Please summarize the following article. Has to be TWO pages.
King-wa Fu et al.: Attempted
Crisis©2013;
Suicide
2013 Vol.
Hogrefe
on34(6):406–412
a Microblog
Publishing
Research Trends
Responses to a Self-Presented
Suicide Attempt in Social Media
This document is copyrighted by the American Psychological Association or one of its allied publishers.
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
A Social Network Analysis
King-wa Fu1, Qijin Cheng2, Paul W.C. Wong3, and Paul S. F. Yip4
1
Journalism and Media Studies Centre, University of Hong Kong, Hong Kong, China, 2Department of
Psychiatry, University of Rochester Medical Center, NY, USA 3HKJC Centre for Suicide Research and
Prevention, University of Hong Kong, China, 4Department of Social Work and Social Administration,
University of Hong Kong, Hong Kong, China
Abstract. Background: The self-presentation of suicidal acts in social media has become a public health concern. Aims: This article
centers on a Chinese microblogger who posted a wrist-cutting picture that was widely circulated in Chinese social media in 2011. This
exploratory study examines written reactions of a group of Chinese microbloggers exposed to the post containing a self-harming message
and photo. In addition, we investigate the pattern of information diffusion via a social network. Methods: We systematically collected
and analyzed 5,971 generated microblogs and the network of information diffusion. Results: We found that a significant portion of written
responses (36.6%) could help vulnerable netizens by providing peer-support and calls for help. These responses were reposted and
diffused via an online social network with markedly more clusters of users – and at a faster pace – than a set of randomly generated
networks. Conclusions: We conclude that social media can be a double-edged sword: While it may contagiously affect others by spreading
suicidal thoughts and acts, it may also play a positive role by assisting people at risk for suicide, providing rescue or support. More
research is needed to learn how suicidally vulnerable people interact with online suicide information, and how we can effectively intervene.
Keywords: attempted suicide, microblog, China, social network analysis, social media
Digital technologies and the recent development of the Internet have given rise to Web 2.0 (Oreilly, 2007) and a multitude of social media (Kaplan & Haenlein, 2010) applications (e.g., Wikipedia, YouTube, blogs, microblogs [Twitter or Sina Weibo in China], and social networking sites
[Facebook/MySpace or Renren in China]). These Internet
applications depart from the conventional static and noninteractive Internet sites and enable online users to create
user-generated content, participate in collaborative projects, and interact and connect with their social network in
real time. Social media not only enrich the content and
scope of personal communication, it also facilitates uninhibited communication and selective self-presentation of
undesirable behavior (Kaplan & Haenlein, 2010). From a
research perspective, social media can provide an excellent
platform for collecting data and studying human behaviors,
especially rare behaviors such as suicide and suicide prevention (Cheng, Chang, & Yip, 2012).
The association between social media and suicide has
recently become a public health concern (Luxton, June, &
Crisis 2013; Vol. 34(6):406–412
DOI: 10.1027/0227-5910/a000221
Fairall, 2012). Studies on suicide and the Internet emerged
about a decade ago (Fu, Wong, & Yip, 2009). Several lines
of inquiry have formed, with one line focused on how information about suicide methods or communication is
spread through the Internet (eventually negatively impacting suicidal behavior; Fu et al., 2009; Rajagopal, 2004;
Ruder, Hatch, Ampanozi, Thali, & Fischer, 2011). Another
line investigates the extent to which various types of suicide-related information are accessible on the Internet
(Biddle, Donovan, Hawton, Kapur, & Gunnell, 2008;
Cheng, Fu, & Yip, 2011; Recupero, Harms, & Noble, 2008;
Wong et al., 2013). The third line examines whether an
individual’s suicidal ideation is linked to Internet addiction
symptoms (Fu, Chan, Wong, & Yip, 2010).
One important, yet understudied, research area is how
social media affect people’s communication about suicide.
Suicidal people often communicate with ambiguity, being
in a state between dying by killing oneself and seeking the
attention and help of others (Farberow & Shneidman,
1961). However, the pattern of suicide communication may
© 2013 Hogrefe Publishing
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This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
King-wa Fu et al.: Attempted Suicide on a Microblog
have actually changed with the advent of the Internet. Vygotsky (1978) long argued that communication tools allow
for the extension of human capabilities. Communication
tools include traditional analog (e.g., pens, telegraph, telephone) and digital forms, the latter having upended our traditional ways of communication. It is therefore important
to investigate how computer-mediated communication differs from nonmediated or face-to-face communication with
respect to the psychological processes and outcomes. Several general approaches or theories have been developed to
conceptualize computer-mediated communication (Walther, 2011). For example, the hyperpersonal model presumes that an individual’s online self-presentation can be
a form of personal impression and relationship management that has capabilities far exceeding face-to-face communication (Walther, 1996). Through a channel of reduced
communication cues and asynchronous interaction, Internet message senders may selectively present themselves in
ways “that are more stereotypically desirable in achieving
their social goals” (Walther, 1996, p. 28), such as managing
a desirable personal image or building intimacy. On the
receiving end, message receivers opt to idealize the sender
and to “build stereotypical impressions of their partners
with qualifying the strength of such impressions in light of
the meager information” (Walther, 1996, p. 29). In the context of a suicidal act, because of their capacity to enable
self-disclosure of uninhibited behavior social media may
lower the threshold of vulnerable and suicidal people. Consequently, such people may be more apt to present selfharm intentions or behaviors to a network of people, including both close friends and loose acquaintances. In the
context of suicide communication, the hyperpersonal model posits that the intentions of suicidal individuals to selfharm are uninhibited in social media by allowing them to
selectively present themselves crying out for help. On the
receiving end, decoders have to rely on limited communication cues and personal attitudes to respond to such signals.
As of March 2013, over 200 million active Twitter user
accounts are generating over 400 million tweets every day
(Wickre, 2013). Although Twitter is not accessible in China, local microblogging sites, like Sina Weibo and Tencent
Weibo, have rapidly grown on their own to become major
channels for Chinese Internet users to read, write, communicate, and forward 140-character messages via a variety
of technology platforms. These two leading microblogging
service providers in China each claim their registered account base reached 500 million at the end of 2012 (Mozur,
2013). According to CNNIC (China Internet Network Information Center, 2012), the total number of Chinese microbloggers reached 274 million by mid-2012, comprising
51% of the total Internet users in China. The total number
of microbloggers is estimated to reach 400 million by the
end of 2014 (iResearch, 2011). As Western media put it,
microblogging has emerged to become one of the major
“free-speech platforms” in China (Richburg, 2011). This
new medium gives Chinese Internet users unprecedented
© 2013 Hogrefe Publishing
407
opportunities for sharing information as well as expressing
opinions and emotions, thereby serving as “We the Media”
(Gillmor, 2004).
This study is purposely exploratory. We seek to investigate the consequences of presenting self-harm behavior
through social media. Using a case study in China, we address the following questions: (1) How do Chinese microbloggers respond to the self-presentation of self-harm behavior? (2) How are such microblog posts propagated in a
social network? and (3) What are the implications for suicide prevention?
Method
Quantitative content analysis was conducted to study a selfharm entry in a microblog in China. On February 23, 2011,
at 9:56 pm, a wrist-cutting photo was posted on Sina Weibo
by a user J, whose account profile indicated he was a male
living in Shenzhen city. This microblog read, “Today, I returned back to you. That’s all. You made me feel like falling
from heaven to hell. Now I get it.” Once published, the post
and the picture attached were broadly circulated on the microblog system. About 3 hours later, another message posted by User J read, “Sorry, I am so sorry. I didn’t know my
personal issue could draw so much attention here. I am fine.
I have already wrapped up my wound.” According to media
reports on February 25, 2011, the police confirmed User J’s
real identity and his suicidal act.
On the Sina Weibo platform, users can respond to a post
by two different means: reposting or commenting. When
reposting, a microblogger adds a remark and sends the original post to his or her followers. A microblogger can also
respond by commenting on the original post. In the case of
user J’s weibo, the original post was reposted 3,974 times
and received 1,997 comments by 3,696 microbloggers
within 3 hours (as of February 24, 1:05 am), yielding 5,971
microblog pieces of content that we collected and analyzed.
We used the Application Programming Interface (API)
provided by Sina Weibo to gather reposts and comments
on March 15, 2011. Reposters’ self-reported sex, follower
counts, friend counts, and provinces of origin were also
collected. One thousand randomly generated 10-digit user
identity codes served as control subjects to represent the
overall microblogger population.
In addition, user names contained in the reposts were
extracted. When a microblog is reposted, a reference in the
format of “//@screen_name,” where screen_name is the
displayed user name, is offered by default at the beginning
of the reposting text and is preserved in its entirety if not
deleted by the author. We took advantage of this property
to trace the pattern of reposting.
To generate a coding framework, the first author analyzed collected reposts and comments inductively, and then
classified and regrouped them into an initial category
framework. Two native Chinese coders were recruited to
Crisis 2013; Vol. 34(6):406–412
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408
King-wa Fu et al.: Attempted Suicide on a Microblog
conduct the classification. After a training session, the coders provided feedback in a subsequent review meeting. The
categories were amended accordingly and the final coding
framework was developed. Next, 100 posts were randomly
selected from the dataset and coded by two coders in a
parallel and independent manner to assess intercoder reliability. The κ coefficient of the classification was 0.66,
which can be considered to be substantial agreement (Landis & Koch, 1977). Finally, one coder completed the coding
of the entire dataset using the coding framework.
Interconnections (e.g., a link between two nodes signified a repost sent from one microblogger to another) between microbloggers are represented by a directed social
graph. To analyze the graph, we used R version 2.12.1 (R
Development Core Team, 2010). Specifically, we used the
network research package igraph (Csardi & Nepusz, 2006)
to conduct social network analysis, evaluating the nodelevel parameters (e.g., in-degree, out-degree, and betweenness centrality measures), which are used to represent the
importance of each individual microblogger in a network
(Freeman, 1978). For example, the out-degree centrality of
a microblogger M means the number of other microbloggers who repost M’s message. The in-degree centrality of
M represents the frequency with which M reposts messages
received from others. The betweenness centrality of M represents the total count of pairs of nodes whose shortest path
between them consists of M, thereby denoting the relative
importance of the position M has in the network. Moreover,
network-level topological parameters, including average
pathlength and global cluster coefficient, were deployed to
compare different networks (Lewis, 2009). The average
pathlength of a network is equal to the average number of
shortest paths over all direct paths connected between
nodes in that network. The global cluster coefficient is an
indicator of the extent to which the nodes of a network
cluster together. Fuchterman and Rheingold’s graph layout
algorithm (R’s igraph package) was used to visualize the
network. Moreover, a set of social graphs was randomly
generated using the Erdos-Renyi model (Csardi & Nepusz,
2006), a common approach for social network comparison
(Chau & Xu, 2007).
mation diffusion took a shorter distance on average to propagate the message from one node to the others. The larger
global cluster coefficient of the repost graph reflects the
existence of many relatively isolated and densely-knit user
clusters in the network.
A total of 3,696 microbloggers reposted the message;
Table 3 shows their self-reported sex, locations, and follower and friend counts. Compared to the random sample
obtained from the microblogger population, the data show
that people who contributed to reposting were more likely
to come from cities in China that are economically well
developed and top ranked in GDP per capita (National Bureau of Statistics of China, 2012). The five top ranked cities
were Shanghai (1st ranked in GDP per capita, the same as
below), Beijing (2nd), Jiangsu (4th), Zhejiang (5th), and
Guangdong (7th). In addition, these reposters had a higher
likelihood of having more than 1,000 followers and 200
friends.
Table 1. Classification of microbloggers’ responses to the
original message (N = 5,971)
Type of response
%
Translated examples
Caring, showing empa- 19.8
thy, and giving advice
“Are you alright? Hope you are
fine.”
“Brother, I wish you are ok.”
“Don’t . . . Life is so important. If
you give up your life, you lose your
love too.”
Calling for help
16.8
“Damn it. Call the police now. He is
in Shenzhen.”
“110, 120, SOS . . . Help this guy.”
“My God. Who knows his address?
Call emergency now.”
Cynical or indifferent
comments
23.4
“Why make your hand full of chocolate?”
“Save your blood. Many hospitals
need that.”
“[Angry] I hate these self-harmers.”
Shocked
19.5
“OMG. So scary!!”
“What’s up? You scare me!!”
“Ah! Live Weibo broadcast of suicide at midnight?”
Forward to others with 20.4
no comment
Reposting Weibo post
Results
In total 5,971 microblogs were collected and analyzed. Table 1 shows the categories of the microbloggers’ written
reactions. Among the collected microblogs, 36.6% concerned caring, showing empathy, and calling for help (see
examples in Table 1), 23.4% evidenced a negative attitude
(i.e., cynical or indifferent comments), 19.5% were emotional presentations of shock, and 20.4% were merely reposts.
Table 2 demonstrates that the repost graph evidenced a
slightly shorter average path length than the group average
of the randomly generated graphs, indicating that its inforCrisis 2013; Vol. 34(6):406–412
Table 2. Comparisons between the repost graph and the
randomly generated graphs
Repost graph
Random graphs
Number of nodes
3,696
3,696
Number of edges
1,813
1,813
–4
Density
1.33 × 10
1.33 × 10–4
Average degree
0.981
0.981
Average path length
1.93
1.96
2.9 × 10–4
Global cluster coefficient
4.92 × 10–3
Note. Random graph indicators were obtained by calculating mean
values from 30 randomly generated graphs.
© 2013 Hogrefe Publishing
King-wa Fu et al.: Attempted Suicide on a Microblog
409
Table 3. Characteristics of reposters
Characteristics Categories
Reposters
sample
(N = 3,696)
Frequency (%)
Random
samples
(N = 1,000)
Frequency (%)
Sex
Male
54.4
55.0
Female
42.8
44.9
Not mentioned
2.8
0.1
Guangdong
26.7
15.1
Peking
16.4
4.3
Shanghai
9.7
3.7
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Location
Zhejiang
3.3
4.2
Jiangsu
3.6
5.8
International
3.3
1.1
Others
3.4
7.3
Sichuan
3.3
4.4
Fujian
2.3
4.5
Hubei
1.2
2.8
Other provinces 26.8
46.8
No. of followers 0–999
No. of friends
90.3
100.0
1,000–1,999
5.0
0
2,000–2,999
1.7
0
3,000–3,999
0.6
0
4,000–4,999
0.4
0
≥ 5,000
2.0
0
0–199
52.7
99.0
200–399
24.6
0.8
400–599
8.7
0.2
600–799
4.5
0
800–999
2.8
0
Figure 1. Graphical visualization of the repost network.
Note. Each node represents a microblogger, and an arrow
represents a message reposted from one microblogger to
the other. The nodes with name labels are the top ten most
influential reposters.
In Table 4, bloggers J1 to J10 denote the top ten most
influential microbloggers who participated in reposting the
original weibo. They were ranked by their betweenness
centrality, an indicator of its importance in the network of
information diffusion. None of the top ten microbloggers
made cynical or indifferent comments. Figure 1 is a graphical visualization of the information diffusion, indicating
how the reposters were intercommunicated. As seen in Figure 1, the major reposters were often positioned at cluster
locations of the network and linked with a large number of
other reposters.
Table 4. Characteristics of the 10 most influential microbloggers who reposted the original message
Name of blogger
Sex
Type*
Time reposted
No. followers
Out degree**
In degree**
Betweenness**
Blogger J1
F
2
22:17:54
4,075
11
3
108
Blogger J2
F
2
22:17:56
12,795
7
1
80
Blogger J3
F
4
22:17:51
655
4
1
64
Blogger J4
F
4
22:17:38
462
2
1
57
Blogger J5
F
5
22:17:26
268
19
1
52
Blogger J6
F
4
22:17:51
801
4
1
51
Blogger J7
M
1
22:17:50
2,067
4
1
48
Blogger J8
F
5
22:17:50
829
5
1
44
Blogger J9
M
2
22:18:13
6,447
37
3
44
Blogger J10
F
4
22:17:45
691
10
1
43
Note. *Type of response: (1) “Caring, showing empathy, and giving advice”; (2) “Calling for help”; (3) “Cynical or indifferent comments”; (4)
“Shocked”; and (5) “Only reposting with no comment.” **Out-degree centrality of a microblogger M means the number of other microbloggers
who repost M’s message. In-degree centrality of M represents the frequency that M reposts the message received from others. Betweenness
centrality of M represents the total count of pairs of nodes whose shortest path between them consists of M, denoting the relative importance
of the position where M is located in the network.
© 2013 Hogrefe Publishing
Crisis 2013; Vol. 34(6):406–412
410
King-wa Fu et al.: Attempted Suicide on a Microblog
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Discussion
This exploratory study indicates that there were various
types of responses from Chinese microbloggers to an individual’s online presentation of self-harm. A significant portion of the responses appeared to be positive, characterized
functionally by efforts of caregiving and offers of assistance to the call for help. The top 10 most influential microbloggers who reposted the original message showed
concern and care for the person who self-harmed. Drawing
on the hyperpersonal model (Walther, 1996), the consequence of these caregiving responses may positively address and reinforce a suicidal individual’s underlying goal
of self-presentation: the cry for help (Farberow & Shneidman, 1961).
Although media presentation of suicide is often considered harmful to vulnerable suicidal people (Niederkrotenthaler et al., 2012), and suicide-related communication
within a cluster may be contagious (Joiner, 1999), this
study and others (Ruder et al., 2011; Silenzio et al., 2009)
suggest a potential positive function of social media in suicide prevention. Specifically, diffusion of messages about
one’s suicidal thoughts or behaviors on social media may
serve as an early identification tool and as a rescuing platform for those who are at suicidal risk or a strategy of engaging socially isolated individuals. For instance, Facebook has launched a number of initiatives to assist users in
identifying others who exhibit suicidal tendencies (Ruder
et al., 2011). Our findings, like those of others, suggest that
online media can also be constructively utilized to detect
individuals with suicidal risks earlier, thereby ensuring a
speedy and timely rescue. Increasing amounts of supporting empirical evidence prompt us to wonder if it is necessary to reexamine the suicide reporting guidelines in the
international media, especially given the special nature of
online social media. Perhaps new guidelines should be developed specifically for online service and information providers.
Furthermore, our social network analysis shows that
there were more user clusters in the repost network (i.e.,
larger cluster coefficient) than in the random network, and
that the speed of information diffusion was faster (i.e.,
shorter average pathlength), suggesting that a repost network can be activated quickly for effective communication
in emergency situations. It also suggests that loose acquaintances, known as “weak ties” (Granovetter, 1973), might
be more helpful than a closed group within an interpersonal
network in terms of responding to emergencies such as suicide attempts. Recent studies on social media information
diffusion demonstrate that removing weak ties from the
network considerably decreases the effectiveness of information diffusion (Zhao, Wu, & Xu, 2010). A weak-ties network via social media may therefore effectively contribute
to the early identification of people at risk from the population at large. Therefore, if suicide prevention professionals or organizations can build up an online social media
Crisis 2013; Vol. 34(6):406–412
platform, it would be helpful to build up a network of gatekeepers or spectators who are able to contribute to early
identification of people at risk from the population at large.
Most influential reposters could serve as suicide prevention gatekeepers: They are more likely to show caring attitudes toward the attempter. Given the assumption that the
selected incident is not an isolated case, and the reactions
of the reposters are indeed common, suicide-prevention
professionals may consider developing awareness campaigns and gatekeeper training programs that target active
and popular online users.
Meanwhile, we acknowledge that it is still premature to
conclude that engaging with online social networks eventually reduces an individuals’ suicide risk (or at a minimum
does no harm). In this specific case, 20% of the messages
expressed a cynical or indifferent attitude toward the suicidal person’s self-presentation, with some considered cyberbullying. Disconfirmation may have undesirable effects
on the emotions of the attempter and other suicidal individuals who are exposed to these messages. This phenomenon
may be more pronounced if the post belongs to a celebrity,
much like the prominent impact of media reports of celebrity suicide (Fu & Yip, 2009). In addition, we do not know
whether the suicidal person received any proper help or
support from professionals and/or his offline social network after being found by the police, given that mental
health services are generally not very accessible in China
(Cheng et al., 2012). From the written responses, we could
not find any microbloggers exhibiting suicidal risks when
receiving and/or forwarding J’s message, but we remain
uncertain whether readers’ mental well-being would be impacted over a longer period of time. Online self-presentation may have other side effects not examined in the current
study.
The Chinese government recently imposed a legal requirement of using one’s real name when registering to use
social media (Bradsher, 2012). Early evidence suggests this
has had a chilling effect on political comments in China
(Fu, Chan, & Chau, 2013). Such a requirement may also
discourage vulnerable individuals’ expressions of feelings
or calls for help. The impact on the behavior of microbloggers is yet to be recognized, with more studies needed in
order to understand the requirement’s effect on the microblog usage in China.
Conclusion
Diffusion of suicide-related content across social media is
a recent and rapidly growing phenomenon. There are not
enough empirical data to suggest whether the benefits or
harms brought by social media on suicidality outweigh one
another. This study, however, suggests a suicidal attempt
can be disrupted in time if social media is harnessed in
positive ways. Researchers should closely monitor the effects of new media on individuals’ mental health and sui© 2013 Hogrefe Publishing
This document is copyrighted by the American Psychological Association or one of its allied publishers.
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King-wa Fu et al.: Attempted Suicide on a Microblog
cidal acts. Clinicians who help suicidal individuals should
explore their clients’ use of social media and suggest ways
to make social media one of the safety nets available to
them when necessary. Moreover, an appropriate referral
system needs to be established to provide follow-up support and services to individuals who self-present suicidal
thoughts and/or behaviors online. Suicide researchers
should closely monitor the potential effect of the new media on individual’s mental well-being and suicidality. Understanding how and why new information technologies
are adopted marks important research areas. Public health
and media professionals may consider developing guidelines to respond to this exploding phenomenon. Social media can be known as a double-edged sword: On the one
hand, it is a platform for spreading suicidal thoughts or
mimicking suicidal acts, whereas on the other hand it also
plays a constructive role in early detection of people at suicidal risk. Further empirical research is needed to reveal
how the suicidal population interacts with the social media
and what we can do to intervene effectively.
Acknowledgments
The authors wish to acknowledge Chrissy Yu and Alison
Hui for their assistance in data collection and coding of the
Internet content, and Helen Ma for her effort in editing the
manuscript. Qijin Cheng’s work is partially supported by a
Public Policy Research grant (HKU 70330-PPR-12) and a
grant from the Fogarty International Center of NIH, USA
(D43 TW009101).
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About the authors
Received September 18, 2012
Revision received April 3, 2013
Accepted April 8, 2013
Published online July 26, 2013
Journalism and Media Studies Centre
The University of Hong Kong
Pokfulam, Hong Kong
China
Tel. +852 3917-1643
Fax +852 2858-8736
E-mail kwfu@hku.hk
Crisis 2013; Vol. 34(6):406–412
Dr. King-wa Fu is an Assistant Professor at the Journalism and
Media Studies Centre (JMSC), The University of Hong Kong
(Hong Kong SAR). His research interests include political participation and media use, mental health/suicide and the media, health
communication, young people’s Internet use, and computational
method for media studies.
Dr. Qijin Cheng is a Postdoctoral Fellow at Department of Psychiatry, University of Rochester Medical Center, Rochester, NY,
USA as well as at HKJC Centre for Suicide Research and Prevention, the University of Hong Kong (Hong Kong SAR). Her research focuses on suicide, media, and social context.
Dr. Paul Wong, DPsyc (Clinical), is Assistant Professor at the
Department of Social Work and Social Administration, University
of Hong Kong (Hong Kong SAR). He is a National Representative of the International Association of Suicide Prevention. His
research interests include aborted suicide attempt, postvention,
homicide-suicide, Internet and suicide, and evaluation of suicide
prevention programs.
Prof. Paul Yip is Director of the Centre for Suicide Research and
Prevention and a professor at the Social Work and Social Administration Department, University of Hong Kong (Hong Kong
SAR). He is the recipient of Stengel Researcher’s Award (2011)
of the International Association of Suicide Prevention. His interests lie in adopting a public health approach for suicide prevention
and population health studies.
Dr. King-wa Fu
© 2013 Hogrefe Publishing
Behavioral Neuroscience
2011, Vol. 125, No. 1, 29 –36
© 2011 American Psychological Association
0735-7044/11/$12.00 DOI: 10.1037/a0021952
This document is copyrighted by the American Psychological Association or one of its allied publishers.
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
Strain-Specific Cognitive Deficits in Adult Mice Exposed to Early Life Stress
Mukti Mehta
Claudia Schmauss
New York State Psychiatric Institute
New York State Psychiatric Institute and Columbia University
Early life stress is a prominent risk factor for the development of adult psychopathology. Numerous
studies have shown that early life stress leads to persistent changes in behavioral and endocrine responses
to stress. However, despite recent findings of gene expression changes and structural abnormalities in
neurons of the forebrain neocortex, little is known about specific cognitive deficits that can result from
early life stress. Here we examined five cognitive functions in two inbred strains of mice, the stressresilient strain C57Bl/6 and the stress-susceptible strain Balb/c, which were exposed to an infant maternal
separation paradigm and raised to adulthood. Between postnatal ages P60 to P90, mice underwent a series
of tests examining five cognitive functions: Recognition memory, spatial working memory, associative
learning, shifts of attentional sets, and reversal learning. None of these functions were impaired in IMS
C57Bl/6 mice. In contrast, IMS Balb/c mice exhibited deficits in spatial working memory and extradimensional shifts of attention, that is, functions governed primarily by the medial prefrontal cortex. Thus,
like recently discovered changes in frontocortical gene expression, the emergence of specific cognitive
deficits associated with the medial prefrontal cortex is also strain-specific. These findings illustrate that
early life stress can indeed affect specific cognitive functions in adulthood, and they support the
hypothesis that the genetic background and environmental factors are critical determinants in the
development of adult cognitive deficits in subjects with a history of early life stress.
Keywords: early life stress, inbred mouse strains, recognition memory, working memory, attention
set-shifting
ment than the stress-resilient strain C57Bl/6 (Millstein & Holmes,
2007).
ELS can provoke long-lasting effects on endocrine responses to
subsequent stress (Ladd et al., 2004) and the related gene expression changes (Navailles et al., 2010). Moreover, ELS induces
alterations in dendritic morphology of pyramidal neurons of the
medial prefrontal cortex (mPFC; Pascual & Zamora-León, 2007)
that resemble those elicited by chronic corticosteroid administration (Cerqueira et al., 2007). Moreover, age-dependent changes in
the densities of calbindin- and parvalbumin-immunoreactive interneurons in subregions of the mPFC (Helmeke et al., 2008) and
altered monoaminergic innervation of the mPFC (Braun et al.,
2000) have been reported to result from ELS. Recently, strainspecific changes in fronto-cortical gene expression have also been
found in adult mice exposed to ELS. For example, Balb/c, but not
C57Bl/6, mice exhibit increased expression of G␣q (Bhansali et
al., 2007; Schmauss et al., 2010), decreased expression of the
plasticity-inducible transcription factor egr-1 (Navailles et al.,
2010), and increased expression of extensively edited mRNA
isoforms encoding 5-HT2C receptors with decreased G-proteincoupling efficiency (Bhansali et al., 2007; Schmauss et al., 2010).
These genes can play a role in forebrain neocortex-governed
cognitive functions, especially in the mPFC (working memory,
set-shifting) and the orbital fontal cortex (reversal learning): signaling through Gq-coupled receptors is necessary for working
memory (Runyan et al., 2005); induced egr-1 expression can lead
to long-lasting synaptic changes that influence behaviors associated with learning and memory (Cole et al., 1989); and 5-HT2Creceptor signaling in the orbital frontal cortex plays a role in early
phases of spatial reversal learning (Boulougouris & Robbins,
2010).
For several heritable psychiatric disorders, the interaction between gene and environment is thought to be critical for modulating outcome or mutating genetic risk (Kendler, 2005; Kendler &
Baker, 2007). This is best documented for mood disorders in
subjects with distinct genetic variants in serotonin-related genes
(Caspi et al., 2010). Moreover, the impact of environmental factors
on the development of psychopathology depends upon the age of
exposure. The most persuasive example, early life stress (ELS),
exerts profound effects on adult emotional behavior and increases
risk for depression, anxiety disorders, and substance abuse (Holmes et al., 2005).
In studies on the impact of ELS on adult psychopathology,
inbred strains of mice provide a source of natural genetic variability and phenotypic differences. For example, the isogenic strains
C57Bl/6J and Balb/cJ differ in their sensitivity to ELS and adult
stress (Holmes et al., 2005; Millstein & Holmes, 2007), with
Balb/c being more susceptible to stress-induced behavioral impair-
Mukti Mehta, Department of Molecular Therapeutics, New York State
Psychiatric Institute; Claudia Schmauss, Department of Molecular Therapeutics, New York State Psychiatric Institute and Department of Psychiatry, Columbia University.
We thank Kristin Bornello for assistance in behavioral testing. This
work was supported by National Institutes of Health Grant MH078993 to
C.S. and, in part, by a National Institutes of Health Conte Center Grant P50
MH062185.
Correspondence concerning this article should be addressed to Claudia
Schmauss, Department of Psychiatry and Molecular Therapeutics, Columbia University and New York State Psychiatric Institute, 1051 Riverside
Drive, New York, NY 10032. E-mail: cs581@columbia.edu
29
MEHTA AND SCHMAUSS
30
Despite the findings of altered neuronal morphology and gene
expression changes, the effects of ELS on frontocortical-governed
cognitive functions remain to be investigated. In the present study,
we tested the hypothesis that, like the persistent frontocortical gene
expression changes elicited by ELS exposure, ELS-induced cognitive deficits also occur in a strain-specific manner. Therefore, we
examined several cognitive functions, including recognition and
working memory, associative learning, attention-set-shifting, and
reversal learning, in C57Bl/6 and Balb/c mice with and without
exposure to ELS.
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Method
Subjects
Male and female Balb/cJ and C57Bl/6J mice were housed in a
temperature-controlled (26 ⫾ 2 °C) barrier facility with a 12-hr
light– dark schedule (lights on at 6:00 a.m.) and free access to food
and water. All experiments involving animals were performed in
accordance with the National Institutes of Health Guide for the
Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committees at Columbia University
and the New York State Psychiatric Institute. All efforts were
made to minimize both the number of animals and the discomfort
of the animals used.
Infant Maternal Separation (IMS)
Pups of first-time mothers were separated from their dam daily
for 3 hr (from 1:00 to 4:00 p.m.) from postnatal age Day 2 (P2)
until P15. Control animals were standard-facility-reared (SFR)
offspring of first-time mothers and were subjected to the same
housing and husbandry conditions. Only litters of 6 to 8 pups were
selected for this study. For SFR and IMS mice, a total of 10 and 12
litters, respectively, were used. Because IMS mice exhibit a delayed postnatal development as indicated, for example, by a 4-day
delay of eye opening and because they are still being nursed by
their dams at P21, all pups were weaned at P28. This ensured a
near 100% survival rate of the IMS pups, which throughout postnatal development have about a 20% reduced body weight, even as
young adults (Navailles et al., 2008). Four to five animals randomly selected from four to five different litters were grouphoused by sex. At P60, one cohort of IMS mice and their SFR
controls were selected for behavioral tests of depression- and
anxiety-like behavior (10 mice per group derived from 10 different
litters) while the other cohort was selected for cognitive–
behavioral testing (8 mice per group selected from 8 of the 10
[SFR] or 12 [IMS] litters described above). Behavioral tests of
depression and anxiety-related behaviors were conducted with
male mice. The groups of mice tested in cognitive– behavioral tests
were composed of equal numbers of male and female mice.
Elevated Plus Maze (EPM)
Mice were exposed to an EPM apparatus purchased from Stoelting (Wood Dale, IL), which had two open and two closed arms that
joined to form the center of the maze (lane width: 5 cm, arm
length: 35 cm, wall height: 15 cm, elevation above ground: 55 cm).
Testing (under 100 lux/m2 lightening) was performed between
1:00 and 4:00 p.m. Mice were placed in the center of the maze and
their time spent in open arms during a 5 min test period was
recorded by the investigators during the time of testing.
Forced Swim Test (FST)
The same mice tested in the EPM were tested in the FST 1 week
later. A modified version of the forced swim test was used as
previously described (Bhansali et al., 2007). Briefly, between 1:00
and 4:00 p.m., mice were placed into plastic buckets (23 cm deep
and 19 cm in diameter) filled with 25–28 °C water for 6 min. In
this modified version of the Posolt FST, mice alternate between
active swimming and passive floating, but climbing is not observed. Hence, the number of passive episodes and their duration
(in seconds) was monitored by the investigators during the last 4
min of the test. On the following day, mice were reexposed to the
FST protocol, and their behavior was recorded as described above.
Social Recognition
This test taxes short-term recognition memory and relies on the
ability of adult mice to recognize a juvenile conspecific and to
remember its perceptual features (olfactory, somatosensory, visual) for a period of 2 hr. Adult mice were singly housed 24 hr
before exposure of a nonfamiliar juvenile mouse. During a 5-min
exposure, the time interacting with the juvenile (following, sniffing, licking, etc.) was recorded (T1). Then, the juvenile was
removed, but placed back 2 hr later for a second 5-min test (T2).
In mice with intact recognition memory, the time of social interaction during the second exposure is consistently shorter (i.e.,
T1–T2 equals a positive number). To confirm the validity of this
test as a test of short-term memory, we also exposed additional
groups of mice to a different juvenile during the second exposure.
Attention-Set-Shifting Task (ASST)
A day after completion of the Social Recognition test, mice were
food-restricted such that they gradually (over the period of 5 to 7
days) lost 10% of their free-feeding body weight. Once mice
reached this 10% reduction in body weight, they were tested in the
ASST. The rodent ASST, developed by Birrell and Brown (2000),
uses two stimulus dimensions, odor and texture, which are appropriate for this species. The test apparatus was made of Plexiglas
that resembled the housing cage (dimensions: 32 ⫻ 27 ⫻ 15 cm).
A sliding door separated one third of the apparatus (holding box)
from the remaining two thirds (test area).
On the first day, mice were habituated to the test apparatus.
During this time, they learned to retrieve a food reward deeply
buried in unscented terra cotta pots filled with familiar bedding
media. The habituation period ended when mice retrieved the food
reward in 6 consecutive trials. On the next day, mice performed the
entire ASST in a single session. Briefly, they were first trained on
two simple discriminations (SD) between odor (scented terra cotta
pots) or texture (different digging media). Only one stimulus
dimension indicated the location of the food pellet, and both
dimensions were used in a randomized order. The next task was a
compound discrimination (CD), in which another stimulus dimension was introduced that was not a reliable predictor of food
reward, and the same positive stimulus (a particular odor or tex-
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EARLY LIFE STRESS AND ADULT COGNITIVE DEFICITS
ture) used in the initial SD still guided correct response selection.
In the following intradimensional shift phase (IDS), both relevant
and irrelevant stimuli were changed, but the relevant stimulus
dimension used in the SD and CD (odor or medium texture)
remained the same. Then, the formerly irrelevant dimension became relevant and required an extradimensional shift of attention
(EDS). Finally, the previously positive stimulus of the EDS became a negative one, and the previously irrelevant stimulus indicated food reward (reversal learning; EDS-Rev). In all test phases,
animals had to reach a criterion of six consecutive correct trials.
The number of trials to criterion is the response accuracy, and the
time between stimulus onset and response selection is referred to
as response latency. Details about the stimulus properties used in
the test are described in Glickstein et al. (2005).
Spatial Working Memory (WM)
We used a widely used delayed alternation task performed in a
T-maze as previously described (Glickstein et al., 2002). The maze
was made of 0.6 cm-thick Plexiglas. Its main alley (58 cm long)
was connected to two side arms (30 cm long). Alley and side arms
were 11 cm wide. All walls were 18.5 cm high.
One day after completion of the ASST, mice began their training
for alternate arm entries in the T-maze. The training period (lasting
on average 10 to 14 days) ended when mice reached at least 70%
correct arm entries (in 10 trials per day) on two consecutive days
with no intertrial delay (referred to as 5 s delay, i.e., the minimum
handling time). Then, mice performed the test with three intertrial
delays (15, 20, and 30 sec). Only correct arm entries resulted in
food reward, and their percentage of the total number of trials was
taken as a measure of response accuracy. We have previously shown
that, in this test, mice can hold spatial information in working memory
for up to 20 s, but exhibit chance performance (i.e., only 50% correct
arm entries) at 30 s delay (Glickstein et al., 2002).
31
Figure 1A summarizes results of the FST. There was a significant difference in the total time of immobility between SFR mice
of both strains (ANOVA, F(3, 27) ⫽ 6.61, p ⫽ .0017). Post hoc
Bonferroni Multiple Comparisons tests revealed that SFR C57Bl/6
mice exhibited significantly greater immobility than Balb/c mice
(Figure 1A). Nevertheless, the FST behavior of IMS C57Bl/6 mice
did not significantly differ from their SFR controls. IMS Balb/c
mice, however, exhibited significantly more immobility than their
SFR controls (ANOVA, F(3, 25) ⫽ 7.04, p ⫽ .0014; Figure 1A).
For the EPM test, ANOVA revealed a significant difference
between SFR mice of both strains, F(3, 33) ⫽ 9.608, p ⫽ .0001.
Post hoc Bonferrori tests revealed that SFR Balb/c mice spent
significantly less time in the open arms compared to SFR C57Bl/6
mice (Figure 1B). Moreover, there were differences between SFR
and IMS mice of both strains, F(3, 29) ⫽ 12.96, p ⬍ .00001, with
IMS mice having spent significantly less time in the open arms
compared to their SFR controls (Figure 1B).
In summary, while IMS mice of both strains exhibited similar
anxiety-like behavior in the EPM, only IMS Balb/c mice also
showed increased depression-like behavior in the FST.
Statistical Analysis
The FST, the EPM, and the Social Recognition test data were
analyzed by factorial analysis of variance (ANOVA; effect of
strain and effect of treatment [SFR or IMS]), and statistical differences were resolved post hoc using Bonferroni Multiple Comparisons tests. The data obtained from the ASST and the WM tests
were first analyzed by Repeated Measures ANOVA followed post
hoc by Tukey-Kramer Multiple Comparisons tests to assess the
performances of SFR and IMS mice of each strain in the individual
test phases (ASST) or delay periods (WM test). In addition,
factorial ANOVA was used to test for differences between strains
and treatment. For all cognitive test results, two-tailed Student’s t
tests were used to compare results between groups of males and
females. The statistical analyses were carried out using Graph Pad
InStat Version 3.0 (GraphPad Software, San Diego, CA).
Results
Emotive Behavior of Adult IMS Balb/c and
C57Bl/6 Mice
We first evaluated the impact of early life stress exposure on
adult emotive behavior by comparing the behavioral responses of
SFR and IMS Balb/c and C57Bl/6 mice to FST and EPM exposure.
Figure 1. Performance of SFR and IMS Balb/c and C57Bl/6 mice in the
FST and EPM. (A) immobility measured during the last 4 min of the
second day of FST exposure. Data are mean ⫾ SEM of measures taken
from 10 animals per group and they were compared by two-tailed Student’s
t test. (B) Total time spent in open arms during a single 5 min exposure to
the EPM. Data are mean ⫾ SEM of measures taken from the same 10
animals per group shown in A, and they were compared by two-tailed
Student’s t test. IMS ⫽ infant maternal separation. SFR ⫽ standardfacility-reared controls.
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32
MEHTA AND SCHMAUSS
Social Recognition of SFR and IMS Balb/c and
C57Bl/6 Mice
Performance of SFR and IMS Balb/c and C57Bl/6
Mice in the ASST
In the Social Recognition test, both male and female mice were
used. Two-tailed Student’s t tests revealed no differences between
males and females of either group, neither in T1 measures (Balb/
c-SFR: 131.4 ⫾ 9.5 s [males] and 118 ⫾ 14.5 s [females], p ⫽ .5;
Balb/c-IMS: 117.8 ⫾ 15.5 s [males] and 105.3 ⫾ 14.8 s [females],
p ⫽ .6; C57Bl/6-SFR: 131.9 ⫾ 7.0 s [males] and 155.1 ⫾ 11.5 s
[females], p ⫽ .1; C57Bl/6-IMS: 124.5 ⫾ 14.0 s [males] and 146.4 ⫾
20.2 s [females], p ⫽ .57), nor in the T1-T2 values for reexposure to
the same juvenile (Balb/c-SFR: 56.8 ⫾ 7.2 s [males] and 59.4 ⫾ 9.9 s
[females], p ⫽ .9; Balb/c-IMS: 52.8 ⫾ 8.4 s [males] and 59.4 ⫾ 12.5 s
[females], p ⫽ .70; C57Bl/6-SFR: 45.0 ⫾ 13.4 s [males] and 51.6 ⫾
13.5 s [females], p ⫽ .74; C57Bl/6-IMS: 56.4 ⫾ 16.9 s [males] and
46.0 ⫾ 12.8 s [females], p ⫽ .57). Thus, data from males and females
were combined in each group.
SFR and IMS mice of both strains exhibited no significant
differences in their total times of interaction with a conspecific
juvenile when they were exposed to the same juvenile during the
second exposure (ANOVA, F(7, 35) ⫽ 7.393, p ⬎ .05), that is, the
time of social interaction with the juvenile was on average 50 sec
less than during the first exposure (see Figure 2). Moreover, SFR
and IMS mice of both strains exhibited significant differences in
their interaction times when exposed to the same or a different
juvenile in the second exposure (ANOVA, F(7, 35) ⫽ 7.393; p ⬍
.0001). Post hoc Bonferroni Multiple Comparisons tests revealed
that SFR and IMS mice of both groups spent significantly more
time interacting with the novel juvenile during the second exposure. In fact, the time of interaction was indistinguishable between
first exposure (T1) and second exposure (T2) (see Figure 2).
Altogether, these results indicate unaltered short-term recognition memory of species-relevant sensory information (olfactory, somatosensory, etc.) in both strains of mice exposed to the
IMS.
The various test phases of the ASST engage three specific
cognitive processes: associative learning (CD), maintaining sets/
set-shifting (IDS, EDS), and reversal learning (EDS-Rev). For
SFR mice of both strains, Repeated Measures ANOVA revealed
significant differences in the number of trials to criterion between
test phases (C57Bl/6: F(4, 36) ⫽ 7.01; p ⫽ .0003 and Balb/c: F(4,
20) ⫽ 13.6; p ⬍ .0001). Post hoc analysis showed that both strains
required significantly more trials to complete the EDS (i.e., the
most difficult test phase) than SD, CD, or IDS phases (C57Bl/6:
p ⬍ .01 compared to SD and CD and p ⬍ .001 compared to IDS
and Balb/c: p ⬍ .001 compared to SD, CD, and IDS). Moreover,
whereas ANOVA factorial analyses revealed no significant differences in the number of trials to criterion in each test phase between
SFR mice of both strains, F(9, 68) ⫽ 4.344, p ⬎ .05, there were
strain differences between IMS mice, F(9.71) ⫽ 11.89, p ⫽ .0001.
Post hoc Bonferroni Multiple Comparisons tests resolved these
differences exclusively for the EDS phase in which IMS Balb/c
mice required significantly more trials to criterion that IMS
C57Bl/6 mice ( p ⬍ .001) (see Figure 3). Moreover, while the
performance of SFR and IMS C57Bl/6 mice was indistinguishable
(F(9, 75) ⫽ 5.68, p ⬎ .05 for all test phases), ANOVA revealed
significant differences between SFR and IMS Balb/c mice (F(9,
64) ⫽ 17.889; p ⬍ .0001). Post hoc Bonferroni Multiple Comparisons revealed significantly impaired performance of IMS Balb/c
mice in the EDS phase of the ASST ( p ⬍ .001) (see Figure 3).
Thus, IMS Balb/c, but not IMS C57Bl/6, mice exhibit a deficit in
extradimensional set-shifting.
Like in the Social Recognition test, no differences between
males and females in either group were found for their performance in the ASST, neither in the CD phase (Balb/c-SFR:
6.4 ⫾ 0.2 [males] and 6.5 ⫾ 0.3 [females], p ⫽ .8; Balb/c-IMS:
7.8 ⫾ 0.9 [males] and 6.3 ⫾ 0.3 [females], p ⫽ .15; C57Bl/6SFR: 7.3 ⫾ 0.9 [males] and 9.4 ⫾ 1.0 [females], p ⫽ .2;
Figure 2. Behavior of SFR and IMS Balb/c and C57Bl/6 mice in the Social Recognition test. The difference
in the total time of interaction between the first and second exposure is shown. For C57Bl/6 and Balb/c mice,
data are mean ⫾ SEM of measures obtained from 8 mice per group. SFR(s) and IMS(s), reexposure to the same
juvenile. SFR(d) and IMS(d), reexposure to a different juvenile. Significant differences revealed by ANOVA
were resolved post hoc using Bonferroni Multiple Comparisons tests as indicated.
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EARLY LIFE STRESS AND ADULT COGNITIVE DEFICITS
33
Figure 3. Performance of SFR and IMS Balb/c and C57Bl/6 mice in the ASST. The individual test phases are
indicated in the order they were performed. The numbers for the trials to criterion are mean ⫾ SEM of 8 animals
(4 males and 4 females) per group. Results of Repeated Measures ANOVA are summarized in the text. In this
figure, results of ANOVA factorial analyses are shown that were resolved post hoc using Bonferroni Multiple
Comparisons tests as indicated.
C57Bl/6-IMS: 7.8 ⫾ 0.6 [males] and 8.6 ⫾ 1.5 [females], p ⫽
.55), the IDS phase (Balb/c-SFR: 6.2 ⫾ 0.2 [males] and 6.8 ⫾
0.8 [females], p ⫽ .5; Balb/c-IMS: 10.0 ⫾ 1.4 [males] and 10.4 ⫾
1.7 [females], p ⫽ .8; C57Bl/6-SFR: 7.8 ⫾ 1.0 [males] and 6.8 ⫾ 0.8
[females], p ⫽ .45; C57Bl/6-IMS: 8.3 ⫾ 0.5 [males] and 7.8 ⫾ 0.8
[females], p ⫽ .6), the EDS phase (Balb/c-SFR: 9.4 ⫾ 1.2 [males]
and 11.7 ⫾ 1.8 [females], p ⫽ .32; Balb/c-IMS: 21.5 ⫾ 3.2 [males]
and 22.3 ⫾ 1.9 [females], p ⫽ .85; C57Bl/6-SFR: 7.0 ⫾ 0.7
[males] and 8.8 ⫾ 1.7 [females], p ⫽ .41; C57Bl/6-IMS: 12.5 ⫾
1.3 [males] and 11.0 ⫾ 1.5 [females], p ⫽ .71), nor the EDS-Rev
phase (Balb/c-SFR: 8.8 ⫾ 0.9 [males] and 9.0 ⫾ 1.5 [females],
p ⫽ .9; Balb/c-IMS: 8.8 ⫾ 0.8 [males] and 10.3 ⫾ 0.8 [females], p ⫽ .21; C57Bl/6-SFR: 8.8 ⫾ 1.8 [males] and 12.3 ⫾
1.0 [females], p ⫽ .2; C57Bl/6-IMS: 11.8 ⫾ 1.4 [males] and
9.7 ⫾ 0.9 [females], p ⫽ .3).
Spatial Working Memory of SFR and IMS Balb/c
and C57Bl/6 Mice
Figure 4 summarizes the performance of SFR and IMS Balb/c
and C57Bl/6 mice in the T-maze test. For SFR C57Bl/6 mice,
Repeated Measures ANOVA revealed that the percentage of correct arm entries differed significantly between delay periods (F(3,
15) ⫽ 7.18; p ⫽ .0063). Post hoc Tukey-Kramer Multiple Comparisons tests showed that the percentage of correct arm entries
was significantly higher at the 5 and 15 s ( p ⬍ .01 and p ⬍ .05,
Figure 4. Performance of SFR and IMS Balb/c and C57Bl/6 mice in a test of spatial working memory. The
percentages of correct arm entries at the various delay periods are mean ⫾ SEM of the 8 animals examined in
Figure 3. The line across the bars indicates performance by chance (50%). Results of Repeated Measures
ANOVA are summarized in the text. In this figure, results of ANOVA factorial analyses are shown that were
resolved post hoc using Bonferroni Multiple Comparisons tests as indicated.
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34
MEHTA AND SCHMAUSS
respectively) delays when compared to the 30 s delay (at which
performance by chance was reached). A similar result was obtained for SFR Balb/c mice, F(3, 21) ⫽ 5.0, p ⫽ .0093. Their
percentage of correct arm entries at the 5 s delay was significantly
higher compared to the corresponding percentages of correct arm
entries measures at 20 and 30 s delays ( p ⬍ .05).
For IMS C57Bl/6 mice, Repeated Measures ANOVA also revealed significant differences in the percentage of correct arm
entries at different delay periods (F(3, 18) ⫽ 15.87; p ⫽ .0001). In
these mice, the percentage of correct arm entries at 5 s delay was
significantly higher than the corresponding percentages at the 20
and 30 s delays ( p ⬍ .01 and p ⬍ .001, respectively), and the
percentage of correct arm entries at 15 s was higher compared to
corresponding measures obtained at 30 s delay ( p ⬍ .001). Finally,
for IMS Balb/c mice, significant differences revealed by Repeated
Measures ANOVA, F(3, 21) ⫽ 104.6, p ⫽ .0001 were resolved
post hoc for the percentages of correct arm entries at 5 and 15 s
delays, which were significantly higher than the corresponding
percentages at 20 and 30 s delays ( p ⬍ .001).
A comparison of the percentages of correct arm entries at the 5,
15, 20, and 30 s delays between SFR mice of both strains revealed
no significant differences (ANOVA, F(7, 45) ⫽ 3.85, p ⬎ .05 for
all delay periods). However, strain differences were revealed for
IMS mice (ANOVA, F(7, 52) ⫽ 27.68, p ⬍ .0001), which were
resolved post hoc for the 20 s delay period, at which IMS Balb/c
mice achieved a significantly lower percentage of correct arm
entries when compared to the corresponding percentage of IMS
C57Bl/6 mice ( p ⬍ .01) (see Figure 4).
In addition, there were significant differences between SFR and
IMS Balb/c mice (ANOVA, F(7, 49) ⫽ 19.301, p ⬍ .0001). Post
hoc analysis revealed significantly lower percentages of correct
arm entries for IMS mice at 20 and 30 s delays ( p ⬍ .01) (see
Figure 4). In contrast, there were no significant differences between SFR and IMS C57Bl/6 mice (F(7, 48) ⫽ 5.211, p ⬎ .05 for
all delay periods).
Finally, for the WM test, no differences were found between
males and females, neither at the 5 s delay (Balb/c-SFR: 77.5 ⫾
1.4 [males] and 78.8 ⫾ 5.5 [females], p ⫽ .83; Balb/c-IMS: 73.8 ⫾
2.4 [males] and 77.5 ⫾ 2.5 [females], p ⫽ .32; C57Bl/6-SFR:
77.1 ⫾ 2.6 [males] and 75.0 ⫾ 3.2 [females], p ⫽ .61; C57Bl/6IMS: 72.5 ⫾ 0.6 [males] and 73.3 ⫾ 3.3 [females], p ⫽ .85), the
15 s delay (Balb/c-SFR: 68.3 ⫾ 4.4 [males] and 65.0 ⫾ 3.1
[females], p ⫽ .88; Balb/c-IMS: 75.0 ⫾ 3.5 [males] and 72.5 ⫾ 2.5
[females], p ⫽ .80; C57Bl/6-SFR: 67.5 ⫾ 4.9 [males] and 71.0 ⫾
3.9 [females], p ⫽ .68; C57Bl/6-IMS: 65.0 ⫾ 2.0 [males] and
70.0 ⫾ 2.9 [females], p ⫽ .85), the 20 s delay (Balb/c-SFR: 55.0 ⫾
2.9 [males] and 63.8 ⫾ 7.4 [females], p ⫽ .32; Balb/c-IMS: 42.5 ⫾
4.7 [males] and 46.3 ⫾ 1.3 [females], p ⫽ .48; C57Bl/6-SFR:
56.7 ⫾ 4.6 [males] and 62.5 ⫾ 5.2 [females], p ⫽ .43; C57Bl/6IMS: 57.5 ⫾ 1.4 [males] and 58.3 ⫾ 1.7 [females], p ⫽ .72), nor
the 30 s delay (Balb/c-SFR: 61.7 ⫾ 8.8 [males] and 58.3 ⫾ 3.3
[females], p ⫽ .74; Balb/c-IMS: 48.8 ⫾ 1.3 [males] and 47.5 ⫾ 3.2
[females], p ⫽ .73; C57Bl/6-SFR: 52.5 ⫾ 7.5 [males] and 42.0 ⫾
7.8 [females], p ⫽ .43; C57Bl/6-IMS: 46.2 ⫾ 5.9 [males] and
45.0 ⫾ 8.7 [females], p ⫽ .91).
In summary, while there were no significant differences between SFR mice of both strains at either delay period, the performance of IMS Balb/c mice differed significantly from IMS
C57Bl/6 mice at the 20 s delay ( p ⬍ .01) and from SFR Balb/c
mice at 20 and 30 s delays. Hence, compared to SFR and IMS
C57Bl/6 mice and SFR Balb/c mice, IMS Balb/c mice exhibited
spatial working memory deficits.
Discussion
The present study uncovered two specific cognitive functions,
spatial WM and extradimensional shifts of attention, that were
impaired in adult mice exposed to early life stress. Other functions,
such as short-term memory, associative learning, and reversal
learning, were unaffected. Moreover, these ELS-induced deficits
were detected in the stress-susceptible strain Balb/c, but not in the
stress-resilient strain C57Bl/6. Thus, just as a number of persistent
forebrain neocortical gene expression changes occur in this strainspecific manner (Bhansali et al., 2007; Navailles et al., 2010;
Schmauss et al., 2010), cognitive deficits resulting from ELS are
also strain-specific.
The finding that both WM and extradimensional set-shifting
were affected in IMS Balb/c mice raises the question of a possibility of a common origin of their disruption. At the anatomic
levels, both functions are primarily associated with the mPFC.
Specifically, both functions are sensitive to lesions of the infralimbic and prelimbic subregions of the rodent mPFC (Aggleton et
al., 1995; Birrel & Brown, 2000). Moreover, after exposure to
maternal separation and later social isolation, the same anatomic
subregions experience changes in monaminergic innervation,
namely increased serotonergic innervation of the infralimbic and
decreased dopaminergic innervation of the prelimbic subregions
(Braun et al., 2000).
We also found that impaired performance in the EDS did not
lead to impaired performance in the EDS-Rev. A similar separation of impairment of these two functions has previously been
described for dopamine D2-receptor knockout mice that, despite
normal performance in the EDS phase of the ASST, exhibited
impaired performance in the EDS-Rev (DeSteno & Schmauss,
2009). Furthermore, it has been shown that these two cognitive
domains of attentional control functions also segregate at the
anatomic levels, that is, in rodents, the EDS-Rev performance is
sensitive to lesions of the orbital frontal cortex (McAlone &
Brown, 2004).
Finally, recognition memory, a function governed by the
perirhinal cortex and the hippocampus (Brown & Aggleton, 2001),
was also unaffected in IMS Balb/c mice. Hence, the present
finding suggests that cognitive functions governed primarily by the
infra- and prelimbic subregions of the mPFC are especially sensitive to early life stress exposure.
It is noteworthy that, despite unaffected cognitive functioning in
IMS C57Bl/6 mice, their adult emotive phenotype was affected by
IMS exposure. In fact, just like IMS Balb/c mice, IMS C57Bl/6
mice exhibited increased anxiety-like behavior in the EPM. However, in contrast to IMS Balb/c mice that also exhibited depressionlike behavior in the FST, the behavior of IMS C57Bl/6 mice in this
test did not significantly differ from their SFR controls. It is
possible that increased depression-like behavior further contributes
to the cognitive deficits detected in IMS Balb/c mice. However,
SFR C57Bl/6 mice exhibited significantly more immobility than
SFR Balb/c mice during FST exposure. This difference between
strains, and in particular the higher level of immobility of C57Bl/6
mice, could have obscured interpretation of the FST results de-
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EARLY LIFE STRESS AND ADULT COGNITIVE DEFICITS
scribed—it is possible that the time SFR C57Bl/6 mice spent in
immobility had already reached a ceiling effect.
It is important to note that we found no evidence that the
cognitive deficits detected in IMS Balb/c mice differ between
males and females. This is in contrast to sex differences found for
rodents in certain tests of fear- and anxiety-related behaviors (see,
e.g., Wigger & Neumann, 1999) that may be linked (at least in
part) to different stress sensitivity of females at different stages of
the estrus cycle (Romeo et al., 2003; a finding that motivated us to
delimit our study of the FST and EPM behavior to male mice).
What causes the specific cognitive deficits in mice exposed to
early life stress? It is currently believed that there are two main
contributors to the strain-specific appearance of adult psychopathology after ELS exposure: (1) differences in maternal care and
(2) a genetic susceptibility. The differences in maternal care between C57Bl/6 and Balb/c mice at baseline are well documented:
C57Bl/6 dams exhibit significantly more arched-back nursing and
licking and grooming. They also spend significantly less time “off
the nest” compared to Balb/c dams (Millstein & Holmes, 2007;
Priebe et al., 2005). However, a daily 3-h IMS also alters the
maternal behavior, and dams of both strains have been shown to
spend an increased amount of time tending their pups immediately
upon being reunited. In fact, the strains with lowest levels of
maternal care at baseline, including Balb/c mice, exhibited the
greatest responses to IMS in terms of increased time spent “on the
nest” (Millstein & Holmes, 2007). Thus, it is not very likely that
the cognitive deficits detected in IMS Balb/c mice are solely or
predominantly routed in the maternal behavior they experience
during the IMS. Thus, it will now be important to investigate the
extent to which a genetic susceptibility to stress determines
whether subjects exposed to ELS will develop cognitive deficits.
In this regard, it is relevant to note that, in addition to anatomic
evidence for altered neuronal structure and monaminergic innervation within the mPFC, recent studies also found that IMS Balb/c
mice exhibit changes in the expression of specific genes in the
frontal cortex that are not found in IMS C57Bl/6 mice. Among
them is the G protein alpha q subunit, which is expressed at
increased levels in IMS Balb/c mice (Bhansali et al., 2007;
Schmauss et al., 2010). Interestingly, signaling through Gqcoupled receptors was found to be necessary for working memory
(Runyan et al., 2005), and stress-induced working memory impairments were shown to result from overactivation of PKC (Birnbaum et al., 2004), which can be activated by Gq-induced calcium
increase. Thus, future studies on mechanisms underlying changes
in the expression of this gene in IMS Balb/c mice could provide
important information about the role of genetic or epigenetic
variations that lead to altered G␣q expression following ELS in
one but not the other strain of mice. Moreover, it is important to
extend such studies to other genes implicated in the control of WM
and attention.
Finally, the two cognitive deficits found in the stress-susceptible
Balb/c mouse also serve as endophenotypes for a variety of psychiatric disorders (Erlenmeyer-Kimling et al., 2000; Marazziti et
al., 2010; Park & Holzman, 1992). This is of special interest as the
detection and treatment of these cognitive deficits could permit
early identification and possibly onset-prevention of the deficit’s
associated psychiatric disorders. As such, our present findings
underscore the need for a detailed assessment of the cognitive
deficits of subjects exposed to early life stress, regardless of
35
whether they already have developed clinically manifest psychopathology.
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Received August 9, 2010
Revision received September 24, 2010
Accepted October 11, 2010 䡲
Correction to Teufel et al. (2010)
In the article “On the Relationship Between Lateralized Brain Function and Orienting Asymmetries,” by Christoph Teufel, Asif A. Ghazanfar, and Julia Fischer (Behavioral Neuroscience, 2010,
Vol. 124, No. 4, pp. 437– 445), we wrote that “the likelihood of obtaining at least one significant
result at p ⬍ 0.05 is 3.125%*3 ⫽ 9.4%” (p. 443, “A Note on Statistics”). This is incorrect.
Considering the null hypothesis of equal left and right orienting responses, the (one-tailed)
probability of observing a left (or right) bias in five out of five subjects is 0.03125. With three
(independent) hypotheses, the probability of not obtaining any significant result is (1 ⫺ 0.03125)3 ⫽
0.968753 ⫽ 0.90915, and the probability of obtaining at least one significant result is 1 ⫺
0.968753 ⫽ 0.09085. More generally, the likelihood of obtaining no significant result in a single test
is 1 ⫺ ␣, and with n hypotheses, it is (1 ⫺ ␣)n. The probability of obtaining at least one significant
result is therefore 1 ⫺ (1⫺ ␣)n. We thank Mark Baxter and Jean-Paul Fischer for drawing our
attention to the error. —Christoph Teufel, Asif A. Ghazanfar, and Julia Fischer
DOI: 10.1037/a0022814
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