Elsevier

Biological Psychiatry

Volume 91, Issue 7, 1 April 2022, Pages 676-689
Biological Psychiatry

Archival Report
Behavioral Engagement With Playable Objects Resolves Stress-Induced Adaptive Changes by Reshaping the Reward System

https://doi.org/10.1016/j.biopsych.2021.09.027Get rights and content

Abstract

Background

The reward system regulates motivated behavior, and repeated practice of specific motivated behavior might conversely modify the reward system. However, the detailed mechanisms by which they reciprocally regulate each other are not clearly understood.

Methods

Mice subjected to chronic restraint stress show long-lasting depressive-like behavior, which is rescued by continual engagement with playable objects. A series of molecular, pharmacological, genetic, and behavioral analyses, combined with microarray, liquid chromatography, and chemogenetic tools, are used to investigate the neural mechanisms of antidepressive effects of playable objects.

Results

Here, we show that repeated restraint induces dopamine surges into the nucleus accumbens–lateral shell (NAc-lSh), which cause upregulation of the neuropeptide PACAP in the NAc-lSh. As repeated stress is continued, the dopamine surge by stressors is adaptively suppressed without restoring PACAP upregulation, and the resulting enhanced PACAP inputs from NAc-lSh neurons to the ventral pallidum facilitate depressive-like behaviors. Continual engagement with playable objects in mice subjected to chronic stress remediates reduced dopamine response to new stressors, enhanced PACAP upregulation, and depressive-like behaviors. Overactivation of dopamine D1 receptors over the action of D2 receptors in the NAc-lSh promotes depressive-like behaviors. Conversely, inhibition of D1 receptors or PACAP upregulation in the NAc-lSh confers resilience to chronic stress–induced depressive-like behaviors. Histochemical and chemogenetic analyses reveal that engagement with playable objects produces antidepressive effects by reshaping the ventral tegmental area–to–NAc-lSh and NAc-lSh–to–ventral pallidum circuits.

Conclusions

These results suggest that behavioral engagement with playable objects remediates depressive-like behaviors by resolving stress-induced maladaptive changes in the reward system.

Section snippets

Methods and Materials

The details of methods and materials are available in Supplement 1.

Results

We developed a rodent model to study behavioral effects of playing with objects. Different types of objects that included cork rods, glass marbles, and plastic cryotubes were tested to determine if the objects induced motivated behaviors that involved exploring activity without habituation over repeated exposure. Mice exhibited strong exploring activity on cork rods, but not plastic cryotubes and glass marbles. Because mice chewed and ate parts of the cork rods, we explored if a gauze roll with

Engagement With Playable Objects Produced Antidepressive Effects via Activation of the Reward System

When gauze rolls were presented in a cage, mice actively explored and played with them without habituation over repeated exposure (Figure 1A–E; Figure S2 in Supplement 1; Supplemental Video S1). Continual engagement with gauze rolls increased dopamine release and its metabolite levels in the NAc-lSh (Figure 2E–Q) and rescued stress-induced depressive-like behaviors. In contrast, inhibition of the VTA→NAc-lSh pathway during gauze-roll play blocked antidepressive effects of gauze-roll play (

Acknowledgments and Disclosures

This research was supported by Grant No. 2021R1A2B5B02002245 (to P-LH) from the Ministry of Science, ICT and Future Planning, Republic of Korea.

The authors report no biomedical financial interests or potential conflicts of interest.

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