Rats and humans paying attention: Cross-species task development for translational research.

Demeter, Elise; Sarter, Martin; Lustig, Cindy

doi:10.1037/a0013712

Cited by 105 publications

(175 citation statements)

References 52 publications

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“…Animals also performed a Sustained Attention Task (SAT) (McGaughy and Sarter, 1995;Demeter et al, 2008Demeter et al, , 2011Demeter et al, , 2013Howe et al, 2013). The present evidence indicates that dual cholinergic-dopaminergic lesions increase the rate of falls in situations requiring the attentional control of complex movements, that attentional impairments and fall propensity are correlated, and that cholinergic deafferentation unmasks the contributions of dorsal striatal dopamine to complex movement, balance, and gait control.…”

Section: Introductionmentioning

confidence: 88%

“…SAT. Evidence in support of the validity of the SAT, in terms of generating measures of sustained attentional capacity in mice, rats, and humans, has been previously described (McGaughy and Sarter, 1995;Demeter et al, 2008Demeter et al, , 2013. The SAT also taxes the ability to shift between states of perceptual attention and cue-directed behavior (Howe et al, 2013).…”

Section: Methodsmentioning

confidence: 99%

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Modeling Fall Propensity in Parkinson's Disease: Deficits in the Attentional Control of Complex Movements in Rats with Cortical-Cholinergic and Striatal–Dopaminergic Deafferentation

et al. 2013

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Cognitive symptoms, complex movement deficits, and increased propensity for falls are interrelated and levodopa-unresponsive symptoms in patients with Parkinson's disease (PD). We developed a test system for the assessment of fall propensity in rats and tested the hypothesis that interactions between loss of cortical cholinergic and striatal dopaminergic afferents increase fall propensity. Rats were trained to traverse stationary and rotating rods, placed horizontally or at inclines, and while exposed to distractors. Rats also performed an operant Sustained Attention Task (SAT). Partial cortical cholinergic and/or caudate dopaminergic deafferentation were produced by bilateral infusions of 192 IgG-saporin (SAP) into the basal forebrain and/or 6-hydroxydopamine (6-OHDA) into the caudate nucleus, respectively, modeling the lesions seen in early PD. Rats with dual cholinergic-dopaminergic lesions (DL) fell more frequently than SAP or 6-OHDA rats. Falls in DL rats were associated with incomplete rebalancing after slips and low traversal speed. Ladder rung walking and pasta handling performance did not indicate sensorimotor deficits. SAT performance was impaired in DL and SAP rats; however, SAT performance and falls were correlated only in DL rats. Furthermore, in DL rats, but not in rats with only dopaminergic lesions, the placement and size of dopaminergic lesion correlated significantly with fall rates. The results support the hypothesis that after dual cholinergic-dopaminergic lesions, attentional resources can no longer be recruited to compensate for diminished striatal control of complex movement, thereby "unmasking" impaired striatal control of complex movements and yielding falls.

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Section: Introductionmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Modeling Fall Propensity in Parkinson's Disease: Deficits in the Attentional Control of Complex Movements in Rats with Cortical-Cholinergic and Striatal–Dopaminergic Deafferentation

et al. 2013

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“…Optical stimulation was achieved via a blue laser diode coupled to a fiber optic cable and modulated via a custom written software package to control laser parameters including duration and intensity. Animals underwent a total of 4-6 mo of training of the operant sustained attention task (SAT) (50,51) with the oldest mouse being ∼9 mo old at study conclusion. Once animals achieved performance criterion they were randomly selected to undergo AAV infusions for one of three possible constructs and underwent surgery for optic fiber placement.…”

Section: Methodsmentioning

confidence: 99%

“…Amplitudes did not vary by stimulation duration and the two factors did not interact [main effect of stimulation duration: F(1,29) = 2.90, P = 0.10, duration by power interaction: F(4,116) = 2.07, P = 0.11]. Compared with the shorter stimulation duration, 1,000-ms stimulation generated transients that peaked later [F(1,29) = 94.40, P < 0.001] and required more time to return within 50% of baseline [t 50 ; F(1,29) = 73.32, P < 0.001; Fig. 2E].…”

Section: Significancementioning

confidence: 99%

Cortical cholinergic signaling controls the detection of cues

Gritton

Howe

Mallory

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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175

208

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The cortical cholinergic input system has been described as a neuromodulator system that influences broadly defined behavioral and brain states. The discovery of phasic, trial-based increases in extracellular choline (transients), resulting from the hydrolysis of newly released acetylcholine (ACh), in the cortex of animals reporting the presence of cues suggests that ACh may have a more specialized role in cognitive processes. Here we expressed channelrhodopsin or halorhodopsin in basal forebrain cholinergic neurons of mice with optic fibers directed into this region and prefrontal cortex. Cholinergic transients, evoked in accordance with photostimulation parameters determined in vivo, were generated in mice performing a task necessitating the reporting of cue and noncue events. Generating cholinergic transients in conjunction with cues enhanced cue detection rates. Moreover, generating transients in noncued trials, where cholinergic transients normally are not observed, increased the number of invalid claims for cues. Enhancing hits and generating false alarms both scaled with stimulation intensity. Suppression of endogenous cholinergic activity during cued trials reduced hit rates. Cholinergic transients may be essential for synchronizing cortical neuronal output driven by salient cues and executing cue-guided responses.V irtually all cortical regions and layers receive inputs from cholinergic neurons originating in the nucleus basalis of Meynert, the substantia innominata, and the diagonal band of the basal forebrain (BF). Reflecting the seemingly diffuse organization of this projection system, functional conceptualizations traditionally have described acetylcholine (ACh) as a neuromodulator that influences broadly defined behavioral and cognitive processes such as wakefulness, arousal, and gating of input processing (1, 2). However, anatomical studies have revealed a topographic organization of BF cholinergic cell bodies with highly segregated cortical projection patterns (3-7). Such an anatomical organization favors hypotheses describing the cholinergic mediation of discrete cognitive-behavioral processes. Studies assessing the behavioral effects of cholinergic lesions, recording from or stimulating BF neurons in behaving animals have supported such hypotheses, proposing that cholinergic activity enhances sensory coding and mediates the ability of reward-predicting stimuli to control behavior (8-17).In separate experiments using two different tasks, we reported the presence of phasic cholinergic release events (transients) in the medial prefrontal cortex (mPFC) of rodents trained to report the presence of cues (18,19). These studies used choline-sensitive microelectrodes to measure changes in extracellular choline concentrations that reflect the hydrolysis of newly released ACh by endogenous acetylcholinesterase (SI Results and Discussion). Importantly, such cholinergic transients were not observed in trials in which cues were missed and in which the absence of a cue was correctly reported and rewarded. Cho...

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“…Following these recommendations the CNTRICS panel devised a similar list of tasks for evaluating these cognitive domains in animals (Carter and Barch, 2007). These tasks were selected based on evidence of face, predictive and construct validity relative to the human CPT and each has been reverse-translated back into human tasks (Demeter et al, 2008;Young et al, 2009a;Young et al, 2013b;Worbe et al, 2014). A key issue that was raised throughout this process was the need for greater translational validity between rodent and human tasks (Hagan and Jones, 2005;Young et al, 2009a).…”

Section: Introductionmentioning

confidence: 99%

Establishing a novel cognitive task in rats of relevance to schizophrenia

Turner¹

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The most debilitating symptoms for patients with neuropsychiatric disorders, such as schizophrenia, are often cognitive deficits; yet they remain largely untreated by current medications. In preclinical animal models, the techniques used to measure cognitive deficits need to be improved to enhance our ability to screen novel drug targets and gain a better understanding of the neurobiological correlates of cognitive dysfunction. Therefore, the aim of this thesis was to develop and test a new high throughput cognitive task in rodents. I have designed a novel Signal Detection Task (SDT) for this purpose.The first aim in developing the SDT was to compare alternative tasks (such as the 5-choice serial reaction time task) and address limitations including the extensive training time required and the lack of control over body position during stimulus presentation.Experiments were then selected to assess the face, construct and predictive validity of the SDT for measuring attentional deficits relevant to schizophrenia. Specifically, I determined if the effects of genetic, environmental, neurobiological and pharmacological manipulations could be detected in rats using this task. The SDT was conducted in rat operant chambers with a series of task variants to probe different components of performance, such as increasing detection difficulty and distraction. Briefly, the studies conducted compared strains (genetics), housing conditions (environment), the impact of a prefrontal cortical lesion (neurobiology) and the effects of amphetamine (pharmacology) on task performance. My findings indicate a relatively short training period was required for rats to perform the SDT with a high level of accuracy compared to other tasks; task acquisition was shown to be dependent on interactions between genetics and environment; prefrontal cortical lesions did not alter baseline performance but impaired attention during distraction and low dose amphetamine significantly improved accuracy. I demonstrated for the first time that the procognitive effects of amphetamine were dependent on baseline attentional performance. In addition, I found that individual variation in baseline performance was related to dopamine metabolism in the striatum.The research outlined in this thesis presents a novel tool for researchers exploring the cognitive phenotype of animal models relevant to neuropsychiatric disorders and for exploring the neurobiology of attention, including mechanisms of action for procognitive medication.ii Declaration by authorThis thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis.

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Rats and humans paying attention: Cross-species task development for translational research.

Cited by 105 publications

References 52 publications

Modeling Fall Propensity in Parkinson's Disease: Deficits in the Attentional Control of Complex Movements in Rats with Cortical-Cholinergic and Striatal–Dopaminergic Deafferentation

Modeling Fall Propensity in Parkinson's Disease: Deficits in the Attentional Control of Complex Movements in Rats with Cortical-Cholinergic and Striatal–Dopaminergic Deafferentation

Cortical cholinergic signaling controls the detection of cues

Establishing a novel cognitive task in rats of relevance to schizophrenia

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