Impaired recruitment of dopamine neurons during working memory in mice with striatal D2 receptor overexpression

Sevil Duvarci,Jochen Roeper,Eric R Kandel,Torfi Sigurdsson,Eleanor H Simpson,Gaby Schneider

doi:10.1038/s41467-018-05214-4

Abstract

The dopamine (DA) system plays a major role in cognitive functions through its interactions with several brain regions including the prefrontal cortex (PFC). Conversely, disturbances in the DA system contribute to cognitive deficits in psychiatric diseases, yet exactly how they do so remains poorly understood. Here we show, using mice with disease-relevant alterations in DA signaling (D2R-OE mice), that deficits in working memory (WM) are associated with impairments in the WM-dependent firing patterns of DA neurons in the ventral tegmental area (VTA). The WM-dependent phase-locking of DA neurons to 4 Hz VTA-PFC oscillations is absent in D2R-OE mice and VTA-PFC synchrony deficits scale with their WM impairments. We also find reduced 4 Hz synchrony between VTA DA neurons and selective impairments in their representation of WM demand. These results identify how altered DA neuron activity—at the level of long-range network activity and task-related firing patterns—may underlie cognitive impairments.

Highlights

The dopamine (DA) system plays a major role in cognitive functions through its interactions with several brain regions including the prefrontal cortex (PFC)
In order to examine whether alterations in the firing patterns and long-range synchrony of ventral tegmental area (VTA) neurons are associated with cognitive deficits, we recorded neural activity simultaneously in the VTA and medial PFC (Supplementary Fig. 1) of D2R-OE and control mice while they performed a delayed non-match to sample spatial working memory (WM) task in a T-maze (Fig. 1a)[21]
We found that the recruitment of VTA DA neurons that occurs on multiple levels during WM—manifesting in WMselective activity patterns as well as in increased local synchrony and long-range coordination with the PFC—was absent in D2ROE mice, which display WM deficits

Summary

Introduction

The dopamine (DA) system plays a major role in cognitive functions through its interactions with several brain regions including the prefrontal cortex (PFC). Whether impairments in long-range synchrony between DA neurons and the PFC are associated with cognitive dysfunction in animal models has not been investigated To address these questions, we recorded from pharmacologically identified VTA DA neurons in mice overexpressing the D2type DA receptor in the striatum (D2R-OE mice)[23] during WM performance. We show that the representation of WM demand, but not reward or choice, by VTA DA and PFC neurons is selectively impaired in D2R-OE mice, suggesting a deficit in a specific neuronal subpopulation Taken together, these findings are the first to define the signatures of altered DA neuron electrical activity—both in terms of their task-related firing patterns and long-range synchrony—which could underlie cognitive dysfunction

Methods

Results

Conclusion