Maternal Behavior and Developmental Psychopathology
James F. Leckman and Amy E. Herman
This paper reviews recent developments in the phenome-
nology, neurobiology, and genetics of maternal behavior
in animal model systems from an evolutionary perspective
on psychopathology. Following a review of the phenome-
nology and neurobiology of maternal behavior, recent
studies addressing the role of genetic factors in the
maternal behavior of rodents were identified in a search of
literature in peer-reviewed journals. Gene knockout stud-
ies were evaluated with regard to mouse strain back-
ground, method of behavioral phenotyping, and quantifi-
cation of the behavioral deficits. Gene knockout data were
then analyzed using a cluster analysis technique. At least
nine genes have been identified that are necessary for the
expression of one or more aspects of maternal behavior.
These genes encode for three transcription factors: three
enzymes, including dopamine beta hydroxylase and neu-
ronal nitric oxide synthase; two receptors, including the
prolactin and the estrogen ␣ receptor; and one neuropep-
tide, oxytocin. Cluster analysis suggested possible rela-
tionships between specific genes. Gene knockout technol-
ogy has provided new insights into the molecular basis of
maternal behavior that are congruent with the existing
neurobiological literature. Future studies of genetic and
environmental influences on maternal behavior have the
potential to inform models of disease pathogenesis. Biol
Psychiatry 2002;51:27– 43 © 2002 Society of Biological
Psychiatry
Key Words: Maternal behavior, evolution, genetics, au-
tism, obsessive-compulsive disorder
Introduction
I do not believe it is possible to understand the functioning of
the mother at the very beginning of the infant’s life without
seeing that she must be able to reach this state of heightened
sensitivity . . . almost an illness . . . and recover from it.
Winnicott 1956
T his article reviews the neurobiological and genetic
determinants of maternal behavior in animal model
systems from an evolutionary perspective on psychopa-
From the Child Study Center, Yale University School of Medicine, New Haven,
Connecticut.
Address reprint requests to James F. Leckman, M.D., Yale University School of
Medicine, Child Study Center, 230 South Frontage Road, New Haven CT
06520-7900.
Received May 30, 2001; revised August 8, 2001; accepted August 13, 2001.
© 2002 Society of Biological Psychiatry
thology. This viewpoint posits that the evolutionary events
that have led to the emergence of the human species and
our particular set of conserved behavioral and mental
capacities has also left us vulnerable to certain forms of
psychopathology (Leckman and Mayes 1998). Maternal
behavior is an example of a highly conserved set of
behavioral and mental capacities. It is our hypothesis
that a detailed understanding of the cascade of genetic and
environmental factors and the resulting neural circuits
required for the expression of maternal behavior may be
valuable in understanding some forms of psychopathol-
ogy.
This review first examines the elements of the behav-
ioral phenotype of maternal behavior with a special
emphasis on rodent model systems. Second, we consider
what is known of the neurobiological substrates of these
behaviors. Third, we review available gene knockout
studies that have resulted in the disruption of one or more
features of maternal behavior. Finally, we consider two
forms of psychopathology, autism and obsessive-compul-
sive disorder (OCD), which may be associated alterations
in this neural circuitry.
Before reviewing specific findings an opening caveat is
in order. Namely, that the use of mouse model systems to
evaluate maternal behavior relevant to humans is inher-
ently problematic. Many species-specific differences exist
that may well confound possible interpretations (Insel and
Young 2001). For example, unlike most mammals, most
strains of laboratory mice do not depend on gestational
hormones to show immediate maternal responsiveness to
neonates; however, this difference may not be a drawback,
as primates are also much less dependent on these hor-
mones for their maternal behavior, so that the mouse might
actually be a good model for humans in this regard.
Behavioral Phenotype of Maternal Behavior
Maternal behavior is a highly conserved set of behavioral
capacities that are crucial for reproductive success. In
humans, this period is associated with intense parental
preoccupations (Leckman and Mayes 1999; Leckman et al
1999; Winnicott 1956). The content of these preoccupa-
tions includes intrusive worries concerning the parents’
adequacy as parents and the infant’s safety and well being.
These thoughts and the harm avoidant behavior they
0006-3223/02/$22.00
PII S0006-3223(01)01277-X
28 BIOL PSYCHIATRY
2002;51:27– 43
engender resemble those encountered in OCD. Even
before the child is born, parents preoccupy themselves
with creating a safe and secure environment for the infant.
Major cleaning and renovation projects are commonplace
as the human form of nest building unfolds. Uppermost
among parental concerns are safety and unimpeded access.
Safety issues include the cleanliness of the infant’s imme-
diate environment. After birth this same sense of height-
ened responsibility will compel parents to check on the
baby frequently, even at times when they know the baby is
fine.
Nursing and feeding are the parental behaviors that are
perhaps most associated with a new infant. Women
describe breast-feeding as a uniquely close, very physical,
at times sensual experience and one that brings a particular
unity between the mother and her infant. Cleaning, groom-
ing, and dressing behaviors also carry a special valence
inasmuch as they permit the closeness between parent and
infant and provide for frequent inspection of the infant’s
body and appearance.
The central role of maternal care in early life is also well
demonstrated in rodent studies. Newborn rodents, virtually
immobile and incapable of body temperature maintenance,
are dependent for their survival on the initiation of a
specific set of maternal behaviors (Rosenblatt and Lehr-
man 1963). Maternal behavior in rodents involves a
complex set of activities, including nest repair, sniffing
and exploration of pups, mouthing, pup retrieval, licking,
grooming, and various forms of nursing (arched-back
nursing, prone nursing, blanket nursing) (Pryce et al
2001).
In addition to caring for their own pups, recently
parturient females avidly display retrieving, licking, and
nursing behavior toward foster pups introduced into the
cage. In contrast, adult virgin female rats do not show
maternal behavior when first presented with foster pups;
however, if virgin female rats are cohabited with young
pups, they will eventually display maternal behavior after
a period of 4 to 7 days (Rosenblatt 1967). This experi-
mental paradigm is referred to as sensitization and can
serve as a useful tool in the behavioral assessment of
maternal behavior.
Key Elements in the Neural Circuitry of
Maternal Behavior
Classic lesion studies done in rodent model systems (rats,
mice, and voles) have implicated the medial preoptic area
(MPOA) of the hypothalamus, the ventral part of the bed
nucleus of the stria terminalis (BNSTv), and the lateral
septum (LS) as regions pivotal for regulation of pup-
directed maternal behavior (Kalinichev et al 2000a, 2000b;
Numan 1994; Numan and Numan 1997; Numan and
J.F. Leckman and A.E. Herman
Sheehan 1997; Sheehan et al 2000) (Figure 1). Estrogen,
prolactin, and oxytocin can act on the MPOA to promote
maternal behavior (Bridges et al 1990; Numan et al 1977;
Pedersen et al 1994). Oxytocin is primarily synthesized in
the magnocellular secretory neurons of two hypothalamic
nuclei, the paraventricular (PVNm) and the supraoptic
(SON) nuclei. The PVNm and SON project to the poste-
rior pituitary gland. Pituitary release of oxytocin into the
bloodstream results in milk ejection during nursing and
uterine contraction during labor. It has also been shown
that oxytocin fibers, which arise from parvocellular neu-
rons in the PVN, project to areas of the limbic system,
including the amygdala, BNST, and LS (Sofroniew and
Weindl 1981).
There are several reports that oxytocin facilitates ma-
ternal behavior (sensitization) in estrogen-primed nullipa-
rous female rats. Intracerebroventricular (ICV) adminis-
tration of oxytocin in virgin female rats induces full
maternal behavior within minutes (Pedersen and Prange
1979). Conversely, central injection of an oxytocin antag-
onist, or a lesion of oxytocin-producing cells in the PVN,
suppresses the onset of maternal behavior in postpartum
female rats (Insel and Harbaugh 1989; Van Leengoed et al
1987); however, these manipulations have no effect on
maternal behavior in animals permitted several days of
postpartum mothering (Pedersen 1997). This result sug-
gests that oxytocin plays an important role in facilitating
the onset, rather than the maintenance, of maternal attach-
ment to pups (Insel 1997).
Brain areas that may inhibit maternal behavior in rats
have been identified (Sheehan et al 2000). The vomero-
nasal and primary olfactory systems have been identified
as brain regions that mediate avoidance behavior in virgin
female rats exposed to the odor cues of pups (Fleming
1998). Input from both olfactory systems is integrated
within the medial amgydala (MA), previously associated
with emotion, fear, and anxiety (Numan and Sheehan
1997). It has been suggested that novel olfactory stimuli
from pups activate fear-inducing mechanisms in the amyg-
dala, and inhibit maternal behavior in virgin females.
Conversely, lesions of the MA in virgin rats promote
maternal responsiveness (Fleming et al 1980). Though it is
not known where the MA projects to inhibit maternal
behavior, the MPOA and BNST have been suggested as
possible regions (Sheehan et al 2000), because these areas
receive strong input from the MA. Connections among
other brain regions, such as the anterior hypothalamic
nucleus (AHN), ventral medial nucleus (VMN), LS, and
dorsal premammillary nucleus (PMN) may also be in-
volved in the neural circuit through which olfactory input
initially inhibits maternal responsiveness (Sheehan et al
2000).
Ascending dopaminergic systems associated with re-
Genetics of Maternal Behavior BIOL PSYCHIATRY 29
2002;51:27– 43

Figure 1. Neural circuitry of maternal behavior. This figure

summarizes classic data from lesion and pharmacologic
studies of rat maternal behavior. Pup: the dashed black arrow
indicates the initial aversion to pup odors observed in the
sensitization paradigm. The solid black lines indicate positive
sensory inputs (olfactory as well as somatosensory—pup
contact, nipple stimulation) that facilitate maternal behavior.
The brown olfactory bulb (OB) nuclei and their efferents can
either serve to inhibit or facilitate maternal behavior. The
mechanisms underlying this transformation are not fully
understood (Numan and Sheehan 1997). The visual, auditory,
and somatosensory pup-related inputs likely involve projec-
tions from primary sensory areas to the orbitofrontal cortex
(white, OFC). Recent work in humans and nonhuman pri-
mates has highlighted the functional importance of the OFC
in affective and motivational behavior. The ventral portion of
the bed nucleus of the stria terminalis (BNSTv), the medial
preoptic area (MPOA), the lateral septum (LS), and certain
monoaminergic brainstem nuclei including the dopaminergic
ventral tegmental area (VTA) and the noradrenergic locus ceruleus (LC) all appear to be crucial for the initiation and maintenance of
maternal behavior. These nuclei and their interconnections are depicted in gold. The paraventricular nucleus (PVN, green) and the
green lines depict oxytocin projections that facilitate maternal behavior throughout the neural axis and through the release of oxytocin
from the posterior pituitary (PP). The green arrow indicates that oxytocin acts on the PVN to enhance its own release. The nuclei
depicted in red and their projections are involved in inhibiting maternal behavior. Lesions in these nuclei, including the anterior
hypothalamic nuclei (AHN), the ventral medial nuclei (VMN), and the medial (MA) nuclei of the amgydala, facilitate maternal
behavior. The OFC also appears to be directly involved in the response to stress. The OFC, mostly medial, provides direct inputs into
the VMN and AHN of the hypothalamus. The OFC is also reciprocally connected with the amgydala and the hippocampus as well as
brainstem nuclei in the LC, VTA, and brainstem autonomic nuclei. These connections facilitate the initiation and regulation of the
endocrine response to stress that is mediated by the hypothalamic–pituitary–adrenal axis. The release of corticotropin-releasing factor
(CRF) from the PVN initiates this response. CRF then promotes the release of adrenocorticotropin (ACTH) from the anterior pituitary
(AP), which in turn initiates the release of glucocorticoids (CORT) from the adrenal cortex (AC). CORT provides negative feedback
to the PVN, among other regions. The hippocampus is active in inhibiting the stress response via a number of direct and indirect
connections with PVN, amygdala, and LC. The distribution of oxytocin (green stars), alpha estrogen (light blue stars), beta estrogen
(dark blue stars), and prolactin (yellow stars) receptors are also depicted in this figure. See text for details and Cavada et al (2000);
Freeman et al (2000); Insel (1997); Kalinichev et al (2000a; 2000b); Kaufman et al (2000); Lopez et al (1999); Numan (1994); Numan
and Sheehan (1997); Österlund and Hurd (2001); Pederson (1997); Sheehan et al (2000); and Shughrue et al (1997). For a more detailed
and anatomically more accurate account of the neural circuitry involved in the control of goal directed behaviors, generally, see
Swanson (2000).

ward pathways (Koob and Le Moal 1997) also appear to
play a crucial role in facilitating maternal behavior. For
example, rat dams given ventral tegmental area (VTA)
microinfusions of the neurotoxin 6-hydroxydopamine (6-
OHDA) to destroy catecholaminergic neurons during lac-
tation showed a persistent deficit in pup retrieval but were
not impaired with respect to nursing, nest building, or
maternal aggression (Hansen et al 1991). There also appears
to be an important interaction between dopaminergic neurons
and oxytocin pathways. Specifically, pup retrieval and as-
suming a nursing posture over pups were blocked in partu-
rient dams by infusions of an oxytocin antagonist into either
the VTA or MPOA (Pedersen et al 1994).
Remarkably many of the same cell groups (Figure 1:
MPOA, AHN, VMN, PVN, PMN, and VTA) implicated in
the control of maternal behavior have been implicated in
the control of ingestive (eating and drinking) behavior,
thermoregulation (energy homeostasis), social (defensive
and sexual) behaviors, as well as general exploratory or
foraging behaviors (with locomotor and orienting compo-
nents) that are required for obtaining any particular goal
object. Many of these same structures are also intimately
involved in stress response (Figure 1: orbitofrontal cortex
[OFC], BSNT, LS, amgydala, hippocampus, MPOA,
PVN, and brainstem monoaminergic nuclei) (Lopez et al
1999). Swanson (2000) has conceptualized this set of
nuclei as being the “behavioral control column” that is
voluntarily regulated by cerebral projections. Consistent
with this formulation, it is readily apparent that mother-
hood presents a major homeostatic challenge within each
of these behavioral domains.
In summary, the initiation and maintenance of maternal
behavior involves a specific neural circuit. With pregnancy or
with repeated exposure to pups, structural and molecular
changes occur, most of which are not yet completely under-
stood, in specific limbic, hypothalamic, and midbrain regions
30 BIOL PSYCHIATRY J.F. Leckman and A.E. Herman
2002;51:27– 43

Table 1. Gene Knockout Studies and Estimation of the Degree of Deficit Regarding Specific Maternal Behaviors
Gene
Class
Mouse strain
Chromosomal location Tests to assess
(human) Observed deficits in Preserved maternal Maternal behaviors not competence in other
Investigators maternal behavior behavioral capacities evaluated domains
FosB
Transcription factor Maternal behavior: Maternal behavior: Maternal behavior: Olfaction: Normal
129/Sv inbred strain and Nest building (.5), Exploration and sniffing Licking and grooming, olfactory discrimination
129/Sv ⫻ BALB/c mixed pup retrieval (.0), of pups (1.0) placentophagia, Lactation: Intact
background crouching (.0), Sensitization: Exploration aggression Problem solving: Normal
(19q13.2) nursing (.0) and sniffing of pups (1.0) Sensitization: Nest Morris water maze
Brown et al 1996 Sensitization: Pup building performance
retrieval (.25)

Peg3
Paternal expressed gene-3 Maternal behavior: Maternal behavior: Maternal behavior: Olfaction: Not evaluated
Transcription factor Nest building (.5), Exploration and sniffing Licking and grooming, Problem solving: Not
129/Sv inbred strain pup retrieval (.5), of pups (1.0) placentophagia, evaluated
(19q13.4) crouching (.0), aggression
Li et al 1999 nursing (.0) Sensitization: Exploration
Sensitization: Nest and sniffing of pups
building (.5), pup
retrieval (.5)

Fkh5
Fork head-5 Maternal behavior: Maternal behavior: Olfaction: Not evaluated
Transcription factor Nest building (.0), Exploration and sniffing Problem solving: Not
129/Sv inbred strain pup retrieval (.0), of pups, placentophagia, evaluated
(15q21-26) crouching (.0), licking and grooming,
Wehr et al 1997 nursing (.0) aggression
Sensitization: Nest
building, pup retrieval,
exploration and sniffing
of pups

Mest/Peg1
Mesoderm-specific Maternal behavior: Maternal behavior: Maternal behavior: Olfaction: Normal latency
transcript/Paternal Nest building Exploration and sniffing Licking and grooming, to find the food pellet
expressed gene-1 (.25), pup of pups (1.0), aggression Lactation: Intact
Enzyme retrieval (.0), Sensitization: Exploration Problem solving: Not
129/Sv inbred strain crouching (.0), and sniffing of pups (1.0) evaluated
(7q32) nursing (.0),
Lefebvre et al 1998 placentophagia
(.0)
Sensitization: Nest
building (.5), pup
retrieval (.0)

Dbh
Dopamine beta Maternal behavior: Maternal behavior: Olfaction: Intact
hydroxylase Nest building (.5), Exploration and sniffing Lactation: Intact
Enzyme pup retrieval (.5), of pups, licking and Problem solving: Normal
Hybrid 129/SvCPJ-C57BL/6J crouching (.0), grooming, aggression Morris water maze
of inbred strains nursing (.0), Sensitization: Exploration performance, but some
(9q34) placentophagia and sniffing of pups deficits in motor
Thomas and Palmiter 1997 (.5) function, learning, and
Sensitization: Nest memory
building (.5), pup
retrieval (.25)
Genetics of Maternal Behavior BIOL PSYCHIATRY 31
2002;51:27– 43

Table 1. (Continued)
Gene
Class
Mouse strain
Chromosomal location
(human) Observed deficits in Preserved maternal Tests to assess competence
Investigators maternal behavior behavioral capacities Maternal behaviors not evaluated in other domains
nNOS
neural Nitric oxide Maternal behavior: Maternal behavior: Nest Maternal behavior: Licking and Olfaction: Not evaluated
synthetase Aggression (.0) building (1.0), exploration grooming Problem solving: Not
Enzyme and sniffing of pups (1.0), Sensitization: Nest building, evaluated
Hybrid 129/SvCPJ- pup retrieval (1.0), exploration and sniffing of
C57BL6J of inbred crouching (1.0), nursing pups, pup retrieval
strains (1.0), placentophagia (1.0)
(12q24.2-24.31)
Gammie and Nelson 1999;
Gammie et al 2000

ER␣
Estrogen ␣ receptor Maternal behavior: Maternal behavior: Unable Maternal behavior: Nest Lactation: Unable to
Receptor Unable to to evaluate building, exploration and evaluate
C57BL/6J and 129 evaluate sniffing of pups, pup retrieval, Problem solving: Normal
(6q25.1) Sensitization: Pup crouching, nursing, licking and Morris water maze
Ogawa et al 1996, 1998 retrieval (.25) grooming, placentophagia, performance (Rissman et
aggression al 1999)
Sensitization: Exploration and
sniffing of pups, nest building

PRLR
Prolactin receptor Maternal behavior: Maternal behavior: Maternal behavior: Licking and Olfaction: Normal
Receptor Nest building (.5), Exploration and sniffing grooming, placentophagia, aversive conditioning
C57BL/6 inbred and pup retrieval (.5), of pups (1.0) aggression test
C57BL/6 ⫻ 129/Sv crouching (.5), Sensitization: Exploration Sensitization: Nest building Lactation: Intact
mixed background nursing (.5) and sniffing of pups (1.0) Problem solving: Normal
(5p14-13) Sensitization: Pup Morris water maze
Ormandy et al 1997, retrieval (.5) performance
Lucas et al 1998

Oxytocin
Neuropeptide Maternal behavior: Maternal behavior: Nest Maternal behavior: Licking and Olfaction: Intact for
C57BL/6/129SvEv Effective nursing building (1.0), exploration grooming detection of non-social
(20q13) (.0) and sniffing of pups (1.0), Sensitization: Nest building, stimuli (Ferguson et al
Nishimori et al 1996 pup retrieval (1.0), exploration and sniffing of 2000)
placentophagia (1.0), pups, pup retrieval Lactation: Failure of milk
crouching (1.0), release
aggression (1.0) Problem solving: Normal
Morris water-maze
performance
(Ferguson et al 2000)
The degree of deficit was quantified on a scale of 0 to 1. A score of 0 represents the complete absence of the behavior. A score of 1 is within the normal range for that
mouse strain. A score of 0.5 or 0.25 represents a partial disruption of the behavior.

that reflect, in part, an adaptation to the various homeostatic
demands associated with maternal care.
Methods
Retrieval of Articles
Relevant studies addressing the role of genetic factors in the
expression of maternal behavior in rodents were identified in a
search of literature in peer-reviewed journals published from
January 1990 to December 2000. The MedLine database was
searched using the key words “maternal behavior” and “gene.”
Eighty articles were identified. Reviewing these reports, 12
articles were identified that associated deficits in maternal
behavior with nine specific gene knockouts (Brown et al 1996;
Gammie and Nelson 1999; Gammie et al 2000; Lefebvre et al
1998; Li et al 1999; Lucas et al 1998; Nishimori et al 1996;
Ogawa et al 1996, 1998; Ormandy et al 1997; Thomas and
32 BIOL PSYCHIATRY
2002;51:27– 43
Palmiter 1997; Wehr et al 1997). A search of the Mouse Genome
Informatics database at the Jackson Laboratory (http://www.
informatics.jax.org/) disclosed reports of three additional knock-
out animals with deficits in maternal behavior.
Evaluation of Articles
Gene knockout studies were evaluated on the following criteria:
1) documentation of mouse strain; 2) the adequacy of the
behavioral phenotypying vis-à-vis maternal behavior; 3) quanti-
fication of the degree of deficit of specific maternal behaviors;
and 4) use of other tests to evaluate the competence of the
knockout animals in other behavioral domains.
We used the presence or absence of the following behavioral
elements to assess the adequacy of the phenotypying methods
employed in each of the knockout gene studies (maternal care:
nest building, exploration/sniffing, pup retrieval, arched back
nursing/lactation, licking/grooming, placentophagia, and mater-
nal aggression toward intruders; sensitization: nest building,
exploration/sniffing, pup retrieval, and licking/grooming). The
degree of deficit was quantified on a scale of 0 –1. A score of 0
was assigned if there was a complete absence of the behavior. A
score of 0.5 represents a partial disruption of the behavior. A
score of 1 is within the normal range for that rodent strain.
Cluster Analysis of Gene Knockout Studies
A cluster analysis was performed according to the algorithm
described by Eisen et al (1998). In this hierarchical clustering
algorithm the similarity metric used is a form of a correlation
coefficient, so that for any two behaviors or any two genes, a
similarity score can be computed. This clustering analysis is
deterministic, such that the genes that are clustered together have
the most similar traits mathematically. Once the input table is
finalized (selecting 0, 0.25, 0.5, or 1 for each gene/behavior
combination), there is no flexibility in how the clustering
locations will turn out. In one tree, the branch lengths within the
tree represented the degree of similarity between genes in terms
of their behavioral consequents. The second tree presents the
degree of similarity between behavioral elements in terms of
their relation to specific genes.
Gene Knockout Studies and Maternal
Behavior
Thus far, at least nine genes appear to be necessary for the
expression of one or more aspects of maternal behavior
(Table 1). These genes encode three transcription factors
(FosB, Peg3, and Fkh5); three enzymes (Mest/Peg1, do-
pamine beta hydroxylase, and neuronal nitric oxide syn-
thase); two receptors (estrogen ␣ receptor [which also
functions as a transcription factor] and prolactin receptor);
and one neuropeptide, oxytocin.
Although the genetic background of the knockout mice
may have contributed to the degree of deficit report in
these studies (Picciotto and Wickman 1998), these differ-
ences are unlikely to account for the specific deficits seen
J.F. Leckman and A.E. Herman
in specific knockouts. For example, the 129/Sv inbred
mouse strain, which was used in many of the studies,
shows dysgenesis of the corpus callosum and impairment
on spatial learning tasks (Gerlai 1996) that in turn may
have contributed to deficits in pup retrieval; however,
because heterozygous animals with the same genetic
background were used as controls in these studies, the
background per se cannot account for the observed defi-
cits. On the other hand, we cannot rule out that the
presence of specific genetic background may be a prereq-
uisite for some of the behavioral defects reported in these
studies.
The results of each knockout study are reviewed below
before considering the results of the cluster analysis.
FosB
FosB, an immediate early gene (IEG), was one of the first
genes identified to play a role in nurturing behavior in
mice. Brown et al (1996) generated FosB knockout mice.
The mice appeared healthy and viable; however, when
homozygous FosB mutant females were mated with ho-
mozygous FosB mutant males, it was observed that the
majority of pups died within 1 to 2 days of birth. Death of
pups in the early postnatal period could result from a
defect in the FosB mutant mothers, the FosB mutant pups,
or both. Brown performed many crosses among the FosB
mutant males and females, and found that the number of
surviving pups per pregnancy was exclusively correlated
with the genotype of the mother. A behavioral assay of
nurturing demonstrated that FosB mutant dams were less
involved in nest building, pup retrieval, and nursing
compared to control mice (Table 1). Brown also demon-
strated that FosB is required for maternal behavior outside
the context of pregnancy by using the sensitization behav-
ioral assay (Table 1).
Additional testing using the Morris water maze did not
reveal any differences in the cognitive performance of
these knockout animals, nor were differences noted in an
olfactory discrimination test. Finally, because the hypo-
thalamus plays a critical role in nurturing behavior, there
was the possibility that FosB mutants could have impair-
ment of other hypothalamic functions. Such hypothalamic
processes as adaptation to cold, eating, and sexual behav-
ior appeared to be normal in the mutant animals.
Brown and co-workers also investigated the expression
of FosB in the MPOA of normal female mice presented
with pups. They found that production of the Fos B protein
was induced in these juvenile conspecifics following a
6-hour exposure to newborn pups. They also reported that
FosB is constitutively expressed in the main and accessory
olfactory bulbs and pyriform cortex, which suggests that
FosB may have a role in the processing of multiple
Genetics of Maternal Behavior
olfactory inputs. FosB was also detected in many other
brain regions, including the cerebral cortex, striatum,
hippocampus, amygdala, and other hypothalamic areas.
Peg3
Paternally expressed gene-3 (Peg3) is an imprinted gene.
Imprinted genes display differential expression according
to their parental origin. Normally, only the paternally
derived Peg3 allele is expressed. Peg3 contains two zinc
finger motifs and two proline or acidic amino acid–rich
repeat domains, which suggests its involvement in DNA
binding and protein–protein interactions (Kuroiwa et al
1996). It has been reported that Peg3 maps to a zinc finger
gene–rich region of human chromosome 19q13.4 (Kim et
al 1997). It has also been suggested that Peg3 interacts
with tumor necrosis factor receptor–associated factor 2
(TRAF2) (Reliax et al 1998) and has a role in the tumor
necrosis factor signaling pathway.
Li et al (1999) disrupted Peg3 by inserting a ␤geo
selection cassette into its 5⬘ coding exon. Pups born to
Peg3 ⫺/⫺ mutant mothers failed to survive. Whereas only
8% of litters born to mutant mothers grew to weaning age,
83% of litters born to wild-type females survived. The
offspring of mutant females and wild-type males (⫹/⫺ ⫻
⫹/⫹) also failed to thrive, suggesting that the genotype of
the mother, not the father, was relevant for their survival.
Because these pups inherited the active paternal Peg3
allele and the silent maternal allele, they should develop as
normal adults. The fact that so few pups survived sug-
gested that there was a defect in maternal behavior. Mutant
primiparous mothers were subjected to a behavioral assay
of nurturing behaviors. As documented in Table 1, these
animals were deficient in nest building, pup retrieval, and
nursing.
Normally in rodent brain, high levels of Peg3 expres-
sion are present in a number of hypothalamic nuclei
(MPOA and PVN), as well as the MA, BNST, hippocam-
pus, and olfactory bulb. Interestingly, in the sensitization
paradigm, Peg3 ⫺/⫺ mutant virgin females did show
appropriate FosB expression in the MPOA after exposure
to pups. This result suggests that the deficit of maternal
behavior associated with Peg3 is independent of FosB
induction.
During the first 3 weeks, surviving offspring of Peg3
mutant females gained less weight compared with the
offspring of wild-type mothers. Histologic examination
revealed that the mutant mothers had fewer oxytocin-
positive neurons in the PVN. Li and co-workers conclude
that the reduced number of oxytocin-producing neurons
may impair the neural signaling required for the postpar-
tum bolus of oxytocin. They suggest that the involvement
of Peg3 in the TRAF signaling pathway affecting cell
BIOL PSYCHIATRY 33
2002;51:27– 43
survival and proliferation could account for the decreases
in oxytocin neurons in the PVN and other hypothalamic
neurons. These findings suggest that Peg3 is required for
nurturing behavior but do not exclude the possibility of
more general defects in the mice, such as deficits in
cognitive abilities, olfaction, and hypothalamic function.
Fkh5
The transcription factor gene Forkhead 5 (Fkh5) also
appears to have a role in maternal behavior (Wehr et al
1997). The prototype gene fork head (fkh) is a region-
specific homeotic gene in Drosophila. The DNA binding
sequence is also called the “winged helix domain.” In
mice, Fkh5 is expressed in the developing central nervous
system, specifically in the mamillary body region of the
caudal hypothalamus, the midbrain, hindbrain, and spinal
cord. After birth, expression persists in the midbrain and in
specific nuclei of the mammillary body.
Wehr et al (1997) generated Fkh5-deficient mice and
found that homozygous Fkh5 ⫺/⫺ mice were born indis-
tinguishable from wild-type and Fkh5 heterozygous litter-
mates; however, about one third of Fkh5 ⫺/⫺ mice died
within the first 2 days after birth, and another one fifth
died before weaning. Homozygous mutant mice became
growth retarded and distinguishable from their heterozy-
gous and wild-type littermates a few days after birth.
Although pregnancies of Fkh5 ⫺/⫺ mothers were carried
to term, all of their pups died shortly after birth. Obser-
vation revealed that mutant mothers neglected their pups
and were deficient at nest building and nursing behavior
(Table 1). Wehr found that cross-fostering of Fkh5 ⫺/⫺
and wild-type pups to a wild-type or Fkh5 ⫺/⫺ mother
assigned the defect to the mutant mothers. Wehr and
colleagues did not use the sensitization paradigm. They
also did not exclude the possibility of a more general
cognitive defect in the mice, nor did they assess the olfactory
or hypothalamic function of the animals. Analysis of the
brains of Fkh5 deficient mice revealed distinct alterations,
including reduced inferior colliculi and an overgrown ante-
rior cerebellum. In addition, the medial mammillary nucleus
was absent, which resulted in disturbance of the layered
structure of the mammillary body. Wehr notes that the
MPOA area is part of the neuronal circuit connecting the
amygdala with the mammillary body.
Mest/Peg1
Mesoderm-specific transcript, also known as paternally
expressed gene 1 (Mest/Peg1) is another imprinted gene
expressed only from the paternal allele during develop-
ment (Kaneko-Ishino et al 1995). The function of the Mest
protein is unknown. Sequence similarities with the ␣/␤-
hydrolase* family suggest that Mest has an enzymatic
34 BIOL PSYCHIATRY
2002;51:27– 43
role. Lefebvre et al (1998) inactivated Mest in mice and
found that paternal transmission (designated Mest ⫹/⫺) of
the targeted allele caused general growth retardation in
mice. The pups grew to become mature and fertile animals,
but they were smaller than their wild-type littermates. Ma-
ternal transmission of the targeted allele (designated Mest
⫺/⫹) did not cause growth retardation. In adults, Mest
expression was confined almost exclusively to the nervous
system. High Mest expression was found in the hypothala-
mus, amygdala, ventral hippocampus, and main and acces-
sory olfactory bulbs. Low levels of Mest expression were
found in cortex, dorsal hippocampus, and striatum.
Mest-deficient females delivered at term, with a normal
pregnancy rate, yet they produced few surviving offspring.
There was no correlation between the genotype of the
newborns and their survival. Observation of maternal
behavior in mutant females revealed that the mutant
mothers failed to display a number of maternal behaviors;
additionally, they did not consume the placenta (Table 1).
Although Lefebvre et al did not detect differences in
olfactory function of the mutant animals, they did not test
for general cognitive or hypothalamic dysfunction. Nor
did they examine the brains of the mutant animals for
structural abnormalities.
Dopamine Beta Hydroxylase (Dbh)
Noradrenergic neurons in the brain project from brainstem
nuclei and innervate virtually all areas of the brain and
spinal cord. The enzyme Dbh synthesizes the adrenergic
receptor ligands norepinephrine and epinephrine. Thomas
et al (1995) disrupted the Dbh gene in mice. Mice
homozygous for the Dbh mutation (Dbh ⫺/⫺) died in
utero, of apparent cardiovascular failure (Thomas et al
1995). Dbh ⫺/⫺ mice could be rescued at birth by
provision of adrenergic agonists or a synthetic precursor
of norepinephrine, L-threo-3, 4-dihydroxyphenylserine
(DOPS), in the maternal drinking water (Thomas et al
1995). The majority of these rescued animals became
viable adults. When subjected to behavioral tests, the Dbh
⫺/⫺ mice displayed some difficulty learning an active
avoidance paradigm and a simple motor task (Thomas and
Palmiter 1997).
In a subsequent study, Thomas and Palmiter (1997)
demonstrated impaired maternal behavior across virtually
all domains evaluated (Table 1). Pups were observed
scattered within the bedding around the nest. Often pups
were not cleaned, and their placentas remained attached.
Milk was not detected in the stomachs of most pups born
to Dbh ⫺/⫺ females, which suggests that the pups were
not nursing despite the presence of normal mammary
gland tissue. Cross-fostering experiments revealed that
almost all cross-fostered litters were raised to weaning.
J.F. Leckman and A.E. Herman
This observation demonstrates that the Dbh ⫺/⫺ dams can
nurse and that lactation is not impaired.
The impairment in maternal behavior in the Dbh ⫺/⫺
animals could reflect a developmental deficit caused by
norepinephrine deficiency, or it could represent a physio-
logic deficit. To distinguish between these possibilities
DOPS was used to restore transiently norepinephrine to
the mutant females. When mutant females were injected
with DOPS on the morning after birth, maternal behavior
was not restored, and all pups subsequently died; however,
when mutant females were injected with DOPS on the
evening before birth, over half of the litters survived. Even
more pups survived when DOPS was injected both in the
evening before and on the morning after birth.
These findings suggest that norepinephrine may play a
key role in initiating a realignment of the dam’s sense of
what is salient and important in the environment. Interest-
ingly, in 85% of the mutant females, the rescue of
maternal behavior by DOPS extended to the mother’s
subsequent pregnancies even in the absence of DOPS
injections; however, DOPS injections did not significantly
enhance pup retrieval by mutant virgin females.
Neuronal Nitric Oxide Synthase (nNOS)
Neuronal nitric oxide synthase (nNOS) has also been
found to play a role in maternal behavior, specifically
maternal aggression (Gammie and Nelson 1999). The gas
nitric oxide (NO) acts as a neuromodulator in the central
nervous system. In male mice, deletion of the nNOS gene
(nNOS ⫺/⫺) and pharmacological inhibition of nNOS
result in increased aggression (Demas et al 1997; Nelson
et al 1995). In virgin female mice, disruption of the nNOS
gene (nNOS ⫺/⫺) did not alter their normally quiescent
behavior (Nelson et al 1995).
Gammie and Nelson (1999) examined the levels of
maternal aggression in lactating mice that were missing
the second exon of the nNOS gene (Table 1). When
compared with lactating wild-type females, lactating
nNOS ⫺/⫺ female mice show deficits in the production of
maternal aggression in terms of the percentage of animals
displaying aggression, the average number of attacks
against a male intruder during the test period, and total
time spent attacking the male intruder.
Gammie and Nelson then investigated whether NO
release might be associated with maternal aggression in
normal animals. Behavioral testing of aggression was
followed by immunohistochemistry in the brain for citrul-
line, the molecule produced when NO is enzymatically
cleaved from the precursor arginine. Levels of citrulline
immunoreactivity were measured in the brains of wild-
type lactating female mice immediately after an aggressive
encounter with an intruder male.
This study is the first to suggest that the MPOA has a
Genetics of Maternal Behavior
role in maternal aggression, and that NO in females may
have an excitatory role in the production of maternal
aggression. Specifically, the MPOA, as well as the supra-
chiasmatic nucleus (SCN) and the subparaventricular zone
(SPa) exhibited the greatest increases in citrulline immu-
noreactivity. Analysis of citrulline-positive cells in these
brain regions revealed that the number of citrulline-
positive cells was significantly increased in the aggressive
lactating females relative to the two control groups.
Furthermore, a significant correlation was found between
the amount of time spent attacking the intruder and the
total number of citrulline-positive cells in the MPOA, the
SCN, and the SPa.
Estrogen ␣ Receptor
The estrogen ␣ receptor (ER␣) is a member of the steroid
receptor superfamily of ligand-activated transcription fac-
tors. There are two known ER subtypes, ␣ and ␤. In the
human forebrain, both estrogen receptor subtypes are
predominantly expressed in limbic-related areas, although
they show distinct distribution patterns (Figure 1; Öster-
lund and Hurd 2001; Shughrue et al 1997).
ER␣ was first disrupted in the early 1990s (Lubahn et al
1993). ER␣⫺/⫺ mutant females survived to adulthood but
were found to be infertile and to have high levels of
circulating testosterone. Although it is impossible to di-
rectly evaluate the maternal behavior of these animals,
Ogawa et al (1996, 1998) have assessed reproductive-
related behaviors in female mice using the sensitization
paradigm. Remarkably, ER␣ ⫺/⫺ mutant females showed
such a high degree of infanticidal behavior when exposed
to newborn pups that the investigators stopped their study.
Even after gonadectomy, the ER␣ ⫺/⫺ mutant females
showed a high rate (50%) of biting and attacking the pups,
as well as poor pup-retrieving behavior.
A number of studies have also examined the problem-
solving abilities of the ER␣ ⫺/⫺ mutant females (Rissman
et al 1999). For example, although gonadectomized ER␣
⫺/⫺ mutant females rapidly learn to escape from the
Morris water maze as rapidly as wild-type animals do,
exogenous estrogen treatment prevents the wild-type
females from learning this task, yet has no effect in
ER␣ ⫺/⫺ mutant females.
Prolactin Receptor
Prolactin (PRL) is synthesized and secreted by the lac-
totrophic cells of the anterior pituitary. Prolactin plays an
important role in the stimulation of mammary gland
development during pregnancy and regulation of lactation
during the postpartum period (Freeman et al 2000). Be-
cause levels of PRL increase in the bloodstream just
before parturition, it is implicated as playing a key role in
BIOL PSYCHIATRY 35
2002;51:27– 43
the regulation of maternal behavior. Prolactin binds to the
PRL receptor (PRLR), a transmembrane protein belonging
to the cytokine receptor superfamily. The PRLR has two
forms, a short form and a long form. The long form of the
PRLR is expressed in MPOA, PVN, and VMN, among
other hypothalamic nuclei (Figure 1; Bakowska and Mor-
rell 1998). A significant increase in PRLR-expressing cells
has been identified in the MPOA before parturition.
Ormandy et al (1997) identified multiple reproductive
defects in PRLR ⫺/⫺ mice. Despite regular mating,
homozygous females were found to be completely sterile.
Further investigation revealed that PRLR ⫺/⫺ mice had
irregular menstrual cycles, reduced fertilization, defective
preimplantation embryonic development, and lack of
pseudopregnancy. In heterozygous females, there is a
complete impairment in the ability to lactate after their
first, but not subsequent, pregnancies. This deficit was
attributed primarily to a defect in mammary gland
development.
In a separate study, Lucas et al (1998) examined
maternal behavior PRLR deficient mice and found deficits
in nest building, pup retrieval, and nursing (Table 1). In
addition, no cognitive impairment or deficits in olfaction
were observed. Lucas and co-workers suggest that the
PRLR-dependent defect in maternal behavior may be
mediated by brain regions whose primary function is to
regulate maternal responsiveness; however, the density of
PRL binding sites in the MPOA following pup contact
were not examined in this study.
In contrast to the PRLR findings, disruption of the
prolactin (PRL) gene was not found to alter maternal
responsiveness in mice (Horseman et al 1997). The rea-
sons for this apparent contradiction are unclear but may
involve compensatory changes in the PRL knockout ani-
mals over the course of development, such as up- or
downregulation of other gene products.
Oxytocin
Oxytocin is a peptide hormone synthesized in the hypo-
thalamic PVN and SON. Oxytocin is believed to play an
important role in several aspects of mammalian reproduc-
tion, such as sexual behavior, induction of labor, milk
ejection, and maternal behavior (Insel and Young 2001;
Young et al 1997).
Nishimori et al (1996) created mice deficient in the
oxytocin peptide. It was predicted that oxytocin-deficient
mice would be impaired in mating, delivery, lactation, and
maternal behavior; however, females deficient in oxytocin
had normal gestation periods, built typical nests, and had
normal deliveries (Nishimori et al 1996). There did not
appear to be an overt impairment in maternal behavior.
Nevertheless, pups from oxytocin-deficient females died
36 BIOL PSYCHIATRY J.F. Leckman and A.E. Herman
2002;51:27– 43

within 24 hours, owing to the mother’s inability to eject

milk. Exogenous oxytocin given to the oxytocin ⫺/⫺
homozygote females every few hours rescued this behav-
ior, allowing pups to develop normally.
The lack of impairment in most maternal behaviors in
the oxytocin-deficient animals suggests that in mice, the
neural circuitry for maternal behavior is independent of
oxytocin per se (Young et al 1997). This finding differs
from the observations in rats that central infusions of
oxytocin in the virgin rat facilitate the onset of maternal
behavior (Pedersen and Prange 1979), and that central
infusions of oxytocin receptor antagonists block the induc-
tion of maternal behavior (Van Leengoed et al 1987).
Together these data suggest that other neuropeptides
binding at the oxytocin receptors may be important in the
initiation of maternal behavior in some species. Further, it
also seems plausible to argue that although the observable
overt maternal behavior is “intact” in the oxytocin ⫺/⫺
mice, their functional ability to nurse is profoundly defi-
cient, leading to pup starvation. Consequently, we have
rated “nursing/lactation” in the oxytocin ⫺/⫺ animals as
0.0 in Table 1 and Figure 2.
Figure 2. Dendrograms of the phenotypic components of mater-
nal behavior and of the genes implicated in maternal behavior.
Other Knockout Animals with Deficits in Maternal The color of each cell quantitatively reflects the presence of a
Behavior particular maternal behavior in each set of knockout animals:
bright green ⫽ normal behavior; green ⫽ approximately 50%
A search of the Mouse Genome Informatics database at decrement; dark green ⫽ 75% decrement; and black ⫽ the
the Jackson Laboratory (http://www.informatics.jax. org/) complete absence of the behavior. Gray cells indicate a lack of
disclosed three additional knockout animals with deficits data on a particular behavior for a particular knockout. The
results of the cluster analysis suggest that there are four sets of
in maternal behavior. These animals were deficient in closely associated genes: 1) FosB and Mest; 2) nNos and PRLR;
Herc2, Hubb, and Rora. A review of the behavioral 3) Dbh, oxytocin, and Peg3; and 4) ER␣ and Fkh5. See text for
phenotypes of these animals reveals that animals deficient details. The behaviors, on the other hand, although showing a
in Herc2, Hubb, and Rora exhibit a multitude of motor and nested pattern of relationships, were generally less closely
problem-solving defects. The fact that these animals ex- interrelated.
hibit gross defects in other systems suggests that Herc2,
Hubb, and Rora do not have specific roles in maternal
behavior. Rather, the involvement of these genes in many pression of Peg3 in these brain regions, it is likely that
other processes, such as gait and reproductive function, Peg3 interacts with many other genes that have an impact
may prevent the mutant females from displaying normal on maternal behavior. The grouping of Peg3 and oxytocin
maternal responsiveness. in the cluster analysis is of interest, given that Li et al
(1999) report that postpartum Peg3 mutant mothers have
reduced oxytocin-positive neurons in the hypothalamus
when compared with wild-type females. As a transcription
Cluster Analysis of the Gene Knockout Data factor, Peg3 might activate a program of gene expression
Application of the cluster analysis independently gener- that facilitates certain aspects of maternal behavior that
ated two dendrograms— one for behaviors and another for involve oxytocin-containing cells.
genes (Figure 2). This clustering technique empirically The cluster analysis paired neuronal nNOS and the
identified four sets of potentially closely related genes: 1) PRLR. This result is consistent with a known association
Peg3, Dbh, and oxytocin; 2) nNOS and the PRLR; 3) FosB between nNOS and PRLR (for review see Freeman et al
and Mest/Peg1; and 4) ER␣ and Fkh5. 2000). Specifically, for proper surface targeting, glycosyl-
Peg3 expression occurs at high levels in the hypotha- ation of the asparagyl residues of the extracellular domain
lamic nuclei, including the MPOA, MA, PVN, BNST, of the PRLR is a crucial requirement for prolactin-R
hippocampus, and olfactory bulb, regions that mediate activation. Nitric oxide activates N-acetylglucosamine
maternal behavior (Figure 1). Given the widespread ex- transferase, which is responsible for glycosylation of these
Genetics of Maternal Behavior
intracellular receptors and promotes migration of these
newly glycosylated receptors to the cell surface.
The cluster analysis also found an association between
FosB and Mest. As a transcription factor, FosB might
activate a program of gene expression that facilitates
maternal behavior. Indeed, the expression of FosB and
Mest in similar brain regions (olfactory bulb, amygdala,
and hypothalamus) may suggest that FosB activates Mest
in particular brain regions associated with maternal behav-
ior. In future work, it will be useful to determine if Mest is
indeed a target gene of FosB. A similar argument could be
made for exploring the whether or not ER␣ is a target gene
for Fkh5 or vice versa, because both can function as
transcriptional regulators; however, the limited phenotypic
data available on the ER␣ ⫺/⫺ animals cautions against
placing too much importance on this possible association.
Inspection of the behavioral dendrogram in Figure 2
also reveals a close relationship between nest building,
pup retrieval, pup retrieval under sensitization testing
conditions, and placentophagia. This set of four behaviors
in turn was progressively related to sniffing and explora-
tion of pups (under both testing conditions), maternal
aggression toward intruders, and nest building under
sensitization testing conditions; however, as very little
data were available concerning some of these behaviors,
this behavioral cluster should be viewed with caution.
Future Directions in the Study of the
Interplay of Genetic and Environmental
Factors in Shaping Maternal Behavior
Neuroscience research has provided some delineation of
the circuitry underlying maternal behavior in rodents.
Neurobiological data from gene knockout studies comple-
ment previous neurobiological literature and are consistent
with the results from experimental intervention studies
that emphasize the crucial role of perinatal experience in
programming aspects of later maternal behavior (Caldji et
al 1998, 2000; Francis et al 1999, 2000; Liu et al 1997,
2000; Pryce et al 2001).
At least nine genes have been found to be necessary for
the expression of one or more aspects of maternal behav-
ior. These genes encode a broad range of proteins that are
involved in intracellular signaling, gene transcription, and
neuromodulation. Although many of these genes are
pleiotropic, such that they can influence many different
cell types and contribute to multiple phenotypes, they all
can be seen to impact the circuitry underlying maternal
behavior.
Another, perhaps more surprising conclusion is that
because two of these genes, Mest/Peg1 and Peg3, are
paternally imprinted, the paternal copies of both of these
BIOL PSYCHIATRY 37
2002;51:27– 43
genes are essential for the proper expression of maternal
behavior.
Different genes appear to affect distinct aspects of
maternal behavior. The cluster analysis suggests in a
preliminary fashion a series of possible relationships
between features of maternal behavior and specific genes
or sets of genes. Future work is likely to reveal a more
detailed and accurate picture of cascades of gene expres-
sion, neuroanatomic co-localization of genes, and interde-
pendence of function.
There are many areas of investigation that would be
useful to explore in future work, including development of
a standard battery of tests for behavioral and molecular
phenotyping; the identification of additional genes that
underlie maternal behavior; exploration of different rodent
strains and the development of inducible knockouts; in-
vestigation of interactions among genes with known im-
pact on maternal behavior; investigation into the role of
environmental events; extension of these methods and
findings to the study of maternal behavior in primates; and
investigation of these loci for possible mutations in spe-
cific neuropsychiatric disorders associated with deficits or
dysregulation of affiliative behavior.
Development of a Standard Battery of Tests for
Behavioral and Molecular Phenotyping
In the studies reviewed above, there was marked variabil-
ity in the behavioral tests of maternal behavior. For
example, for only six of the nine knockouts were sensiti-
zation data available to assess maternal responsiveness in
virgin mice. Most remarkably, none of the studies docu-
mented the degree of licking and grooming and arched
back nursing among the mouse dams. This is a major
weakness. As documented in an elegant series of handling
and cross-fostering studies by Francis et al (1999), licking
and grooming and arched back nursing among rat dams
appear to mediate the nongenomic transmission of these
same maternal behaviors to the next generation—when the
female pups mature and become dams themselves. Natu-
rally occurring variations in licking, grooming, and arched
back nursing have also been associated with the develop-
ment of individual differences in stress response and in
other behavioral responses to novelty in adult offspring as
well as a range of neurobiological differences affecting
hypothalamic and hippocampal regions in the adult off-
spring (Caldji et al 1998, 2000; Francis et al 1999, 2000;
Liu et al 1997, 2000). In future studies, it would be useful
to have a standard battery of behavioral measures for
maternal behavior. This battery would include measures of
licking and grooming and arched back nursing, as well as
measures of latency to sensitization in virgin adult females
(Pryce et al 2001).
38 BIOL PSYCHIATRY
2002;51:27– 43
Identification of Additional Genes that Underlie
Maternal Behavior
It is likely that many more genes will be identified as
essential for the development of maternal behavior. As in
hypertension and other genetically complex diseases, our
knowledge of some of the molecular and anatomic pathways
involved in maternal behavior provides a background for
future areas of investigation. It is likely that developmental
genes active in the formation of the hypothalamus may have
a role in maternal behavior. For example, expression of the
homeobox-containing gene Orthopedia (Otp) has been iden-
tified in several hypothalamic nuclei, the MA, and the BNST,
regions that have been demonstrated to mediate maternal
behaviors in rodents (Acampora et al 1999; Diano et al,
unpublished data); however, it may necessary to develop
conditional knockouts to demonstrate convincingly that such
genes are directly necessary for the expression of maternal
behavior, as the loss of a developmental gene may simply
preclude the behavior, because the necessary biological
substrate is missing.
Pragmatically, the most promising approach would
involve a standard battery of behavioral measures for
maternal behavior, discussed above. This battery should
be administered to animals in the large-scale mutational
screenings that are being done at the Jackson Labs and
other mouse genome centers. Perhaps most efficiently this
battery would focus on measures of latency of sensitiza-
tion in adult virgin females. This strategy would likely
take less time than doing gestational monitoring, and it
would also identify deficits that would otherwise go
undetected if the knockout animals were infertile. For
example, the deficits in maternal behavior associated with
knocking out the ER␣ gene would not have been discov-
ered (Ogawa et al 1996, 1998). On the other hand, certain
deficits in maternal behavior could only be established by
using a full battery of behavioral assessments of new
mothers (Pryce et al 2001).
Development of Inducible Knockouts
In most current knockout studies, the mutated gene is
nonfunctional throughout mouse maturation; thus, mouse
development may be impaired, resulting in death or
abnormal brain function (Gingrich and Hen 2000). In the
absence of a gene, a mouse may undergo compensatory
changes, such as up- or downregulation of other gene
products, resulting in secondary phenotypical changes
(Gerlai 1996). Compensatory changes may spare behav-
ioral function and obscure the interpretation of the normal
contribution of the gene to behavior. To overcome these
limitations it will be necessary to develop conditional
mouse mutants in which the gene is inactivated at partic-
ular points of development. Future investigation using
J.F. Leckman and A.E. Herman
inducible knockouts, in which the timing and placement of
the targeted gene disruption can be controlled, will be an
important tool. For example, such studies have the poten-
tial to resolve the apparent contradiction between the
results of the PRLR (Ormandy et al 1997) and the PRL
(Horseman et al 1997) knockout studies with regard to
maternal behavior.
Investigation of Interactions among Genes with
Known Impact on Maternal Behavior
In future work, it will be necessary to study further the
interactions among the genes with known impact on
maternal behavior. The clearest example thus far is the
known functional relationship between nNOS and the
PRLR. In the case of the transcription factors, it will be
useful to study the mechanism of their induction in
particular brain regions, to identify target genes that
mediate nurturing, and to elucidate the specific adaptive
changes that enhance the nurturing response following
repeated exposure to newborn pups. Investigation of target
genes will likely be aided by DNA microarray technology.
Investigation of Nongenomic Influences on
Maternal Behavior
Thus far, several experimental interventions have been
shown to have effects on aspects of maternal behavior,
including licking and grooming, high arched backed nurs-
ing, and aggression toward an intruder. More recently,
other maternal behaviors have also been systematically
evaluated (Pryce et al 2001). In general, these findings
suggest that maternal behavior in the days following birth
serves to “program” the subsequent maternal behavior of
the adult offspring as well as establishing the pups’ level
of hypothalamic–pituitary–adrenal responsiveness to
stress (Denenberg et al 1969; Francis et al 1999; Levine
1975). More extreme forms of maternal deprivation have
also been shown to have profoundly negative effects on
the development of maternal behavior in adult primates
(Harlow and Harlow 1987).
This complex programming also appears to influence
aspects of learning and memory. Further, many of the
brain regions implicated in these experimental interven-
tions are the same as those implicated in mediating aspects
of maternal behavior (Figure 1). For example, the finding
that maternal stress in the immediate perinatal period can
lead to deranged maternal care (and reduced levels of
licking and grooming), as well as higher levels of hypo-
thalamic corticotropin-releasing factor (CRF) in their adult
offspring (Plotsky and Meaney 1993; Francis et al 1999) is
consistent with the observation that ICV infusions of CRF
inhibit maternal behavior in both naı̈ve and experienced
dams in a dose-dependent fashion (Pedersen et al 1991).
Genetics of Maternal Behavior
Another fascinating environmental effect is observed
among the Dbh ⫺/⫺ mutant females. Specifically,
Thomas and Palmiter (1997) demonstrated that a single
bolus of norepinephrine in pregnant Dbh mutant females,
shortly before birth, induced females that would have
otherwise abandoned their litters to nurture their young
and this restoration of maternal behavior carried over to
subsequent pregnancies, even when norepinephrine was
no longer present.
In human subjects, it is fascinating that there is evidence
for the transmission from mother to daughter of styles of
maternal care and control (Miller et al 1997). It will important
to determine through cross fostering studies if such patterns
are transmitted genomically or nongenomically.
Neurobiology of Maternal Behavior in Primates
Although maternal separation during early postnatal life
has been studied in nonhuman primates, studies of mater-
nal behavior per se are relatively rare (Harlow and Harlow
1987; Higley et al 1991; Kraemer et al 1989). Future gene
knockout studies in primates may allow investigators to
assess directly the importance of these genes in mamma-
lian species more closely related to humans.
Clinical Perspectives on Disorders Associated with
Deficits or Dysregulation of Affiliative Behavior
In recent years, molecular genetic approaches have broad-
ened our understanding of the pathophysiology of com-
plex disorders. For example, much work has been done on
the identification of single genes responsible for forms of
severe hypertension. Molecular genetic studies have now
identified mutations in eight genes that cause Mendelian
forms of hypertension and nine genes that cause Mende-
lian forms of hypotension in humans (Lifton et al 2001).
Identification of these mutations has provided insight into
the molecular pathways by which the genes act. Thus far,
the mutations alter blood pressure through a common
pathway, the regulation of salt reabsorption in the kidney.
This work illustrates the power of molecular genetic
approaches to understanding the physiology of hyperten-
sion, and possibly other disorders. Similarly, a deeper
understanding of the genetic and neurobiological sub-
strates of maternal behaviors and the timing and nature of
their enduring impact on the behavior and neurobiology of
their offspring pup may advance our understanding of a
range of disorders involving disruptions or distortions of
affiliative behavior. Earlier reviews have focused on the
possible involvement of portions of this neural system in
establishing a vulnerability to mood and anxiety disorders
(Kaufman et al 2000; Ladd et al 2000). Here we make the
case that a failure of this system to develop normally may
lead to some forms of autism and that an inappropriate
BIOL PSYCHIATRY 39
2002;51:27– 43
activation or a failure to down-regulate this system may
lead to some forms of OCD.
Autism and Related Disorders
Marked social impairment, communication abnormalities,
and stereotyped behaviors characterize autism. We have
proposed that autism and other pervasive developmental
disorders are etiologically heterogeneous disorders in
which the circuitry needed to initiate and sustain maternal
and other affiliative behaviors is lost or dysfunctional
(Insel et al 1999; Leckman and Mayes 1998, 1999). The
formation of parent-child dyads and pair-bonds are based
on a capacity for social reciprocity that fails to develop in
individuals with autism. Further evidence in support of
this hypothesis includes postmortem brain studies docu-
menting structural abnormalities in brain regions impli-
cated in maternal behavior, including the mammilary
body, medial amygdala, and hippocampal regions (Bau-
man and Kemper 1994; Saitoh et al 2001). Autistic
subjects have also been reported to have lower serum
levels of oxytocin (Modahl et al 1998) and to release an
altered form of oxytocin that is typically seen during only
fetal life (Green et al, in press). Many individuals with
autism also exhibit dysregulation of the hypothalamic–
pituitary–adrenal axis (Tordjman et al 1997).
As genetic factors are known to be involved in the
transmission and expression of autism and related disor-
ders (Lamb et al 2000), it may be appropriate to consider
genes found to underlie maternal behavior as candidate
genes. For example, genetic linkage studies of autism
indicate that a locus on chromosome 7q may be involved
in the etiology of the disorder (Lamb et al 2000). It may be
of interest therefore that Mest/Peg1 maps to 7q34.
Obsessive-Compulsive Disorder
For parents, the perinatal period often involves an altered
mental state characterized by excitement and heightened
sensitivity to environmental and emotive cues (Winnicott
1956; Leckman et al 1999). The infant becomes an
increasingly exclusive focus of thought and action toward
the end of pregnancy and the early postpartum period.
Cues from the infant before and after birth as well as the
infant’s proximity, physical appearance, and temperament
provide a major stimulus for these preoccupations and
associated behaviors. Potential threats from the external
environment provide another source of stimuli and are
associated with a marked increase in anxious intrusive
thoughts and harm avoidant behaviors. We have hypoth-
esized that these anxious intrusive thoughts and harm
avoidant behaviors are related to OCD and that some
forms of OCD are the result of a dysregulation of the
neural circuits that are normally active during the initial
40 BIOL PSYCHIATRY
2002;51:27– 43
phases of parental behavior (Leckman et al 1999). With
few exceptions, however, the evidence supporting this
hypothesis is circumstantial. For example, neuroimaging
studies and neurosurgical findings studies have consis-
tently implicated orbitofrontal and amygdalal regions and
their connections with the thalamus and the ventral stria-
tum in OCD (Saxena and Rauch 2000). In addition, some
OCD patients have high levels of cerebral spinal fluid
oxytocin (Leckman et al 1995). Other OCD patients show
altered levels of prolactin in response to the serotonin
mixed agonist-antagonist meta-chlorophenylpiperazine
and the serotoninergic releasing agent d-fenfluramine
(Erzegovesi et al 2000; Hollander et al 1993).
Perhaps the most compelling evidence is that as many
as 11% to 47% of women have their first onset of OCD in
the peripartum period (Leckman and Mayes 1999; Maina
et al 1999; Williams and Koran 1997). We have further
documented that normally during this period there is a
heightened sensitivity to threat and that both fathers and
mothers experience anxious intrusive thoughts and engage
in compulsivelike harm avoidant behaviors, which bear a
striking resemblance to several of the symptom dimen-
sions of OCD (Leckman et al 1997, 1999).
Genetic studies of OCD are just beginning to yield
promising results, and progress will likely depend on
having more refined phenotypying methods that go be-
yond a simple binary designation of either meeting the
diagnostic criteria for OCD or not. (Leckman et al,
unpublished data; Nestadt et al 2000; Pauls et al 1995).
In recent years, gene knockout technology has provided
new insights into the molecular basis of maternal behavior.
Review of this literature suggests that the expression of
maternal behavior is governed by early events and in-
volves a likely reorganization of hypothalamic and limbic
circuits that are involved in physiologic and hedonic
homeostasis and well as stress response. Studies of genetic
and environmental influences on maternal behavior in
other mammalian species have the potential to inform
models of pathogenesis as well as clinical practice. They
provide a heuristically valuable framework that should
allow for a sensible integration of data derived from
burgeoning areas of science, including evolutionary biol-
ogy, molecular genetics, systems and developmental neu-
rosciences, ethology, child development, and developmen-
tal psychopathology, to name a few.
The Korczak Foundation and grants from the National Institutes of
Health MH49351, HD03008, RR06022, and MH30929 supported this
research.
Aspects of this work were presented as the 20th Annual Daniel Prager
Lecture, The George Washington University, May 2000, Washington,
DC. The authors gratefully acknowledge the assistance of Jason Co-
mander in the cluster analysis. In addition, Flora M. Vaccarino, Linda C.
Mayes, Tamas Horvath, and Sabrina Diano made detailed and useful
J.F. Leckman and A.E. Herman
comments on an earlier version of this report. The constructive critiques
of two anonymous reviewers also greatly improved this article.
Aspects of this work were presented at the conference, “Social
Anxiety: From Laboratory Studies to Clinical Practice,” held March 22,
2001 in Atlanta, Georgia. The conference was supported by an unre-
stricted educational grant to the Anxiety Disorders Association of
America (ADAA) Wyeth-Ayerst Pharmaceuticals, and jointly sponsored
by the ADAA, the ADAA Scientific Advisory Board and the National
Institute of Mental Health.
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