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2 Animal Models on the rCPT: Parallels with Human CPT Data
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.
M. Hvoslef-Eide et al.
2005) and inter-stimulus intervals (Conners et al. 2003; Hervey et al. 2006; Epstein
et al. 2007) in human CPTs suggest that these parameters positively correlate with
false alarms rates and hit rates and hence have more pronounced effects on measures of response criterion (e.g. c) relative to discrimination sensitivity (e.g. d’;
Macmillan and Creelman 2004). Conversely, stimulus degradation manipulations
can produce larger perceptual sensitivity decrements relative to measures of
response criterion (Nuechterlein 1983; Chee et al. 1989; Mass et al. 2000).
Importantly, similar parametric manipulations of inter-stimulus intervals, stimulus
contrasts, stimulus duration, and target probabilities in the rCPT have comparable
effects on the performance of mice and rats (Kim et al. 2015; Nilsson et al. in prep;
Mar et al. in prep), which indicate that the parametric variables have comparable
relationships with performance measures across species. To summarise, performance of both rCPT and human CPT is sensitive to mPFC lesions and prefrontal
GABAergic dysfunction, dependent on the 22q11.2 chromosomal locus (or its
orthologous region in the mouse), and is influenced by manipulations of attentional
and perceptual load.
5 Reversal Learning
intradimensional/extradimensional (ID/ED) protocol in the CANTAB battery,
which has been used to generate a wealth of data in neurodegenerative and neuropsychiatric patients (Downes et al. 1989; Hughes et al. 1994; Pantelis et al. 1999;
Kempton et al. 1999; Shamay-Tsoory et al. 2007: Ceaser et al. 2008; Leeson et al.
2009). In reversal learning, subjects ﬁrst learn a two-choice simultaneous discrimination and then, the stimulus contingencies are reversed (the correct stimulus
becomes the incorrect stimulus, and vice versa). Whereas reversal learning in
human and non-human primates most often is assessed using touchscreen methods
with visual stimuli (Dias et al. 1996; Bussey et al. 2001; Clarke et al. 2004; Leeson
et al. 2009), prevalent rodent analogues typically employ non-visual olfactory,
somatosensory (Schoenbaum and Chiba 1999; Birrell and Brown 2000; McAlonan
and Brown 2003), or spatial cues (Becker et al. 1981; Boulougouris et al. 2007).
Although non-touchscreen visual reversal learning tasks have been used with
rodents, these tests are typically non-automated (Gardner and Coate 1965; Stevens
and Fechter 1968; Sasaki 1969; Mullins and Wineﬁeld 1979; Mason et al. 1980) or
dependent on brightness discriminations (Abdul-Monim et al. 2003; Floresco et al.
2008) with limited resemblance to the automated tasks with complex visual stimuli
used with human and non-human primate subjects. To address these concerns, we
have developed a suite of rodent touchscreen reversal learning tasks and evaluated
their neurocognitive validity on anatomical, pharmacological, and genetic levels.
Here, we provide a few examples.
Cognitive Translation Using the Rodent Touchscreen Testing …
Orbitofrontal and Dorsal Striatal Perturbations Cause
Impairments of Touchscreen Reversal Learning
in Rodents, Non-Human Primates, and Humans
The orbitofrontal cortex (OFC) has been implicated in touchscreen reversal learning
in the mouse (Graybeal et al. 2011), rat (Chudasama and Robbins 2003; Izquierdo
et al. 2013; Alsiö et al. 2015), and non-human primate (Dias et al. 1996), mirroring
the ﬁndings of human imaging studies (Cools et al. 2002; Hampshire and Owen
2006; Clatworthy et al. 2009; Robinson et al. 2010; Hornak et al. 2004).
Chudasama and Robbins (2003) showed that quinolinic OFC lesions impair
touchscreen reversal learning in the rat by increasing the number of early errors.
Similarly, Alsiö and colleagues showed that temporary OFC inactivation impairs
touchscreen visual reversal learning in the rat by selectively increasing the number
of early errors and early response omissions (Alsiö et al. 2015). OFC lesions in the
rat also impair touchscreen reversal learning, and this deﬁcit was interpreted as
more prominent when the animal had to adjust to negative feedback (Izquierdo
et al. 2013). In terms of the dorsal striatum, both mouse and human studies have
found the region to be critical for reversal learning (Graybeal et al. 2011; Robinson
et al. 2010).
It is important to note that OFC dependency in the rodent has also been observed
using more traditional tasks (Birrell and Brown 2000; Schoenbaum et al. 2002;
McAlonan and Brown 2003; Kim and Ragozzino 2005; Boulougouris et al. 2007;
Ghods-Shariﬁ et al. 2008; Bissonette et al. 2008; Castañé et al. 2010). This illustrates an important point: we are not arguing that it is impossible to achieve
effective translation using non-touchscreen tests in rodents. However, we do believe
that using similar, validated, and more reproducible tests across species can make
successful translation much more likely.
Serotonergic Manipulations Affect Both Rodent
and Human Touchscreen Reversal Learning
Demonstrations of cross-species parallels within reversal learning are not restricted
to the involvement of speciﬁc brain regions, but extend to a variety of signalling
systems (Frank and O’Reilly 2006; Robbins and Roberts 2007), perhaps most
notably serotonin (5-hydroxytryptamine, or 5-HT; Daw et al. 2002; Roberts 2011).
Acute tryptophan depletions in healthy subjects can impair touchscreen reversal
learning (Park et al. 1994; Rogers et al. 1999; but see Evers et al. 2005; Talbot et al.
2005; Finger et al. 2007; Cools et al. 2008), and behavioural genetic studies suggest
that 5-HT signalling efﬁcacy is bidirectionally related to reversal learning performance in humans (den Ouden et al. 2013). Comparable effects have been observed
in non-touchscreen assays in the rodent with systemic pharmacological manipulations to 5-HT levels affecting bowl-digging (Lapiz-Bluhm et al. 2009), go/no-go
M. Hvoslef-Eide et al.
(Masaki et al. 2006), and spatial probabilistic reversal learning (Bari et al. 2010) in
As in human studies, rodent touchscreen reversal learning has been shown to be
sensitive to pharmacological and genetic manipulations of 5-HT levels. In the
mouse, hetero- and homozygous deletions of the 5-HT transporter cause
dose-dependent elevations in cortical and striatal 5-HT levels (Mathews et al. 2004;
Daws 2006) and induce parallel dosage-dependent improvements in touchscreen
reversal learning observed as decreases in trials and errors to criterion (Brigman
et al. 2010). Moreover, pharmacologically induced elevation of cortical 5-HT
through subchronic fluoxetine treatment (Cryan et al. 2004) decreases trials and
incorrect responses to criterion during the early phase of learning when responding
is biased towards the previously correct stimulus (Brigman et al. 2010). Taken
together, there are clear demonstrations of translation between the rodent, monkey,
and human with regard to both speciﬁc regions and neurotransmitter systems
central for reversal learning.
Cross-Species Impairments in Touchscreen Reversal
Learning Following a Disc Large 2 Mutation
As part of the touchscreen test battery assessment of the Dlg2 gene knockout mouse
previously mentioned, visual reversal learning was assessed (Nithianantharajah
et al. 2012a, b). In a clear example of cross-species translation, both human carriers
of the Dlg2 mutation and Dlg2−/− mice showed comparable deﬁcits in touchscreen
visual reversal learning, observed as a decrease in accuracy during early sessions,
suggesting impairments in behavioural inhibition/cognitive flexibility
(Nithianantharajah et al. 2012a, b).
6 Limitations and Challenges
These examples demonstrate how touchscreen behavioural paradigms can be
readily translatable between human participants and rodents. Like any method,
these protocols nevertheless contain limitations—many of which are the focus of
reﬁnement in ongoing experiments. For example, some rodent touchscreen tasks
may require extensive training (e.g. PAL, 5-CSRTT). However, many
non-touchscreen tasks of complex cognition also require lengthy training, and
furthermore, touchscreen automation allows the parallel testing of numerous animals at once, mitigating the time cost of extensive training. A major challenge for
touchscreen translation is to experimentally demonstrate neurocognitive validity for
every rodent touchscreen test and its human counterpart—but again, this challenge
is not speciﬁc to touchscreens, and validation of the touchscreen tests is ongoing.