Social behavior in mice following chronic optogenetic stimulation of hippocampal engrams

https://doi.org/10.1016/j.nlm.2020.107321Get rights and content

Highlights

  • Chronic stimulation of hippocampus engrams variably modulates social behavior.

  • These effects were independent of changes in neurogenesis and multi-region cFos activity.

  • Our data provide further insight to the behavioral and neural effects of chronic optogenetic stimulation of hippocampus-mediated engrams.

Abstract

The hippocampus processes both spatial-temporal information and emotionally salient experiences. To test the functional properties of discrete sets of cells in the dorsal dentate gyrus (dDG), we examined whether chronic optogenetic reactivation of these ensembles was sufficient to modulate social behaviors in mice. We found that chronic reactivation of discrete dDG cell populations in male mice largely did not affect social behaviors in an experience-dependent manner. However, we found that social behavior in a female exposure task was increased following chronic optogenetic stimulation when compared to pre-stimulation levels, suggesting that the protocol led to increased social behavior, although alternative explanations are discussed. Furthermore, multi-region analysis of neural activity did not yield detectable differences in immediate-early gene expression or neurogenesis following chronic optogenetic stimulation. Together, these results suggest that the effects of chronic optogenetic stimulation in the dDG on social behaviors are independent of the contextual experience processed by each cellular ensemble.

Introduction

Social behaviors are dramatically impaired across many psychiatric disorders, though the underlying mechanisms sufficient to precipitate or alleviate such impairments remain largely unknown. Promisingly, previous studies have demonstrated that chronic optogenetic reactivation of both cell bodies and projection-specific elements can “reprogram” circuit-level and behavioral outputs in healthy and maladaptive states (Creed et al., 2019, Tye, 2014). However, the behavioral effects of chronic optogenetic stimulation of memory ensembles are region-specific and experience-dependent. Specifically, reactivating dDG cells that were previously active during female exposure was sufficient to rescue depressive-like behavior in mice, while chronically reactivating dDG cells previously active during fear conditioning was sufficient to either suppress or enhance a context-specific memory (Ramirez et al., 2015, Chen et al., 2019). To elucidate the potential lasting effects of chronic circuit-level manipulations, we examined whether chronic optogenetic reactivation of ensembles in the dDG which are active during putative positive or negative experiences is sufficient to alter behavior and brain activity during three social tests. Our findings suggest that chronic optogenetic stimulation alters social behavior, and that these effects are independent of the contextual experience processed by the reactivated hippocampal ensemble.

Section snippets

Subjects

Wild-type C57BL/6J male mice (40–41 days; Charles River Laboratories) were housed with littermates in groups of 2–5 mice per cage. Mice were acclimated to the animal facility for 72 h upon delivery before experimental procedures began and kept on a 12:12-hour light cycle (lights on at 7:00). Food and water were available ad libitum. Animals were put on a diet containing 40 mg/kg doxycycline (dox) after the acclimation period and 24–48 h before receiving surgery between 6 and 7 weeks of age.

Results

Hippocampal cells were tagged during either a positive, negative, or neutral behavioral epoch, a design that was implemented to allow for stimulation of similarly sized cellular ensembles encoding experiences of different valences. Mice showed no differences across groups in the number of eYFP + dDG cells (One-Way ANOVA, F2,13 = 1.392, p = 0.2834) (Fig. 1C-D). Animals then underwent a previously established (Chen et al., 2019, Ramirez et al., 2015) 10-minute optogenetic stimulation protocol

Discussion

Our findings demonstrate that chronic stimulation of dDG neurons involved in the encoding of distinct behavioral experiences did not drive differential social or cellular effects post-stimulation. After five days of chronic stimulation, we observed no differences in the amount of time experimental mice interacted with a conspecific mouse in the social interaction test or a novel male mouse in the resident intruder test. Although mice interacted more with the female mouse in a female exposure

CRediT authorship contribution statement

E.D., E.M., H.L., A.M., C.C., J.L., S.L.G., and S.R. designed and performed the experiments. E.D., E.M., A.M., H.L., and S.R. wrote the paper. All authors edited and commented on the manuscript.

Declaration of Competing Interest

The authors declare no competing interests.

Acknowledgements

We would like to thank Joshua Sanes and his lab (Center for Brain Science, Harvard University) for providing laboratory space within which the initial experiments were conducted; Harvard University’s Center for Brain Science Neuroengineering core for providing technical support. We thank Abby Finkelstein for helpful comments on the manuscript. Finally, we would like to thank Susumu Tonegawa and his lab (Massachusetts Institute of Technology) for providing the activity-dependent virus cocktail.

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