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Endophenotypes of Psychiatric and Neurodegenerative Disorders in Rodent Models,

2009: 000-000 ISBN- 000-00-000-0000-0 Editor: Sylvie Granon

Modeling symptoms of mental

disorders using a dimensional
approach in the rat
Marion Rivalan, Candice Blondeau and Franoise Dellu-Hagedorn
Universit Bordeaux 2; Universit Bordeaux 1; CNRS; UMR 5227, 146 rue
Lo Saignat BP 31, 33076 Bordeaux cedex, France

Abstract
Mental disorders can be conceptualized as
extreme manifestations of behavioural dimensions.
However, most experimental animal researches does
not encompass this dimensional aspect since they
consist in reproducing one or several specific
symptoms by specific experimental manipulations. A
promising alternative is to model human behavioural
dimensions based on behavioural traits or capacities
existing spontaneously in rats. The purpose of this
chapter is to show that selecting animals exhibiting
Correspondence/Reprint request: Dr. Franoise Dellu-Hagedorn, Universit Bordeaux 2; Universit Bordeaux 1
CNRS; UMR 5227, 146 rue Lo Saignat BP 31, 33076 Bordeaux cedex, France
E-mail: francoise.dellu@lnpb.u-bordeaux2.fr

Marion Rivalan et al.

extreme behaviours (i.e. impulsive responses, hyperactivity, high number of

working memory errors) is of great benefit in exploring their
psychobiological bases. Impulsivity-related disorders like mania, personality
and conduct disorders, attention deficit-hyperactivity disorder (ADHD) or
even substance abuse are associated with deficits in executive functioning
such as impulsiveness, working memory impairments and poor decisionmaking. The common deficits observed in these psychiatric disorders
supports the hypothesis of common brain mechanism dysfunction.
We will present studies aimed to explore associations between several
executive functions and related behavioral traits based on a dimensional
approach. They consist of modeling executive dysfunction in the rat using
subjects with high scores on behavioural traits such as the impulsive and
sensation-seeking traits. We will show that studying these particular
individuals can not only reveal information on their psychobiological
profiles, but also more broadly on executive functioning across life. This
dimensional approach has also been successful in modeling a particular
disorder, ADHD, based on its major symptoms. By exploring inter-individual
differences in attention, impulsiveness and motor activity, we identified
distinct subgroup behaviours that parallel those observed in human. Studying
these subjects will help to better understand the biological bases of ADHD
subtypes and their therapeutic responsiveness.

Introduction
Due to the influence of the Diagnostic and Statistical Manual of Mental
Disorders (DSM-IV), psychopathologies are usually conceptualized as
categories with the assumption that there are clear boundaries delineating
disorders and normality. However, this classification is now questioned and
one of the major goals of the future classification (DSM-V) is to take into
account that most psychiatric symptoms occur across a continuum and can be
conceptualized as extreme manifestations of behavioural dimensions. Thus, a
dimensional approach could more closely conform to clinical reality.
No animal model can ever fully mirror the human situation [53], and one has
to keep in mind that similar behaviours may have different meanings [101].
However, progress in biomedical therapy closely depends on animal models and
it is a challenge to establish models of behavioural perturbations similar to those
observed clinically. Most neuroscientific experimental research using animal
models does not encompass a dimensional view as they consist in reproducing
one or several specific symptoms by experimental manipulations (e.g. surgical
lesioning, genetic, pharmacologic, environmental) and then comparing them with
normal control conditions. The main difficulty with such models is that these

Animal behavioural traits to model symptoms of mental disorders

manipulations induce readaptations, and the extent to which they interact with
other neuroanatomic activity, neurochemistry, synaptic or genetic plasticity, or in
other behavioural outcomes is often unknown [80]. A promising alternative is to
model human behavioural dimensions based on spontaneous individual
differences in animals behaviour. Selecting spontaneously extreme or
maladapted behaviours broadens the relevance of the model, notably for the
search of endophenotypes, as no particular hypothesis is established about their
origins. In neurobiological research, inter-individual differences in animal
behaviour are usually considered as a random and uncontrollable phenomenon.
The main criticism is that considering animals as an individual reflects
anthropomorphic projections. However, studies on inter-individual differences in
behaviour reveal striking similarities in the pattern and structure of behavioural
responses in a wide variety of species, from octopuses and fish to apes and
humans [48,51]. Human and animal personality can be viewed as a system of
stable traits which must be inferred from observed behaviours in various
situations. There is a large literature on animal behavioural disorders. For
example, dogs develop conditions analogous, and possibly homologous, to some
human psychiatric disorders; which may include generalized anxiety disorder,
attachment disorder, panic and aggressive impulse control disorders [80].
Unfortunately, there is no unified body of research on animal personality and
studies are dispersed across multiple disciplines. This is well illustrated by the
impressive review of Gosling, a leader in the field, that summarizes most of the
research that has been published on animal temperament and personality [52].
In neuroscience and cognitive science, the relevance of studying
temperaments and personalities (integrated behavioural phenotypes and
stable traits that are consistent over time and across situations), is under
investigated. The purpose of this chapter is to demonstrate that behavioural
traits or capacities existing spontaneously in rats can be assessed, and that
selecting animals showing extreme or maladapted behaviours is of great
interest to explore their psychobiological particularities. Moreover, the study
of the evolution of these behavioural traits during development and their
long-term consequences on adaptation is much easier than in humans, given
the relatively short life-span of small rodents and the possibility of strict
control of their environment. The relevance of developing animal models of
psychopathology by the means of a differential approach will be illustrated by
research based on impulsivity and sensation-seeking behavioural traits in rats.

Investigating inter-individual differences

There are several general designs for investigating individual differences
that will be illustrated in this chapter. The more common is to use

Marion Rivalan et al.

correlational-based techniques. Correlations or multivariate analyses examine

the degree of associations between variables. However, these techniques,
centered on the variables, are not appropriate to describe individual
behaviour. Another possible method is to separate a group of subjects into
two or more subgroups based on a behavioural response. The parameter to be
selected for classifying individuals can be chosen among several parameters
of interest, based on its behavioural relevance and representativeness, and of
course, a large variance. This approach allows to describe in detail subgroups
differing in the behaviour of interest, and to compare individual dynamic or
complex responses (e.g. time-courses, dose-effects of drugs, longitudinal
data). A question to solve is whether the subgroups continue to differ along
distinct dimensions of behaviour or biological responses.
The grouping of subjects can be achieved in several ways. Samples can
be split at the median of the relevant variable (particularly in the case of a
small sample). Another is to consider separately the extremes of a continuum
(i.e. upper and lower quartiles) and the remaining individuals (intermediate
scores) to magnify differences. Correlational and subgroup analyses are
complementary and can often be used on the same data set. Finally, the
cluster analysis is a descriptive statistical method by which inter-individual
behavioural differences are used to categorize subjects into groups. This is
based on a measure of similarities between scores obtained across several
parameters. This analysis produces subgroups of individuals with similar
behavioural profiles [117].

Inter-individual differences in impulsive-related

behaviours
Impulsivity is a dimensional personality trait that has been applied to
many different aspects of the behaviour of humans and animals. This trait
covers a wide range of actions that are poorly conceived, prematurely
expressed, unduly risky, or inappropriate to the situation and that often result
in undesirable consequences [19]. Through the use of various scales based
on self-report questionnaires, personality theorists have demonstrated that
impulsivity demonstrates individual differences [10,11,44]. Extraverted
adults, compared to introverts, have been characterized as more impulsive,
more sensation-seeking, more responsive to rewards and less able to sustain
attention in situations of low stimulation [44]. To a pathological extent,
impulsiveness is a key aspect of mania, personality disorders and conduct
disorders, and is also regarded as the most relevant symptom in attention
deficit-hyperactivity disorder (ADHD) [75,92,108]. It also plays a key role in
substance abuse [58,115], a disorder clearly associated with conduct

Animal behavioural traits to model symptoms of mental disorders

disorders [34,125] as well as ADHD [121], personality disorders (e.g.

borderline, antisocial) and mania [97,116].

Multi-factorial nature of the impulsivity trait

Deficits in behavioural inhibition [102], waiting capacity [109], timing
[10,98], behavioural switching [56] and tolerance of delay of gratification
[68,74] have been proposed to reflect impulsiveness [57], and such disparate
behaviours reflect a multifactorial process [41]. The multi-factorial nature of
this personality trait [39] has been largely ignored due to a lack of consensus
on its definition and appropriate measures. Impulsivity is mentioned in the
DSM-IV diagnostic criteria as prominent in several psychiatric disorders, but
it is never explicitly defined [38].
Impulsivity has been studied more systemically in animals across the last
ten years by devising various operant behaviour tasks aimed at describing
several aspects of impulsiveness [41]. However, information relating to the
inter-relationship between characteristics of impulsivity [21,123] are just
beginning to emerge. To address this issue, different aspects of impulsiveness
were investigated in Sprague-Dawley rats based on spontaneous interindividual variability in behavioural responses [21]. The primary objective
was to determine to what extent various aspects of behaviours related to
impulsiveness can be spontaneously expressed in a standard healthy
population of inbred rats. Furthermore, by measuring these behaviours in the
same individuals, it was possible to determine the nature of the relationship
between different kinds of impulsive behaviours. Impulsiveness was tested in
operant tasks covering different aspects of impulsive behaviours that have all
been clinically related to impulsivity (Table 1). Impulsive behaviour that has
negative consequences or that leads to a lower efficiency is related to poorly
Table 1. Principal characteristics of the tasks measuring impulsive-related behaviours.
Cognitive impulsivity

Motor impulsivity

Tasks

Choice

FCN8

FI

EXT

Evaluation of negative consequences

Behavioral inhibition

Waiting, tolerance to delay of gratification

Timing to avoid inefficient responses

Requirements

Delay discounting task (Choice), Fixed consecutive number schedule of reinforcement (FCN8),
Fixed-interval (FI) and extinction (EXT) schedule of reinforcement (Reprinted from [21] with
permission).

Marion Rivalan et al.

conceived or prematurely expressed actions, and could therefore be referred

to as cognitive impulsivity. It reflects a failure to resist an impulse, drive or
temptation and acting without consideration of alternatives and/or
consequences. Motor impulsivity could rather refer to a higher level of
activity which is not adequate to the environmental contingency, i.e. in a
situation that does not require activity (i.e. a waiting situation), with no direct
negative consequences.
Marked individual differences were observed in all behavioural tasks
and, as previously reported [11,24], behavioural measures were stable and
reproducible over the testing period. Impulsive and non-impulsive rats were
selected according to the upper and lower quartiles in each task, the
remainder constituting an intermediate group. When a rat from an extreme
quartile had identical scores to an intermediate animal, it was included in this
latter group.
Cognitive impulsiveness can be typically measured in a delay
discounting task. This task is the most widely used paradigm to test
intolerance to situations when reward is delayed [13,43,42,109]. It is based
on a choice between a small immediate reward and a bigger one after a
waiting period. By increasing the delay to reinforcement, the relationship
between the magnitude of delay and choice between larger, delayed or
smaller, immediate reinforcers can be determined.
Large inter-individual differences in rats were demonstrated in this task
(Figure 1) and these differences were independent of the ability to learn the
task. The time lapse at which rats no longer preferred the larger reward
(breakpoint) was as early as 5 sec for four impulsive rats whereas ten nonimpulsive rats still preferred the delayed larger reward during the 30 s delay.
Performances in this task are strain dependent: similar inter-individual
differences have been reported between Sprague-Dawley and Spontaneously
Hypertensive rat strains, while smaller differences have been found in the
Wistar Kyoto strain [2].
Cognitive impulsiveness as measured in a fixed consecutive number
schedule of reinforcement (FCN8) tests the ability to complete a long chain
of 8 consecutive presses on a lever followed by one press on another one, to
obtain food. It requires inhibition of premature ending of the chains of
presses but the performance could also be, in part, related to time estimation
[89]. The task does not require waiting, contrary to the previous task.
Impulsive rats in the fixed consecutive number schedule test (Figure 2) had
difficulty pressing the first lever more than 6-7 times before switching to the
other lever, thus making mainly inefficient chains of presses to obtain food.
In contrast, the less impulsive rats made most of the responses efficiently.
Non-impulsive rats did not differ from impulsive rats in the learning of the

Animal behavioural traits to model symptoms of mental disorders

Figure 1. Inter-individual differences in delay-discounting. A: distribution of individual

scores of each rat (mean percentage of choice for the large reward after 5 to 30 sec
delays) and selection of rats with high choice for large reward (HIGHCH scores > 75%)
low choice for large reward (LOWCH, scores < 55%) and intermediate rats (INTCH). B:
Percentage choice of the large reinforcement of the three groups according to the length
of the delay before obtaining it: LOWCH had no preference for any lever at delays 5 to 15
sec and then shifted their preference for the immediate reward, whereas HIGHCH
preferred the largest reward whatever the delay. Comparisons with chance level (50%):
significant difference with chance for scores above or below 50% show a preference for
the large or the small reward respectively. Student t-test: **, ++, , p<.01; *, +, , p<.05.
(Reprinted and adapted from [21] with permission).

task, demonstrating that impulsive rats lower efficiency was not due to a
learning deficit. Furthermore, the rate of responding on both levers was
higher in non-impulsive rats, probably because of their higher motivation for
performing primarily rewarded chains of presses rather than hyperactivity, a
finding that has been previously reported [24]. This behaviour cannot be
attributed to a decrease in motivation for food reward, given that the latencies
to collect food did not differ.
Motor impulsiveness was tested through two different schedules
measured in a two-component 2-min fixed interval (FI) 5-min extinction
(EXT) schedule of reinforcement (adapted from [12]). This task, that assesses
general behavioural inhibition in two different contexts, has been used to
reveal hyperactivity and impulsiveness in both laboratory and clinical
populations, most notably in the Spontaneous Hyperactive Rat model of

Marion Rivalan et al.

Figure 2. Inter-individual differences in impulsivity of rats measured in the FCN8

task (adapted from [40]). A: distribution of individual scores of rats (mean chain
length over the last 7 days) and selection of rats with high level of inhibition
(HIGHFCN, scores > 8) low level of inhibition (LOWFCN, scores < 6) and intermediate
levels (INTFCN); B: distribution of mean chain lengths (%) of efficient ( 8) or
inefficient chains (< 8) of the three groups. Optimal performance (8) is indicated by
the vertical line. (Reprinted from [21] with permission).

ADHD and in children diagnosed with ADHD [93,110]. During FI, responses
during the time-interval (2 min) have no consequence, but the first response
after the interval has elapsed produces the delivery of a food pellet. The
differences in activity levels between hyperactive vs hypoactive SpragueDawley rats in both FI and EXT schedules were very important, a factor of
10 separated the more and the less active rats (Figure 3). These differences
were approximatively two-times greater than between Spontaneously
Hypertensive and the Wistar Kyoto strains on both schedules, despite a lower
global activity of the Sprague-Dawley strain in this task [93]. These
differences in activity levels are remarkably similar to differences observed
between ADHD children and their controls in a similar protocol [94]. The
reinforcement contingency typically generates a scalloped pattern with
little or no responding early in the interval and a progressive increase in rate
when the opportunity for reinforcement delivery approaches [45]. Temporal
discrimination is probably involved, and excessive lever presses could reflect
over-anticipation of the reward [54], perhaps caused by an over estimation of
time. However, the hyperactivity observed in this task is not only related to
earlier anticipation of reward, but also to higher sustained activity that lasts
throughout the session.

Animal behavioural traits to model symptoms of mental disorders

Figure 3. Inter-individual differences in activity of rats measured during the FI-EXT

schedule: A: distribution of individual scores of rats during FI and selection of
hypoactive (LOWFI, scores < 50) hyperactive (HIGHFI, score > 130) and intermediate
rats (INTFI); B: Mean number of lever presses by each group during the 2-min FI
component as a function of 10-s segments of the FI period. C: Inter-individual
differences in activity of rats measured during the EXT schedule: distribution of
individual scores of rats and selection of hypoactive (LOWEXT, scores < 8)
hyperactive (HIGHEXT, scores > 20) and intermediate rats (INTFI). D: Mean number of
lever presses by each group during the 5 min EXT component as a function of 1 min
segments of the EXT period. (Reprinted from [21] with permission).

During extinction, the absence of light (which had been paired with the
availability of a reward during the fixed interval session) clearly indicates
that no reinforcement is available. Thus, when the rat continues to press the
lever excessively, this hyperactivity might be considered as a perseverative
behaviour, an aspect of disinhibition reflected by a tendency to pursue a goaldirected behaviour that is no longer appropriate and that might also be related
to poor attentional processes [93].
Whereas, numerous intra-task correlations were evidenced [21], only a
few inter-test relationships were found, strongly suggesting that the
behaviours measured are not underpinned by a unitary process, according to
the literature in human and animals [70,123]. The more significant
correlations obtained concerned measures of similar activities attesting to the
coherence of the measures. For example, activity during extinction periods
was only correlated with total activity in the delay discounting task,
confirming that this measure involves another aspect of motor impulsivity in
which hyperactivity is observed independently of the context. Surprisingly, a
relationship between incapacity to terminate a chain of presses in the FCN8
task and hyperactivity during extinction periods was also observed. This
relationship seems to be driven by some particular rats that cannot extinguish
their activity during extinction periods (see Figure 2C). These rats exhibit a
high level of behavioural disinhibition that is reflected in the FCN8 task,

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Marion Rivalan et al.

namely they are less disposed to inhibit premature responding. This result is
in line with the hypothesis that extinction deficit could explain response
disinhibition [60].

Impulsivity and the sensation-seeking trait

Personality theorists have identified a factor called impulsive
unsocialized sensation-seeking, linking impulsivity to the sensation-seeking
trait [130]. This factor has been shown to correlate with early onset of
drug use and later drug abuse [66,81,130,133]. The "sensation-seeking"
personality trait, first described by Zuckerman [129,132], has been defined in
humans by the "need for varied, novel and complex sensations and
experiences. Sensation-seeking includes four components: 1) thrill and
adventure-seeking characterized by the search for sensation through risky but
exciting sports and other activities; 2) experience-seeking reflected in the
search for novel experiences and a nonconforming life-style; 3) disinhibition
associated with the seeking of social stimulation; 4) susceptibility to boredom
or an aversion to monotonous, invariant situations, and restlessness when
exposed to such situations. Parallels of these human personality traits or
dimensions were researched in animals. In rats, high-levels of activity in
open-field tests have been related to extraversion [48]. Inter-individual
differences in response to novelty and risk-seeking in rats has further been
explored [26,29] and a behavioural trait that may be related to the human trait
of sensation-seeking, has been evidenced. Some rats, defined as highresponders (HR), exhibit a strong tendency to seek novelty, sensory
stimulations and "stressful" situations like human high-sensation seekers
(Figure 4). These HR, as opposed to Low-responders (LR) were shown to be
highly reactive when exposed to a novel environment in a variety of tasks
involving a free or forced exploration response: they seek novelty, variety,
stimulating and risky environments. HR rats also presented a higher
sensibility to different kinds of reinforcements like drugs or food [29]. When
isolated several times in a small and sound isolated chamber, boredom
susceptibility or need for a change can be measured by giving rats the
possibility to make a change in their environment. By pressing a lever
delivering a flickering light, rats typically make a response for an
environmental change and this light could be rewarding by increasing arousal
level [122]. Again, important individual differences in light self-stimulation
were observed and HR pressed significantly more on the light lever compared
to the control lever and compared to LR (Figure 4E). Some HR rats activated
the light more than 100 times during a 30 min session whereas some LR were
disinterested and just pressed on this lever a few times.

Animal behavioural traits to model symptoms of mental disorders

11

Figure 4. Behavioural characteristics of high-responders (HR) and low-responders to

novelty (LR). A: individual values of novelty-induced locomotion measured in a
circular corridor over 2h. The median separates HR from LR. Time-course of
exploration in a Y-maze of HR (B) and LR (C) rats. HR made more visits to the novel
arm compared to familiar arms previously visited, 30 min earlier. Statistical
significances: ANOVA, ***, p<0.001; * p<0.05. Percentage number of visits in the
novel arm over the first 2 min (inserts) were compared to chance (33%), , p<0.01.
D: Latency to emerge from dark to brightly illuminated compartment was shorter in
HR compared to LR rats in the dark-light emergence task. Statistical significance, ttest, ***, p<0.001. E: Light-contingent lever-pressing in an operant chamber of HR
and LR rats. HR had a higher rate of pressing on the active lever that delivered a
flashing light compared to the inactive one. Insert: total number of presses on both
levers during 2h. Statistical significance, ANOVA, ***, p<0.001; *, p<0.05. Fig. 4AD reprinted and partially adapted from [26,29], Copyright (2008), with permission
from Elsevier.

The neurobiological bases of HR subjects, at risk for dependence to

drugs [84], have been well explored over the last 20 years. Briefly, HR and
LR rats mainly differ in reactivity of the mesolimbic dopaminergic system
[84,86,90,91]. Locomotor response to novelty is well correlated with

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Marion Rivalan et al.

locomotor response to amphetamine [21]; HR rats have a higher and longer

lasting locomotor response to an amphetamine challenge (Figure 5AB). Light
self stimulation is also potentiated by amphetamine injection, this effect
being only significant in HR rats (Figure 5C-F). The two groups differ in
sensitivity to drugs of abuse, as well as in the hypothalamo-pituitary adrenal
axis reactivity [28,29,85]. They also exhibit distinct patterns of gene
expression in neural circuits that modulate responsiveness to stressful
situations [61]. HR rats are more prone to acquire amphetamine selfadministration compared to LR [84] and glucocorticoids could play a role in
determining the higher dopaminergic activity that characterizes drug proned
individuals [90]. These results are consistent with the role of dopaminergic
neurons in the response to novelty and in drug taking behaviours [6].

Figure 5. Locomotor response to novelty (A) and to saline and amphetamine injection
(s.c. 1mg/kg) (B) of high-responders (HR) and low-responders (LR) to novelty in a
circular corridor. Light contingent lever pressing of LR (C-D) and HR rats (E-F) after
saline or amphetamine injection (i.p. 2 mg/kg). Arrows represent time for saline or
amphetamine injections.

Animal behavioural traits to model symptoms of mental disorders

13

Figure 6. Comparisons of locomotor reactivity of rats with low (LOWFCN) and high
(HIGHFCN) levels of inhibition selected in the FCN task in response to saline and
amphetamine injections (1mg/kg i.p.). LOWFCN had a higher locomotor response to
amphetamine compared to HIGHFCN lasting 1h after injection. ANOVA (NK): ***
p<0.001; ** p<0.01, * p<0.05. (Reprinted from [21], with permission).

HR and LR rats have been compared for various aspects of impulsive

behaviour [21]. Whereas response to novelty was not found significantly
related to any measure of impulsivity, locomotor response to amphetamine
did, perhaps by strengthening inter-individual differences. Impulsive rats in
the FCN8 task had a higher locomotor response to amphetamine compared to
non-impulsive ones, a characteristic shared by HR individuals attesting to a
common biological characteristic (Figure 6). This task predominantly
requires behavioural inhibition of premature responses that have negative
consequences. In this context, anticipated responses could be considered as
risk-taking behaviour. These behavioural responses are somehow reminiscent
of aspects of the sensation-seeking trait in which risk-taking behaviour in
many activities has been related [31,131]. Like sensation-seekers, impulsive
rats in the FCN8 schedule may have deficits in estimating negative
consequences of anticipated response: some characteristics similar to those
observed in the impulsivity/sensation-seeking trait described in humans.

Stability of the behavioural traits

Inter-individual differences in impulsivity measured in the different
paradigms described above are stable and reproducible [21]. In spite of the

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Marion Rivalan et al.

general decrease in impulsivity with aging, significant differences in

impulsivity between HIGHFCN and LOWFCN rats remained one year later,
demonstrating the consistency of this behavioural trait over time [24]
(Figure 7A-B). This result is in accordance with several data provided by
self-reports or subjective measurements and observations in human, reporting
impulsivity as stable with time [11,59,67,76-78].
Similarly, as in humans, in whom sensation-seeking is one of the few
personality traits that declines with age [18,128], we have found that the
behavioural characteristics of HR rats are still observed at middle-age, but
tend to disappear with advancing age [27,29] (Figure 7 C-F).

Figure 7. Longitudinal studies of behavioural traits of impulsivity and sensationseeking. A-B: Performances of impulsive rats (LOWFCN) are lower than those of
intermediate (INTFCN) and non-impulsive rats (HIGHFCN) under a FCN8 schedule of
reinforcement, at 6 and 15 months. (adapted from [21]). C: The difference in novelty
reactivity over 2h characterizing HR and LR remains until middle-age and then
disappears with age. D: Dark-light emergence task: the difference in the latency to
emerge from dark to brightly illuminated compartment between HR and LR rats
during youth disappears with aging. E-F: Light-contingent lever-pressing: rats with a
higher self-stimulation of a flashing light (HSS) compared to rats with a low selfstimulation (LSS) still presented a higher rate of stimulation when old. Statistical
significance, ANOVA, ***, p<0.001; **, p<0.01; *, p<0.05. Fig. 7AB reprinted and
partially adapted from [24], Copyright (2008), with permission from Elsevier and
Fig.7C reprinted from [29], Copyright (2008) with permission from S. Karger AG.

Animal behavioural traits to model symptoms of mental disorders

15

Linking disinhibition with other cognitive deficits

Impulsivity-related psychiatric disorders are characterized by other
cognitive deficits, notably in attention and working memory [5]. These deficits
have been demonstrated in personality and conduct disorders [33,65,106],
ADHD (for review, see [7]), mania [1,36,71,107], and subjects predisposed to
substance abuse [4,20,46,47,83]. In these psychiatric disorders, the association
of impulsivity and these cognitive deficits suggests that common brain
mechanisms may underlie their etiologies. It has been proposed that deficits in
the executive control system of working memory may give rise to some of the
cognitive and behavioural problems exhibited by impulsive people
[47,112,120]. Inversely, in a conceptual model of ADHD, it has been proposed
that deficient inhibition could be the primary disturbance that impairs executive
functions, such as working memory [7]. Modelling the relationships between
executive functions existing spontaneously in the rat may be a start for
understanding the nature of this link in pathological conditions.

Life-span study of memory performances in relation with

inhibitory capacities
A possible impairment in working memory capacities of impulsive rats
and sensation-seekers has been explored. In youth, only hyperactivity during
an extinction schedule revealed a clear association with lower capacities in
working memory measured in the 8-arm radial maze [21]. This association
supports the hypothesis of a cognitive deficit origin of the inability to
extinguish a response [93]. Behavioural inhibition measured in the FCN8
task, which is related to inhibition during extinction, has also been associated
with working memory deficits in youth but only a transient and subtle
impairment could be evidenced [23]. However, these memory deficits were
potentiated by aging, indicating that a deficient inhibitory response control
has long-term deleterious effects on cognitive functions (Figure 8), and is
thus a risk factor of working memory impairment [24].
Given that impulsiveness seems to be related to reduced efficiency in
information processing, which is amplified by aging, it may be a common
feature or perhaps a common origin of many disorders related to impaired
inhibitory behavioural control. Our findings may have clinical application for
a preventive follow-up of impulsive subjects who may be at risk for
pathological cognitive aging. These results are in accordance with
longitudinal clinical studies of children with ADHD followed into adult life
reporting that one- to two-third of children continue to manifest appreciable
ADHD symptoms [14,96,114,119]. Forgetfulness or poor memory is among
the more frequent complaints presented by adults with ADHD.

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Marion Rivalan et al.

Figure 8. Cognitive performances of middle-aged impulsive (LOWFCN) and nonimpulsive rats (HIGHFCN) characterized in the FCN8 schedule during youth. A:
Time-course of working memory performances of the two groups measured in an 8arm radial-maze. B: After stabilisation of the performances, effect of confinement
duration before a choice was tested on working memory performances. Statistical
analysis: ANOVA, ** p<0.01; * p<0.05. within comparisons: p<0.01. C: Timecourse of place discrimination learning of the two groups in a water-maze. D: Probe
trial (platform omitted): percentage mean time spent by the two groups in a 60 cm
diameter virtual circle around previous position of the platform. Statistical analysis:
t-test: * p<0.05. Fig. 8A-B reprinted and partially adapted from [26,29], Copyright
(2008), with permission from Elsevier.

Animal behavioural traits to model symptoms of mental disorders

17

In sensation-seeking rats, no significant difference could be observed

during youth in learning and memory, measured in a water-maze or a 4-arm
radial maze (reference memory), or in a 8-arm radial maze (working
memory). Spatial recognition memory assessed in a Y-maze does not differ
between high and low sensation-seekers [25]. However, HR rats show less
latent inhibition than LR (Figure 9), a process by which preexposure to a
stimulus prevents subsequent conditioned associations with that stimulus.
This inhibitory control plays a key role in execution of many cognitive
processes like selective attention, reasoning, recall [30]. This inhibitory
deficit could be related to an altered dopaminergic activity in the
mesocorticolimbic system, given that latent inhibition is largely dependent on
DA activity in the nucleus accumbens [124]. Thus, poorer performances in
negative priming have been found in impulsive children compared to controls
[113], as well as in impulsive-related psychopathologies like ADHD and
personality disorders compared to controls [35,79]. This similarity in
behavioural characteristics of impulsive/sensation-seeking confirms the face
validity of this animal model: the behavioural disturbances being assessed are
indicative of the symptoms associated with human pathology.

Figure 9. Capacities of latent inhibition of a conditioned taste aversion in High (HR)

and Low (LR) responders to novelty. HR and LR rats have been splited into 2 groups:
one preexposed during three sessions to a conditioned stimulus (saccharin solution)
before conditioning and a non-preexposed group. Conditioning consists in associating
lithium chloride induced illness with saccharin consumption. HR rats present a deficit
in latent inhibition compared to LR. Statistical significance: (ANOVA), ** p<0.01.

18

Marion Rivalan et al.

Like the impulsivity trait, the behavioural trait of sensation-seeking in

rats has also been associated with age-related cognitive deficits. Deficits in
memory recognition have been found in old HR rats compared to LR rats,
whereas no differences in performances of the two groups could be observed
earlier in life [27]. Long-term hyperactivity of the hypothalamo-pituitary
adrenal axis of HR compared to LR rats that precedes the appearance of the
memory deficits may be a causal factor [28].
The biological basis of these long-term effects on cognitive processes is
probably the result of cumulative effects over time of genetic or epigenetic
characteristics, that remain to be determined. Nevertheless, our findings show
that a behavioural trait evidenced early in life can have long term effects on
cognitive processes and open new perspectives in the search for risk or
protective factors detectable early in life. This approach, almost impossible in
human studies, is of particular interest for screening for risks or protective
factors of aging processes. Given that impulsiveness decreases with age when
cognitive impairments appear, a classical cross-sectional study would have
failed to reveal such a relationship.
A prime candidate for a brain substrate that might contribute to such
individual differences in memory and inhibition processes is the prefrontal
cortex (PFC), a brain area associated with cognition, motivation, memory,
response inhibition and decision making [49]. It is noteworthy that interindividual differences in locomotor response to amphetamine, that are related
to both the sensation-seeking trait and behavioural inhibition, are correlated
with working memory capacities during youth [22]. The antagonism between
performances in working memory and locomotor response to amphetamine
corroborates the hypothesis of a balance between prefrontal and mesolimbic
dopamine transmissions [64,88,111]. It has been proposed that working
memory requires an optimal level of dopaminergic receptor stimulation in the
PFC [50]. A reduced DA transmission in this area may be concurrent with
increased subcortical transmission [32,118]. Thus, reduced prefrontal
monoaminergic transmission, reflected by lower working memory and
inhibitory capacities, could enhance behavioural effects associated with
stimulation of mesolimbic dopaminergic activity, reflected in an enhanced
locomotor response to amphetamine. Moreover, working memory and
behavioural inhibition can be similarly modulated by amphetamine stimulation
according to an inverted-U shape relationship between initial performances and
the level of dopaminergic stimulation (amphetamine dose-effect) [23].

Modeling the main symptoms of ADHD

Impulsiveness is increasingly seen as the symptom of greatest
significance in ADHD [87,99]. Indeed, a similarity can be drawn between

Animal behavioural traits to model symptoms of mental disorders

19

ADHD in children and extreme extraversion in adults: the description of

extraverted people is very similar to what is observed in hyperactive children
[37]. Attention-deficit/hyperactivity disorder (ADHD), one of the most
common behavioural disorders of childhood, is heterogeneous: symptoms of
impulsivity, hyperactivity and inattention are expressed with various degrees
of severity [38]. Three subtypes of ADHD can be distinguished:
predominantly inattentive, predominantly hyperactive/impulsive, and
combined, the latter of which is the most prevalent clinically. Whether
subtypes of this disorder are aspects of the same disorder, and whether they
are sustained by common biological dysfunctions or not [8,55,63,73,82], a
crucial point for targeting pharmacological treatments, is currently a subject
of debate. Pharmacological therapy acts on the norepinephrine and dopamine
systems, leading to the long-standing hypothesis of catecholamine
dysfunction in ADHD. The most commonly administered treatments are the
psychostimulants, methylphenidate and d-amphetamine. Although these
drugs are highly effective, it is estimated that at least 30% of individuals do
not respond adequately to treatment [9,104]. A non-stimulant agent,
atomoxetine, a potent noradrenergic reuptake inhibitor [16] is rapidly gaining
recognition as an alternative treatment [72,103,105]. However, the efficacy of
these pharmacological agents in relation to the subtypes of ADHD is largely
unknown and their mechanisms of action on each of the symptoms are yet to
be clarified.
Given the large inter-individual differences observed in a standard
population of rats in attention, memory, impulsivity and locomotor
reactivity, we investigated if we could model ADHD in normal rats,
based on its main symptoms [15]. For this purpose, the ability to sustain
spatial attention and response inhibitory control were measured in the 5choice serial reaction time task paradigm (5-CSRTT) in which rats are
required to spatially discriminate between short visual stimuli occurring
randomly in one of five locations. By the use of a cluster analysis
separating subgroups on the basis of their behavioural similarities in
attention (accuracy of reporting stimuli) and impulsivity (premature
responding), four distinct subgroups were identified: efficient, middle,
inattentive, and inattentive-impulsive (Figure 10A-B) [15]. These
subgroups strikingly parallel those observed in human [69]. These
subgroups were further characterized by testing their adaptation to more
challenging conditions in the 5-CSRTT: they were differently affected by
variation of experimental conditions that could compensate for inattention
or impulsivity of the last two groups [15]. To possibly evidence enhanced
motor activity in any of the identified subgroups, motor activity was
evaluated in various experimental conditions (activity in a cage, locomotion

20

Marion Rivalan et al.

in a circular corridor and in a running-wheel). Only the inattentiveimpulsive subgroup demonstrated hyperactivity, which was expressed in a
cage both during initial and basal activities (Figure 10 C-D). This
hyperactivity could reflect that of ADHD children in low environmental
stimulations: clinical and neuropsychological data in humans indicate that
the expression of hyperactivity in ADHD is related more to a general level
of activity than to an increased locomotion [95,100] and tends to increase in
situations of low environmental stimulation [3,126,127].

Figure 10. A: Individual scores of attention (correct responses) and impulsivity

(premature responses) of a group of rats (n=50) in the 5-CSRTT. A hierarchical
ascendant cluster analysis was performed on these parameters and designed four
subgroups: an efficient group of attentive and non-impulsive rats (E), a group of
inattentive rats (NA), a group of impulsive and inattentive rats (NA-I) and the
remainder with mildly attentive and impulsive rats, pooled in the middle group
(M). B: Mean correct and premature responses of the four groups. Statistical
comparisons (ANOVA) with E: *** p<0.001; with M: p<0.001, p<0.05 ; with
NA: +++ p<0.001. Comparisons of motor activity in a cage between subgroups in
response to novelty (20min) (C) and nocturnal basal activity over 12h (D).
Statistical comparisons, ANOVA, * p<0.05. Reprinted from [26,29], Copyright
(2008), with permission from Elsevier.

Animal behavioural traits to model symptoms of mental disorders

21

Analysis of ADHD subtypes in rats opens new, promising perspectives,

notably for verifying the hypothesis of their common versus distinct
neurobiological substrates. It will help to better understand the actions of
drugs and to determine which therapies are likely to be efficient depending
on ADHD subtypes. Regarding efficacy of drugs, atomoxetine has been
shown to be particularly efficient at a low dose (0.1 mg/kg) in reducing
premature responding of impulsive-inattentive and inattentive subgroups
[15]. This result has recently been confirmed clinically [17], attesting to the
good predictive validity of this model.

Conclusions
Psychiatric disorders are among the least well understood, the most
complex and the most incapaciting of all pathological conditions. Given that
psychiatric disorders are solely defined on the basis of their behavioural
particularities, a challenge for biomedical research is to better model their key
symptoms in animal models [38]. Experiments presented here have been
designed to support analogies between behavioral abnormalities in animals
and human traits and pathology. This approach supports our working
hypothesis that individual differences in animal behaviour can reliably
exhibit dimensions that model some human behavioural dimensions. This
original research paradigm allows us to build animal models offering good
face validity: extreme behaviours being assessed in rats are reminiscent of the
symptoms associated with human pathology. These models offer good
construct validity as they have been shown to rely on similar underlying
mechanisms. Finally, they have a good predictive validity, with respect to the
selectivity of responses to specific drugs and to environmental and temporal
challenges. Cross-species comparisons of behavioural traits can be made
using top-down or bottom-up approaches. A top-down perspective allows
us to examine in more details or to experimentally confirm what is already
observed in humans. A bottom-up perspective uses animal models to generate
hypotheses in humans, in a simplified and more controlled context [52]. The
experiments discussed here combine both kinds of approach.
From a developmental perspective, this paradigm is of major interest. It
has shed light on the impact of personality and behavioral traits on adaptive
resources and on the effects of early environmental exposure on personality
development as well. Finally, this approach can be extended to other kinds of
mental disorders, which opens new promising perspectives for the
understanding of psychopathologies. It is in line with dimensional views of
psychopathology assuming the absence of natural boundaries between mental
disorders and normality or health [62]. Even if there is a growing

22

Marion Rivalan et al.

assumption, at least within the research community, that most currently

recognized psychiatric disorders are not disease entities, this statement has
never been demonstrated. We propose that a possible research issue for this
demonstration could be inspired from animal studies based on a dimensional
approach.

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