
an essentially random set of glomeruli (11),
which is in line with the odor responses of
an individual Kenyon cell varying between
individual flies (12).
This result might seem puzzling: Why
would the ordered, odor-evoked map established in the antennal lobe be randomized
in the mushroom body? The answer may
lie in the way odors are represented there:
Any given odor activates only about 5% of
the Kenyon cells, regardless of the number of active glomeruli (13). To understand
how random connectivity affects the formation of these sparse representations, we
devised a computational model of the fly
olfactory circuit in collaboration with Larry
Abbott. The model reveals that randomization of Kenyon cell input allows the mushroom body to generate activity patterns that
www.sciencemag.org
SCIENCE
VOL 342
Published by AAAS
1 NOVEMBER 2013
574b