Download Modular genetic control of innate behaviors

Insights & Perspective
Ideas & Speculations
Modular genetic control of innate
behaviors
Xiaohong Xu
Many complex behaviors are genetically hardwired. Based on previous
findings on genetic control of mating and other behaviors in invertebrate
and mammalian systems, I suggest that genetic control of complex behaviors is modular: first, dedicated genes specify different behavioral patterns;
secondly, separable genetic networks govern distinct behavioral components.
I speculate that modular genetic encoding of complex behaviors may in part
reflect modularity in brain development and function.
Introduction
Many animals are born with the abilities
to perform complex tasks: garden
spiders spin intricate webs soon after
they hatch, birds raised in isolation
build elaborate nests, ground squirrels
raised in captivity readily distinguish
acorns of closely related oak species
and selectively cache the correct ones
[1–3]. Indeed, naı̈ve animals display a
wide range of species-specific behaviors
including courtship, nest building, nursing, territorial aggression, migration, predation, and predator avoidance. These
behaviors, essential for the survival of
individuals and the propagation of the
species, are programmed into an animal
at a genetic level and are termed innate
or instinctual. Innate behaviors persist
stably under different environments and
vary little among individuals of the
same species, consistent with the idea
that such behaviors are genetically
hardwired. The rigidity of innate behavioral patterns is in stark contrast to the
malleability of learned behaviors, which
adjust with environment and experience. How do genes control innate
behaviors? Do innate behaviors arise
diffusely from interactions of many
genes such that no one gene is particularly associated with one behavior? Or
are there dedicated genetic networks
that specify each innate behavioral pattern? Here, I will present evidence from
both invertebrate and mammalian
systems that suggest genetic control
of innate behaviors is surprisingly
modular.
.
Keywords:
behavioral genetics; evolution; innate behaviors; male copulation; modular;
neuroscience; steroid hormone
DOI 10.1002/bies.201200167
Institute of Neuroscience, Shanghai Institute of
Biological Sciences, Chinese Academy of
Science, Shanghai, P. R. China
Corresponding author:
Xiaohong Xu
E-mail: [email protected]
Bioessays 35: 421–424,ß 2013 WILEY Periodicals, Inc.
Genetic dissection of
innate behaviors
Dedicated genes specify innate
behaviors
Drosophila biologists have been pioneering the genetic dissection of innate
behaviors since the 1960s. By inducing
small lesions in the fly genome and
analyzing mutant flies for behavioral
deficits, the late Seymour Benzer and
his colleagues showed unequivocally
that innate behaviors such as circadian
rhythm, courtship, and even the ability
to learn are determined by a small
number of dedicated genes [4]. For
example, the male courtship routine
in fruitflies consists of stereotyped steps
of tapping, wing vibration, licking,
and abdominal bends that lead to
copulation [5]. This complex behavioral
routine is controlled by male-specific
splicing of fruitless (fruM), which gives
rise to putative transcription factors that
delineate male-specific neural circuitry
[6]. Deletion of fruM abolishes all aspects
of male courtship without affecting any
other behaviors, while forced expression
of fruM in female fruitflies is sufficient to
specify male courtship. Similarly, in the
nematode Caenorhabditis elegans, Sydney
Brenner and colleagues have identified
hundreds of genes and associated neural
structures that control specific innate
behaviors [7]. For example, mab (male
abnormal) genes control the development
of male-specific components of the
nervous system and are essential for
male mating behaviors in C. elegans [8].
Unlike flies and worms, mammals
undergo an extended period of postnatal
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Ideas & Speculations
X. Xu
development that requires intense
parental care before reaching adulthood. Because of this, it has been
argued that behaviors in mammals are
mostly acquired through learning rather
than being genetically determined.
However, multiple lines of evidence
suggest a strong genetic basis for mammalian behaviors as well. Long before
the discovery of DNA, humans have
bred domesticated mammals for desirable behavioral traits such as tameness,
herding, and hunting [9]. Scientists are
now comparing the genomic sequences
of different breeds of dogs as well as
recently domesticated wild foxes to
narrow down genomic loci associated
with specific behavioral traits [9, 10].
Likewise, modern day scientists have
selectively bred and created strains of
mice that differ in burrowing behaviors,
and performed genome-wide association studies to dissect how genomic
variations contribute to quantifiable
behavioral differences [11]. Perhaps
one of the most intriguing examples of
how genes dictate mammalian behaviors is that the naturally occurring variation in the expression of Avpr1a, a
neuropeptide receptor, appears to
underlie species differences in mate
preference and pair bond formation in
promiscuous and monogamous voles
[12]. Taken together, studies in both
invertebrates and mammals support
the idea that dedicated genes specify
innate behaviors.
Separable genes control distinct
behavioral parameters
How might a small number of dedicated
genes control complex behavioral patterns? In the following section, I will
present recent studies in mice that
suggest genetic control of innate behaviors is hierarchical and modular.
Male mice court females in sequential and stereotyped steps of sniffing,
mounting, intromission, and ejaculation (Fig. 1). Male mating is coordinated
by gonadal steroid hormones including
estrogen and testosterone, which signal
through their receptors including estrogen receptors a and b (ERa and ERb),
and androgen receptor (AR), respectively. ERa and AR are analogous to
fruM in that they control all aspects of
male courtship in mammals [13]. Male
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Insights & Perspective
.....
Sniffing
Mounting
Intromission
Ejaculation
0
5
10
15
time (min)
20
25
Figure 1. Male courtship is stereotyped. Representative raster plot of male mating behaviors.
The Y-axis lists behaviors displayed by the male toward a receptive female. The X-axis
represents time in minutes. Each tick denotes a single event for the behavior indicated on
the left. When paired with a female, a male mouse will emit ultrasonic vocalizations and
investigate the female (sniffing). He then proceeds to press his forepaws on the female’s
flanks while thrusting his pelvis (mounting). If the female is in heat and receptive, male pelvis
thrusts become rhythmic (intromission) and culminate in the transfer of sperms (ejaculation).
mice mutated for AR are feminized
externally and engage in no sexual
behaviors. Similarly, male mice lacking
ERa also fail to exhibit any sexual
behavior. In contrast, animals with a
brain-specific deletion of AR retain
low levels of sexual behavior, but mount
and intromit at a much lower frequency
than controls [14]. These steroid hormone receptors are cognate nuclear
receptors, which upon ligand binding
translocate to the nucleus to regulate
expression of target genes. Target genes
downstream of hormone receptors have
been identified in the brain and are
expressed in overlapping but non-identical patterns, raising the possibility that
these genes regulate different aspects of
male mating [15].
Sytl4, one such hormone target
gene, encodes a protein that regulates
synaptic vesicle release, and therefore
synaptic signaling between neurons
[16]. Sytl4 is highly expressed in the
bed nucleus of stria terminalis (BNST),
a brain region that when lesioned
specifically impairs intromission [17].
Interestingly, male mice mutant for
Sytl4 sniff less but are more likely to
intromit. Moreover, the latency to intromit, a parameter that correlates with
mating success (ejaculation) in wild
type animals, is no longer a predictor
of the consummatory outcome of male
mating in Sytl4 mutant animals. The
effects of Sytl4 on male mating behaviors are extremely specific – all other
behavioral
parameters
examined
appear not to be affected by the Sytl4
mutation. Together, these data show
that Sytl4 specifically regulates the
intromission step of the male mating
routine. Similarly, another hormone
target gene, Brs3, which encodes a G
protein-coupled receptor, controls the
timing of intromission but not other
aspects of male mating. Thus, Sytl4 and
Brs3 are likely part of a gene network that
function modularly to control intromission. It is probable that additional extant
gene networks control other behavioral
components in male mating.
Similar to their roles in male mating,
hormone target genes also regulate
behavioral parameters in other innate
behaviors coordinated by gonadal steroid
hormones including male territorial
aggression, maternal care, and female
sexual behavior. For example, male mice
mutant for Brs3 are quicker to initiate a
fight, and female mice mutant for Cckar
are less receptive to male mating
attempts but normal in maternal care
and other behaviors. Taken together,
these data suggest that genetic control
of reproduction-related innate behaviors
is hierarchical and modular: steroid
hormones signal through their receptors
to orchestrate several behavior routines,
while genes downstream of hormone
receptors regulate specific parameters
of individual behavioral components.
Overlapping genetic networks
govern innate behaviors
In arguing for a model of modular
genetic control of innate behaviors, I
have so far not discussed the pleiotropic
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Insights & Perspective
modularity in brain development and
function [22]. During development, progenitor cells in the nervous system
express combinatorial codes of transcriptional factors that initiate a cascade
of cell fate specification [23]. These transcription factors regulate expression of
target genes involved in cell migration,
connectivity, and signaling. As mentioned above, both transcriptional regulation and protein signaling are highly
modular. Not surprisingly, the brain, as
a three-dimensional readout of modular
genomic information, is also highly
modular, both anatomically and functionally (Fig. 2A) – For instance, the
hypothalamus consists of anatomically
separable nuclei that regulate circadian
rhythm, sleep, feeding, mating, aggression, and other behaviors (Fig. 2B).
Neural pathways underlying innate
behaviors are genetically specified
during development and are embedded
within compartmentalized brain functions. In other words, dedicated genes
that specify innate behaviors may act
during development to create specific
neural pathways for innate behaviors,
and thereby achieve modular genetic
encoding of behaviors. Consistent with
this idea, AR, which specifies male
courtship, is a transcription factor and
AR expressing cells delineate a malespecific neural circuit that is activated
Modular genetic control of
innate behaviors: Possible
mechanisms
The definition of ‘‘module’’ is an independent and operable unit that performs a specific function within a
system. Modularity is in fact a recurring
theme in biology [20]. Independent
cis-elements, each of which confers
expression in a specific tissue or cell
type, modularly control transcription
of genes. Similarly, signal transduction
proteins contain modular domains
that separately perform ligand binding,
protein interaction, or catalysis function. A high degree of modularity is
hypothesized to be evolutionarily adaptable because modular configurations
can generate more novel functions
with simple genetic events [21]. Innate
behaviors are essential to an individual’s survival and the propagation of
the species. Therefore, modular genetic
encoding of innate behaviors may have
occurred as a consequence of stringent
natural selection.
In addition, modular encoding of
innate behaviors may in part reflect
Figure 2. The brain is anatomically and functionally modular. A: Cartoon depiction of a
sagittal section of a mouse brain with major structures differentiated by color. This panel is
adopted from GENSAT database website (www.gensat.org). B: Cartoon depiction of a
coronal section of a mouse brain. The left side represents Nissl staining of the section and
the right annotates different nuclei. This panel is adopted from Allen Brain Atlas
(www.brain-map.org).
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Ideas & Speculations
properties of genes [18]. For example,
Brs3, which regulates the latency to
intromit during mating, also regulates
the latency to attack during territorial
aggression; and Cckar, which controls
female receptivity during mating, also
regulates satiety during feeding [19].
Thus, one can not assert a one-to-one
relationship between a genetic mutation
and the observed behavioral phenotype
without exhaustive phenotypic profiling, which is laborious and seldom carried out. However, these caveats do not
negate the fact that genetic networks
controlling innate behaviors are modular. At the first level, dedicated genes
specify different innate behaviors. At
the second level, separable genes govern different behavioral parameters. In
reality, genetic networks controlling
innate behaviors are likely to overlap
and interact with each other.
Consequently, while only affecting isolated components of a given behavioral
program, mutations in single genes
could affect more than one genetic
module and thus cause multiple behavioral phenotypes.
X. Xu
Ideas & Speculations
X. Xu
during mating [24]. Moreover, adjacent
neural structures marked by different
transcription factors form separate neural pathways responsible for mating or
defensive behaviors [25].
Besides generating dedicated neural
pathways, genes may also control
innate behaviors by recruiting modular
brain functions specified by other pathways during development. Consistent
with this idea, Sytl4 and Brs3, two signaling proteins that regulate male intromission, are both expressed in the
BNST, a brain structure that when
lesioned specifically impairs intromission. Similarly, Cckar, a neuropeptide
receptor that controls female mating,
is highly expressed in the ventral medial
nuclei of hypothalamus (VMH), a region
that when lesioned diminishes female
mating [26]. Thus, modularity in brain
function may partially account for modular encoding of innate behaviors.
Identifying region and cell-type specific
genetic networks within the context of
neural circuits that drive innate behaviors will be the future challenge for
behavioral genetic studies.
Finally, a model of modular genetic
control of innate behaviors predicts that
quantitative differences in gene expression can lead to measurable shifts in
behaviors. Indeed, different strains of
inbred mice exhibit significant differences
in key parameters of mating and maternal
care [27, 28]. Interestingly, experience
also affects displays of innate behaviors,
albeit in more limited ways. For example,
experienced males are quicker to mate
with a female; and veteran mothers
are faster at retrieving displaced pups
[29, 30]. It remains to be determined
how genetic backgrounds or past experiences affect gene expression to regulate
displays of innate behaviors. Ultimately,
understanding how behaviors evolve as a
consequence of natural selection and
genome-environment interaction will be
central to our understanding of genetic
control of innate behaviors.
Conclusion
Complex behaviors can occur without
learning. These innate behaviors, essential for an individual’s survival and the
propagation of the species, are deter-
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Insights & Perspective
mined genetically. Genetic control of
innate behaviors is complex but modular in nature. For example, the stereotyped mating steps of male mice are
broadly orchestrated by dedicated genes
(AR/ERa) while downstream genes
(Sytl4/Brs3/Cckar) regulate specific
parameters of individual behavioral
components. I speculate that such modular genetic encoding of innate behaviors may arise as a result of modular
brain development and function.
Future studies of cell-type specific
genetic networks and neural circuits
that drive innate behaviors will shine
more light on genetic and neural encoding of innate behaviors.
Acknowledgments
I thank O.M. Ahmed and D.S. Manoli for
their comments and help on the manuscript. This work is supported by funding from Chinese Academy of Sciences.
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