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1 Alzheimer’s Disease and Acetylcholine: Pharmacological and Genetic Translations

1 Alzheimer’s Disease and Acetylcholine: Pharmacological and Genetic Translations

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430



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.



3.2



Serotonin Depletion Results in Parallel Deficits Across

Species



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

species.



Cognitive Translation Using the Rodent Touchscreen Testing …



3.3



431



Some Limitations of the 5-Choice Serial Reaction Time

Task



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,



432



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.



4.1



CPT and rCPT: Convergence by Functional Anatomy

and Pharmacology



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).



4.2



Animal Models on the rCPT: Parallels with Human

CPT Data



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 …



433



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.



4.3



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.



4.4



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.



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