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"《神经回路发育与功能：健康与疾病大脑》（Neural Circuit Development and Function in the Healthy and Diseased Brain, 2013）是一本旨在填补神经发育科学领域知识空白的重要资源。它强调了理解基因、分子和细胞层面的神经发育机制对于理解进化和神经系统疾病的重要性。随着遗传、分子和细胞生物学方法的最新进展，大量新信息不断涌现，但缺乏全面且及时的综述、参考文献和历史观点的整合。本书由约翰·R·鲁宾斯坦教授（University of California at San Francisco, 精神病学系）和帕斯科尔·拉基奇教授（耶鲁大学医学院Kavli神经科学研究所，神经生物学和神经学杜贝格教授）共同主编，两位在神经科学领域的权威人士为该系列著作奠定了坚实的基础。这本著作旨在为基础和转化神经科学家、临床医生以及学生提供宝贵的参考书籍，帮助他们深入研究神经系统的发育过程及其在健康和疾病状态下的功能变化。本书涵盖了神经回路的综合发展，探讨了从基础理论到实际应用的广泛内容，包括神经元的形成、连接网络的构建、信号传递的调控，以及这些过程如何在健康状态下保持正常，以及在疾病条件下如神经退行性疾病、精神障碍等中的异常表现。此外，书中还可能涉及神经可塑性、神经再生、以及神经保护策略等前沿议题。值得注意的是，版权信息表明，该书是学术出版社Elsevier旗下的Academic Press出版，首次发行于2013年，并强调所有内容受版权保护，未经许可不得任何形式的复制、存储或传输。通过阅读这本书，读者将获得一个系统性的框架，以便于跟踪神经发育领域的发展动态，为未来的科学研究和临床实践提供强有力的支持。"

CHAPTER

The Form and Functions of Neural Circuits

in the Olfactory Bulb

G. Lepousez, P.-M. Lledo

Institut Pasteur, Paris, France; Centre National de la Recherche Scientifique, Paris, France

OUTLINE

1.1 Introduction 3

1.2 Synaptic Organization of the Mammalian

Olfactory Bulb 4

1.2.1 Organization of Sensory Inputs 5

1.2.2 Synaptic Processing Within Olfactory Bulb

Microcircuits 6

1.2.2.1 Synaptic Transmission at the First

Synapses 6

1.2.2.2 The Dendrodendritic Synapse

Provides the Major Source of

Inhibitory Contact to Output

Neurons 8

1.2.3 Sensory Processing in the Output

Layer 9

1.2.4 Centrifugal Fibers from Higher Brain

Structures Profusely Innervate the Olfactory

Bulb 12

1.3 Circuit Development: A Lesson from Adult

Neurogenesis 13

1.3.1 Neurogenesis of Sensory Neurons in the Adult

Olfactory Epithelium 13

1.3.2 Adult-Born Interneurons in the Olfactory

Bulb 13

1.4 Structural and Experience-Induced Plasticity in

the Olfactory Bulb 14

1.4.1 Activity-Dependent Plasticity in the

Olfactory Bulb: Cell Properties and

Transmitters 14

1.4.2 Adult-Born Neurons Are Substrates for

Experience-Induced Plasticity 15

1.5 Concluding Remarks 16

Acknowledgments 16

References 16

1.1 INTRODUCTION

Sensory systems are specialized biological devices by

which organisms perceive the external sensory space. Sen-

sory perception allows the deconstruction of this external

world and the subsequent emergence of an internal per-

cept. Following this Aristotelian principle, animals can dis-

criminate and recognize an enormous range of physical

and chemical signals in their environment, which may

profoundly influence their behavior and provide them

with vital information for reproduction and survival.

Several sophisticated sen sory channels are available

for that purpose, but all of them rely on a specific set

of rules by which information is transposed from one

dimension to another. For the chemical senses, this

transposition concerns the ways in which chemical infor-

mation gives rise to specific neuronal responses in a

dedicated sensory organ (Ache and Young, 2005). In

comparison to other sen sory stimuli, odorant molecules,

that is, volatile molecules that are perceived as odors, are

infinite in terms of molecular formulae and cannot be

classified with onl y objective dimensions such as fre-

quency in the case of auditory stimuli (Laurent, 2002).

The task of perceiving an odorant is made even more

complex because a single odor usually is composed of

many types of molecules (e.g. chocolate contains more

3Neural Circuit Development and Function in the Brain: Comprehensive Developmental

Neuroscience, Volume 3 http://dx.doi.org/10.1016/B978-0-12-397267-5.00138-2

than 600 types) and is still perceived as one unique ob-

ject, distinct from its components (a process called pat-

tern completion). In addition, odor intensity (i.e.,

molecular concentration) can vary without changes in

the perceived quality (a process called perceptual stabil-

ity; Gottfried, 2010).

The origin of chemical detection (also called chemo-

sensation) certainly dates back to the begi nning of pro-

karyotes. It has evolved into distinct modalities in

vertebrates to meet crucial needs such as locating poten-

tial food sources, detecting dangers such as predators,

and mediating social and sexual interactions. Despite

these functions, which are highly conserved throughout

the evolution of species, interest in audition and vision

has largely dominated the sensory research field in neu-

roscience, leaving behind the understanding of the more

primitive chemical sense. Nevertheless, during the last

two decades, neuroscience has made considerable pro-

gress in understanding how the brain perceives, discrim-

inates, and recognizes odorant molecules so precisely. In

1991, the description of a multigene family of olfactory

G-protein-coupled receptors provided a molecular basis

for odor recognition (Buck and Axel, 1991). This discov-

ery was of great significance to the neurobiology of olfac-

tion and later was recognized with the Nobel Prize in

2004 (Mombaerts, 2004a). Since then, olfaction has

attracted the attention of neuroscientists who started to

investigate the different stages of chemosensory sys-

tems. As a result, converging approaches including anat-

omy, neurogenetics, biochemistry, cellular biology,

neurophysiology, psychology, and computational neu-

roscience have contributed to provide a picture of how

chemical information is processed in the olfactory sys-

tem, starting from the periphery to higher brain regions.

Although still incomplete, today we have a fairly com-

prehensive picture about how chemicals interact with

their cognate receptors to initiate signal transduction

in the sensory receptor cells. We also know how the ol-

factory sensory information is first transduced in the

sensory neurons located in dedicated olfactory sensory

organs (Mombaerts, 2004b). Among the differen t ele-

ments along the olfactory pathway, local circuits in the

second- and third-order central areas are key elements

that process the simple monophasic sensory signal con-

veyed by the sensory neurons and convert it into a

multidimensional content (Figure 1.1) (Gottfried, 2010;

Wilson and Sullivan, 2011).

Below, we discuss how the chemical information is

encoded and proces sed at the first central relay of the ol-

factory system, the main olfactory bulb, as well as the

functions of the bulbar neural circuits that are relevant

for triggering specific behavioral responses. In addition

to the main olfactory bulb, which relays odorant infor-

mation detected by sensory neu rons of the olfactory

epithelium, a similar structure called the accessory olfac-

tory bulb, located in the caudal part of the olfactory bulb,

relays pheromo nal information detected in the vomero-

nasal organ. Because of space constraints, this chapter

focuses exclusively on the main olfactory bulb and odor

coding in rodents.

1.2 SYNAPTIC ORGANIZATION OF THE

MAMMALIAN OLFACTORY BULB

The olfactory system is responsible for correctly coding

sensory information from thousands of odorous stimuli.

To accomplish this complex task, odor information is

Olfactory

epithelium

Olfactory

bulb

olfactory

Piriform

cortex

Amygdala

Olfactory

tubercle

Entorhinal

cortex

Hippocampus

Hypothalamus

Thalamus

Striatum

Orbitofrontal

cortex

FIGURE 1.1 Schematic representation of the olfactory system. The olfactory system is composed of a sensory organ, the olfactory epithelium,

followed by the olfactory bulb, the first central relay of odor information. The olfactory bulb then projects to different olfactory cortical areas in-

volved in olfactory processing and behavior. Structures in blue that receive direct inputs from the output neurons of the olfactory bulb composed

together the so-called ‘olfactory cortex.’

4 1. THE FORM AND FUNCTIONS OF NEURAL CIRCUITS IN THE OLFACTORY BULB

I. CIRCUIT DEVELOPMENT

processed through distinct units. At each o f these units, a

modified representation of the odor stimulus is generated.

Following a bottom–up approach, we will start our de-

scription from the olfactory sensory organ located in the

nasal cavity.

1.2.1 Organization of Sensory Inputs

The ability to process correctly the physical and statis-

tical properties of chemical information is constrained by

the functional architecture and the synaptic organization

of some dedicated neural circuits. As our knowledge

about the neurobiology of olfaction grows, it is becoming

evident that the main olfactory systems of animals in dis-

parate phyla share many striking features regarding the

functional architecture and the synaptic connectivity

(Bargmann, 2006; Hildebrand and Shepherd, 1997). For

instance, mammals and invertebrate olfactory systems

display common organizational features and functional

characteristics (Wilson and Mainen, 2006). In all cases,

the initial event shared by virtually all odorant detection

systems is the requirement of specific interaction of

odorant molecules with specific receptors expressed on

the cilia of sensory olfactory neurons before conveying

information to central structures (Ache and Young, 2005;

Bargmann, 2006; Mombaerts, 2004b). Essentially, there

are four different features that are common to all olfactory

systems: (1) The presence of soluble odorant binding pro-

teins in the mucus overlying the receptor cell dendrite, (2)

the existence o f G-protei n-coupled receptor acting as spe-

cific odorant receptors, (3) the use of a two-step signaling

cascade in odorant transduction, (4) the presence of

functional anatomical structures at the first central target

in the olfactory pathway called glomeruli (reviewed

by Bargmann, 2006; Firestein, 2001; Mombaerts, 2004b).

If these common features represent adaptive mechanisms

that have evolved independently, their study might bring

valuable knowledge about the way the nervous system

extracts information from olfactory space.

In mammals, olfactory transduction starts with the ac-

tivation of some of the thousand different types of odor-

ant receptors located on the cilia of bipolar olfactory

sensory neurons that comprise the olfactory neuro-

epithelium (1000–1300 genes in the mouse; Buck and

Axel, 1991; Mombaerts, 2004b). It is believed that these

sensory neurons recognize more than a thousand air-

borne volatile molecules called odorants. A general pri n-

ciple is that these receptors exist as separate information

channels, because most sensory neurons express only

one type of olfactory receptor. Because of the broad

chemical tuning of these receptors (Araneda et al.,

2000), the gen eral coding principle is “one odor ¼ one

set of receptor activations” (Firestein, 2001; Mombaerts,

2004b). The olfactory epithelium then projects to the first

central relay of the olfactory system: the main olfactory

bulb (referred to below as the olfactory bulb). As advances

in understanding olfactory transduction progressed,

interest in deciphering some of the olfactory bulb func-

tions grew concomitantly. This heightened interest has

been spurred on, at least in part, by the discovery of the

way in which the sensory organ connects to the olfactory

bulb. We know now that the sensory neurons that express

the same odorant receptor project their axons centrally to

one or two spherical modules in the olfactory bulb called

glomeruli (Zou et al., 2009). Here, sensory information is

transmitted to higher brain centers via output neurons

called mitral/tufted cells. The discrete and spherical glo-

meruli are morphological units made of distinctive bun-

dles of neuropil (Figure 1.2). This terminology reflects

both the homogeneity of the sensory inputs (they all ex-

press only one odorant receptor) and the degree to which

the olfactory bulb neurons connected to the same glomer-

ular unit display a similar receptive field (Dhawale et al.,

2010; Tan et al., 2010). Recently, dramatic progress has

been made in understanding of how olfactory sensory

neurons develop and how they express only one odorant

receptor. This discovery prompted the use of genetic

tools to probe and manipulate specific populations of sen-

sory neurons, resulting in several major breakthroughs

(a) (b)

FIGURE 1.2 Convergence of the olfactory sensory neu-

ron axons into glomeruli. (a) Olfactory sensory neurons la-

beled in blue project their axons on the surface of the

olfactory bulb (note the single glomeruli). (b) Whole-mount

view of the olfactory epithelium (OE) and the olfactory bulb

(OB). Olfactory sensory neurons expressing the olfactory

receptor P2 in the olfactory epithelium (OE) project the

axons towards a single glomerulus (red dashed circle)

on the surface of the olfactory bulb (OB). Adapted from Mom-

baerts P, Wang F, Dulac C, et al. (1996) Visualizing an olfactory

sensory map. Cell 87: 675–686, with permission.

51.2 SYNAPTIC ORGANIZATION OF THE MAMMALIAN OLFACTORY BULB

I. CIRCUIT DEVELOPMENT

regarding axon guidance, axon sorting and axon position-

ing (Sakano, 2010; Zou et al., 2009).

In different species, each glomerular structure results

from the convergence of 5 to 40 thousand axon terminals

of sensory neurons that express the same odorant recep-

tor (Figure 1.2). Therefore, the glomerular layer can

be considered as a two-dimensional anat omical repre-

sentation of the olfactory receptors’ repertoire (also

called ‘chemotopic map’; Johnson and Leon, 2007;

Wachowiak and Shipley, 2006). Because one odor can ac-

tivate several olfactory neurons, odor information is

first encoded by the combinatorial patterns of glomeru-

lar activation. Odorants activate a specific array of olfac-

tory sensory neurons that lead to a chemotopically

fragmented map of activated glomeruli on the surface

of the olfactory bulb (Me ister and Bonhoeffer, 2001).

Remarkably, the precise projection pattern can be repro-

duced from one animal to another and even between

different rodent species (Soucy et al., 2009). Distinct

odorants activate different combinations of glomeruli

and two odors are more difficult to discriminate when

these show a greater overlap in this glomerular chemo-

topic map (Linster et al., 2001). Nevertheless, if such a

spatial pattern coding scheme were only applicable to

several odors, it would not be able to provide a suffi-

ciently large coding space to discern between the mil-

lions of potential odors or mixtures of odor present in

our environment (Laurent, 2002).

The sensory neurons project to paired olfactory glo-

meruli on both the medial and lateral aspects of the olfac-

tory bulb, thus creating two mirror-symmetric maps

(Mombaerts et al., 1996). As each group of glomerulus-

specific output neurons is odorant receptor-specific,

glomeruli form a morphological as well as functionally

defined network somewhat analogous to barrels in the

somatosensory cortex (Johnson and Leon, 2007). In

mammals, the convergence ratio of sensory neurons

to olfactory bulb output neuron is very large: about

1000:1 (Zou et al., 2009). A bulbar output neuron thus

forms its responses to odors from very large numbers

of converging inputs, ensuring detection of faint signals,

increase signal-to-noise ratios and temporal noise

average.

1.2.2 Synaptic Processing Within Olfactory Bulb

Microcircuits

Because of its relatively simple anatomical organiza-

tion and easy access, the olfactory bulb has been a privi-

leged model system for deciphering the principles

underlying ne twork processing of sensory information.

There, odors elicit a well-organized pattern of glomeruli

activation across the surface of the olfactory bulb, but the

mechanisms by which this chemotopic map is processed

into an odor code by the bulbar circuitry has recently

attracted more attention. With the advance in recent

years of in vitro brain slice preparation, as well as in vivo

recording techniques that were applied on behaving an-

imals, the complex processing of the olfactory informa-

tion is starting to be revealed. Since Cajal’s pioneering

studies, it has been known that the main output neurons

of the bulb, the so-called mitral cells, are located in a sin-

gle lamina, the mitral cell layer (Figure 1.3). A second

population of output neurons, namely tufted cells, are

scattered in the external plexiform layer (EPL). The pri-

mary (or apical) dendrite of mitral and tufted cells,

extending vertically from its soma, contacts one glomer-

ulus, whereas their multiple long secondary dendrites

spread in the EPL.

About 50–100 output neurons (mitral/tufted cells)

emanate from each glomerulus and project to a number

of higher centers that compose the olfactory cortex (see

Figure 1.1). Output neurons are the backbone of two se-

rial intrabulbar microcircuits: one between primary api-

cal dendrites and juxtaglomerular cells and the other

between secondary dendrites and granule cells. The

main difference between juxtaglomerular and granule

cells is that the former mediate mostly interactions be-

tween cells affiliated with the same glomerulus, wh ile

granule cells mostly mediate interactions between out-

put neurons projecting to many different glomeruli

(Figure 1.3). Therefore, two potential distinct sites of

odor processing can be distinguished according to the to-

pographical organization of the bulbar circuit. The first

one resides in the glomeruli where local interneurons

shape excitatory inputs coming from sensory neurons.

The second one lies in the EPL, where reciprocal dendro-

dendritic synapses are heavily distrib uted between den-

dritic spines of local interneurons and the dendrites of

output neurons. These two inhibitory microcircuits are

also under the control of centrifugal fibers coming from

cortical and neuromodulatory area.

1.2.2.1 Synaptic Transmission at the First Synapses

The glomerular layer constitutes a first site of integra-

tion for olfactory information. In this layer, axonal ter-

mini of olfactory sensory neurons synapse directly

onto output neurons (50–100 cells per glomerulus)

and also onto local neurons, namely juxtaglomerular

cells (1000–2000 cells per glomerulus). The olfactory

nerve-evoked excitatory responses of both neuron types

comprise fast amino-3-hydroxy-5-methyl-4-isoaxozole-

propionic acid (AMPA) and slow N-methyl-

D-aspartate

(NMDA) components. The latter is particularly long-

lasting and may play an important role in the bulbar out-

put by maintaining a pattern of sustained discharge of

output neurons (Carlson et al., 2000).

6 1. THE FORM AND FUNCTIONS OF NEURAL CIRCUITS IN THE OLFACTORY BULB

I. CIRCUIT DEVELOPMENT

Juxtaglomerular cells have dendrites restricted to one

glomerulus and impinge onto olfactory nerve terminals

or primary dendrites of mitral/tufted cells. Juxtaglomer-

ular cells can be subdivided into three categories

(Figure 1.3). The first category is comprised by periglo-

merular cells, small axonless interneurons that are the

main source of g-aminobutyric acid (GABA) in the glo-

merular layer and which provide feedback and feed-

forward inhibition to output neurons (Wachowiak and

Shipley, 2006). It is noteworthy that a subpopulation of

these GABAergic cells is also dopaminergic (Kosaka

and Kosaka, 2005). Their inhibitory action alters the

strength of sensory signals as they pass out of the bulb,

and it is thought to provide a mechanism of filtering of

weak sensory inputs (Gire and Schoppa, 2009). In addi-

tion, periglomerular cells also exert a presynaptic regu-

lation of sensory inputs thanks to the expression of

GABA

and D

dopamine receptors on olfactory sensory

terminals (Aroniadou-Anderjaska et al., 2000; Hsia et al.,

1999). The second category concerns the superficial

short-axon cells. This heterogeneous cell population,

comprising GABAergic and glutamatergic neurons, dis-

plays dendritic and axonal branching in several glomer-

uli and is thought to mediate lateral inhibition between

glomeruli (Aungst et al., 2003; Kiyokage et al., 2010). The

third group is composed of external tufted cells. These

local glutamatergic cells, distinct from the output tufted

cells, innervate periglomerular cells, short-axon cells,

and mitral cells. Their spontaneous intrinsic rhythmic

activity, synchronized by gap junctions and with the

breathing rhythm, coordinates the activity of the cells lo-

cated within each glomerulus (De Saint Jan et al., 2009;

Hayar et al., 2004). In addition to direct fast excitation

from OSN, external tufted cells provide a significant

slow feed-forward excitation onto mitral cells (Najac

et al., 2011 ). Moreover, activation of external tufted cells

and glutamatergic superficial short-axon cells triggers

lateral excitation of distant periglomerular cells, thus

providing feedforward inhibition onto mitral/tufted cells

of remote glomeruli (Aungst et al., 2003; Wachowiak and

Shipley, 2006). This distributed inhibition mediates a

globally averaged level of feedforward inhibition onto

ONL

dSAC

eTC

sSAC

EPL

MCL

GCL

From the olfactory epithelium

LOT

EPL

MCL

IPL

GCL

RMS

ONL

(a)

(b)

(c)

Centrifugal

fibers

400 µm

100 µm

To the olfactory cortex

FIGURE 1.3 Anatomical organization of the main olfactory bulb. (a) Nissl-stained coronal section of the mouse olfactory bulb showing the

different concentric layers. Inset, a sagittal section showing the rostrocaudal level of the coronal section. (b) Higher magnification view. ONL,

olfactory nerve layer; GL, glomerular layer; EPL, external plexiform layer; MCL, mitral cell layer; IPL, internal plexiform layer; GCL, granule cell

layer; RMS OB, rostral migratory stream of the olfactory bulb. (a) Olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) that express

the same odorant receptors project their axons to the main olfactory bulb into one of the glomeruli that form the glomerular layer (GL). In the GL,

sensory neuron terminals synapse onto the apical dendrites of output neurons, namely the mitral cell (MC) and the tufted cells (TC). In addition,

periglomerular cells (PGC), superficial short-axon cells (sSAC) and external tufted cells (eTC) act on glomerular synaptic transmission exerting

diverse functional effects. In the external plexiform layer (EPL), the lateral dendrites of mitral and tufted cells interact with the dendrites of granule

cells (GC). Granule cells can also be subdivided into distinct subpopulations: superficial granule cells (GC

), which target the superficial lamina of

the external plexiform layer and synapse with tufted cells, and deep granule cells (GC

), which target the deep lamina of the external plexiform

layer are connected to mitral cells. The somas of mitral cells are aligned and delineate the mitral cell layer (MCL), and the somas of tufted cells are

scattered in the EPL. Granule cell somas and also some deep short-axon cells (dSAC) compose the granule cell layer (GCL). Centrifugal fibers from

other brains regions innervate specific layers of the olfactory bulb depending on their brain origin. Lastly, output neuron axons fasciculate to form

the lateral olfactory tract (LOT). All of the cell types colored in orange are glutamatergic; GABAergic cells are in blue. ONL, olfactory nerve layer.

71.2 SYNAPTIC ORGANIZATION OF THE MAMMALIAN OLFACTORY BULB

I. CIRCUIT DEVELOPMENT

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