Optogenetic silencing of locus coeruleus activity in mice impairs cognitive flexibility in an attentional set-shifting task

Abstract

The locus coeruleus (LC) is the sole source of noradrenergic projections to the cortex and essential for attention-dependent cognitive processes. In this study we used unilateral optogenetic silencing of the LC in an attentional set-shifting task (ASST) to evaluate the influence of the LC on prefrontal cortex-dependent functions in mice. We expressed the halorhodopsin eNpHR 3.0 to reversibly silence LC activity during task performance, and found that silencing selectively impaired learning of those parts of the ASST that most strongly rely on cognitive flexibility. In particular, extra-dimensional set-shifting (EDS) and reversal learning was impaired, suggesting an involvement of the medial prefrontal cortex (mPFC) and the orbitofrontal cortex. In contrast, those parts of the task that are less dependent on cognitive flexibility, i.e., compound discrimination (CD) and the intra-dimensional shifts (IDS) were not affected. Furthermore, attentional set formation was unaffected by LC silencing. Our results therefore suggest a modulatory influence of the LC on cognitive flexibility, mediated by different frontal networks.

Pupil Dynamics Reflect Behavioral Choice and Learning in a Go/NoGo Tactile Decision-Making Task in Mice

“…Learning of stimuli presented with induced pupil dilation in humans has been associated with improved learning (Nassar et al, 2012; Hoffing and Seitz, 2015). The causal relationship between pupil-linked neuromodulator systems (including LC) with arousal, learning, sensory discrimination and decision-making could be tested with greater temporal and cell-type specificity in rodent models (Janitzky et al, 2015). …”

The locus coeruleus: Another vulnerability target in Parkinson's disease

“…When combined with pupillometry, the Wisconsin Card Sorting Test (WCST) or the Intra‐/Extra‐Dimensional Attentional Set‐Shifting Task can be used to investigate LC function in humans. According to rodent studies, performance in attentional set shifting is highly dependent on prefrontal cortical noradrenergic activity originating in the LC . Moreover, it is already known that PD patients perform worse in shifting their focus of attention during the WCST .…”

“…According to rodent studies, performance in attentional set shifting is highly dependent on prefrontal cortical noradrenergic activity originating in the LC. 42 Moreover, it is already known that PD patients perform worse in shifting their focus of attention during the WCST. 43,44 However, there are no pupillometric data available during attentional set shifting in manifest, not to speak of prodromal PD patient groups.…”

The role of NMDA receptor‐dependent activity of noradrenergic neurons in attention, impulsivity and exploratory behaviors

“…NR1 DbhCre mice required significantly fewer trials to reach the criterion in the EDS phase of the ASST, resembling the effects of treatment with the NMDA receptor NR2B-subtype specific antagonist Ro 25-6981 (Kos et al 2011). This result is similar to the effects of pharmacological facilitation of NA signaling on attentional set-shifting (Devauges & Sara 1990;Snyder et al 2012) and opposite to optogenetic inhibition of LC firing or lesions of the dorsal NA bundle (Janitzky et al 2015;Tait et al 2007). The result is also similar to the observed effects of elevated NA neuron activity leading to activation of alfa1 adrenergic receptors in the prefrontal cortex (Berridge et al 2012;Lapiz & Morilak 2006).…”

“…) and opposite to optogenetic inhibition of LC firing or lesions of the dorsal NA bundle (Janitzky et al . ; Tait et al . ).…”