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1 Alzheimer’s Disease and Acetylcholine: Pharmacological and Genetic Translations
M. Hvoslef-Eide et al.
et al. 1988) and extracellular B-amyloid plaques (Roth et al. 1966), as well as
reduced efﬁcacy of cholinergic signalling (Davies and Maloney 1976; Whitehouse
et al. 1982). AD is also characterised by attentional impairments (Alexander 1973;
Baudic et al. 2006; Belleville et al. 2007; Silveri et al. 2007) that are observable in
computer-controlled tasks (Oken et al. 1994; Baddeley et al. 1999; Levinoff et al.
2005; Bentley et al. 2008; McGuinness et al. 2010) including the human 5-CSRTT
(Sahakian et al. 1993; Sahakian and Coull 1993). These attentional impairments
may also be produced by cholinergic dysfunction (Lawrence and Sahakian 1995;
Klinkenberg et al. 2011) and may be ameliorated by pharmacological anticholinesterase inhibition (Sahakian et al. 1993; Sahakian and Coull 1993; Foldi
et al. 2005; Gauthier et al. 2007). Similarly, transgenic mouse models with AD-like
pathology also show anticholinesterase-sensitive attentional impairments in the
rodent touchscreen 5-CSRTT (Romberg et al. 2011, 2013).
Sahakian et al. (1993) showed that the anticholinesterase tetrahydroaminoacridine
improved accuracy and decreased reaction times in AD patients on the touchscreen
5-CSRTT. Similarly, the TgCRND8 mouse model with Swedish and Indiana
mutations of the human APP gene showed impaired accuracy in the 5-CSRTT at
shorter stimulus durations (Romberg et al. 2013), and the 3xTgAD mouse model
(Tau-P301L, APP-Swe, and PS1-M146V) showed vigilance-related accuracy
impairments and increased perseveration when tested under challenging conditions
(Romberg et al. 2011). In a clear example of clinical predictive validity, the attentional impairment in the 3xTgAD model was also remediated by the acetylcholinesterase inhibitor donepezil (Romberg et al. 2011). Notably, Bartko et al.
(2011) also showed that global knockout (KO) of the muscarinic (M1) acetylcholine
receptor increased perseverative and premature responding and reduced percent
omissions in the mouse touchscreen 5-CSRTT, further demonstrating the importance
of cholinergic systems for performance on the touchscreen 5-CSRTT.
Serotonin Depletion Results in Parallel Deﬁcits Across
Reduced serotonin transmission has been extensively linked to increased impulsive
behaviour (Evenden 1999; Dalley et al. 2011). The rodent 5-CSRTT is a powerful
tool for the study of motor impulsivity, as the subject is required to inhibit
responding until the stimulus is present. Failure in response inhibition, as observed
through prematurely made responses, is considered a marker of lack of impulse
control. Serotonin depletion in rats as a result of the administration of
5,7-dihydroxytryptamine (5,7-DHT) increases impulsive responding in the
5-CSRTT (Harrison et al. 1997; Winstanley et al. 2004a), and serotonin depletion in
human volunteers increases impulsive responding in the 4-CSRTT mentioned
earlier (Worbe et al. 2014). This is another example of how the use of rodent
touchscreen tasks in human populations can result in parallel ﬁndings across
Cognitive Translation Using the Rodent Touchscreen Testing …
Some Limitations of the 5-Choice Serial Reaction Time
The 5-CSRTT has established construct and predictive validity (Robbins 2002;
Lustig et al. 2013) and has been the gold standard of attentional and impulsive
assessment in the rodent for more than three decades (Carli et al. 1983). Residual
concerns have nevertheless remained, speciﬁcally regarding the absence of
non-target trials and the consequent resistance to signal detection analyses typically
used to evaluate human attentional processes. Furthermore, the rodent 5-CSRTT
assesses divided visuospatial attention, whereas human touchscreen assays of
attentional functioning predominantly measure focused visual attention and employ
complex visual stimuli. In response to some of these concerns, a rodent version of
the continuous performance test (CPT), one of the most widely used tests of human
attentional function (Rosvold et al. 1956; Perry and Hodges 1999; Stopford et al.
2012; Cornblatt et al. 1989; Cornblatt and Malhotra 2001) was developed.
4 The Rodent Continuous Performance Task (rCPT)
Although several rodent attentional paradigms have been translated to the human
experimental and clinical settings (Sahakian et al. 1993; Demeter et al. 2008; Young
et al. 2013), their translational utility is somewhat restricted as a large portion of
human data on attentional functioning continues to be generated by visual or
touchscreen variants of the CPT (e.g. Kofler et al. 2013). In these tasks, a single
target or a non-target stimulus is presented across trials; the participant is required to
respond when the target stimulus is presented and must withhold from responding
when a non-target stimulus is presented. Performance on CPTs is evaluated by signal
detection analyses based on composite measures derived from hit rate (the ratio of
correct responses of the total number of target presentations) and false alarm rate
(the ratio of incorrect responses of the total number of non-target presentations).
These composite measures include discrimination sensitivity indices (such as d’ or
sensitivity index SI) and response criterion values (such as c or b; Frey and Colliver
1973; Green and Swets 1989; Stanislaw and Todorov 1999; Macmillan and
Creelman 2004). Furthermore, performance on CPTs depends on complex visual
discriminations as opposed to the spatial or visuospatial brightness discriminations
employed in rodent attentional tasks (Carli et al. 1983; McGaughy and Sarter 1995;
Young et al. 2009a) and their translated human versions (Sahakian et al. 1993;
Demeter et al. 2008; Young et al. 2013). Like CPTs, the rCPT requires subjects to
detect and respond or inhibit responding to a target stimulus and non-target stimuli,
respectively, presented sequentially in a central location on a touchscreen.
Attentional functioning and behavioural inhibition is evaluated using standard
parametric manipulations also used in human CPTs: increasing the cognitive load
through manipulation of task parameters such as stimulus duration, target ratio,
M. Hvoslef-Eide et al.
inter-stimulus interval, stimulus contrasts, or the addition of flanking distractors. The
ability to measure attentional function in rodents using a task nearly identical to the
task used in clinical research for half a century provides promising opportunities for
bridging the gap between rodent and human work.
CPT and rCPT: Convergence by Functional Anatomy
Human CPTs appears to be contingent upon frontal cortical areas, including the
activity along the medial wall of the prefrontal cortex (mPFC). Lesion (Salmaso and
Denes 1982; Glosser and Goodglass 1990), imaging (Buchsbaum et al. 1990; Keilp
et al. 1997; Fallgatter and Strik 1997; Carter et al. 1998; Adler et al. 2001; Toichi
et al. 2004), and electrophysiological (Valentino et al. 1993; Fallgatter and Strik
1999; Müller and Anokhin 2012) studies show causal and correlative relationships
between CPT performance and prefrontal cortical areas, including the dorsolateral
prefrontal cortex. In broad agreement with these data, we have found that mPFC
lesions in rats and mice impair rCPT performance. In the mouse, lesions centred on
the prelimbic cortex impair performance when animals are challenged with
increased attentional load through decreased stimulus durations, lower target
probabilities, and longer inter-stimulus intervals (Hvoslef-Eide et al. in prep). These
impairments are observed as higher false alarm rates and a more liberal response
criterion, consistent with a role for the mPFC in inhibitory control (Chudasama and
Robbins 2006; Pattij and Vanderschuren 2008; Dalley et al. 2008, 2011).
Excitotoxic mPFC lesions also impair CPT performance in the rat (Mar et al. in
prep), suggesting that performance on touchscreen CPTs depends on the integrity of
the prefrontal cortex across mice, rats, and humans. Moreover, as in the 5-CSRTT
(Sahakian et al. 1993; Romberg et al. 2011), cholinergic signalling modulators such
as nicotine (Levin et al. 1998, 2001; White and Levin 1999) and donepezil
(Friedman et al. 2002) can enhance vigilance in human CPTs. Similarly, donepezil
can dose-dependently improve attentional function in DBA mice under some task
parameters in the rCPT (Kim et al. 2015).
Animal Models on the rCPT: Parallels with Human
Attention-related abnormalities in CPTs represent endophenotypes of many neuropsychiatric and neurodegenerative disorders (Alexander 1973; Cornblatt et al.
1989; Ursu et al. 2003; Corbett and Constantine 2006; Cubillo et al. 2012) perhaps
most notably in schizophrenia (Wohlberg and Kornetsky 1973; Cornblatt and Keilp
1994; Keefe et al. 2007; Filbey et al. 2008; Kahn et al. 2012; Nuechterlein et al.
2015). In the rCPT, analogous impairments are observed in schizophrenia-relevant
Cognitive Translation Using the Rodent Touchscreen Testing …
mouse models, thereby demonstrating the tasks’ construct validity. For example,
conditional knockout of the NR1 subunit in corticolimbic GABAergic neurons
(Belforte et al. 2009) induces an acquisition deﬁcit when the attentional load is
manipulated through shorter stimulus durations in the CPT (Hvoslef-Eide et al.
2013). Moreover, a chromosomal microdeletion at locus 22q11.2 is associated with
a high risk of developing schizophrenia (Schneider et al. 2014) and extensive
attentional deﬁcits (Sobin et al. 2004) including CPT impairments (Shashi et al.
2010, 2012; Hooper et al. 2013; Harrell et al. 2013; Schoch et al. 2014). Hit
rate-related measures in the CPT can also predict the onset of prodromal psychotic
symptoms in individuals with 22q11.2 deletion syndrome (Antshel et al. 2010).
Critically, the Df(h22q11)/+ mouse model of the 22q11.2 microdeletion syndrome
shows a touchscreen CPT deﬁcit that parallels the deﬁcits of 22q11.2 deletion
syndrome patients. These impairments can be expressed on measures of hit rate, d’,
and c challenged with decreased stimulus presentation duration increased
inter-stimulus intervals, and extended session length (Nilsson et al. in preparation).
Thus, the observation of hit rate impairments in the Df(h22q11)/+ mutant parallels
the dysfunction of 22q11.2 deletion syndrome patients as measured by CPTs,
indicating translational validity of the task for assessing attentional functioning.
Vigilance Decrement in the rCPT
Human CPTs measure vigilance as observed by performance decrements across
session length (Rosvold et al. 1956; Nuechterlein 1983; Mass et al. 2000). Although
not often seen in the 5-CSRTT (but see Romberg et al. 2011), within-session performance decrements have been reported for alternative rodent–human translational
paradigms such as the 5-choice continuous performance task (Young et al. 2009a)
and the sustained attention task (Peters et al. 2011), and are also observed in mice
when using the rCPT (Kim et al. 2015). In mice with a C57BL/6 background, hit rates
and false alarms typically decrease with session length, which produce an elevated
response criterion towards the end of the session (Kim et al. 2015; Nilsson et al. in
prep). In mice with a DB2/2J background, hit rates have been found to decrease with
session length, while false alarm rate remains constant (Kim et al. 2015). Thus,
similar to humans, mice show decreased hit rates as a function of session length,
which suggests that the rCPT has translational utility as a measure of vigilance.
Relationship Between Task Parameters
and Performance Consistent Across Species
Manipulations of several task parameters have similar effects on CPT performance
in humans and mice. For example, manipulations of target probability (Berwid et al.