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Microglia depletion facilitates the display of maternal behavior and alters activation of the maternal brain network in nulliparous female rats

Neuropsychopharmacology volume 48, pages 1869–1877 (2023)Cite this article

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Abstract

The peripartum period is accompanied by peripheral immune alterations to promote a successful pregnancy. We and others have also demonstrated significant neuroimmune changes that emerge during late pregnancy and persist postpartum, most prominently decreased microglia numbers within limbic brain regions. Here we hypothesized that microglial downregulation is important for the onset and display of maternal behavior. To test this, we recapitulated the peripartum neuroimmune profile by depleting microglia in non-mother (i.e., nulliparous) female rats who are typically not maternal but can be induced to behave maternally towards foster pups after repeated exposure, a process called maternal sensitization. BLZ945, a selective colony-stimulating factor 1 receptor (CSF1R) inhibitor, was administered systemically to nulliparous rats, which led to ~75% decrease in microglia number. BLZ- and vehicle-treated females then underwent maternal sensitization and tissue was stained for ∆fosB to examine activation across maternally relevant brain regions. We found BLZ-treated females with microglial depletion met criteria for displaying maternal behavior significantly sooner than vehicle-treated females and displayed increased pup-directed behaviors. Microglia depletion also reduced threat appraisal behavior in an open field test. Notably, nulliparous females with microglial depletion had decreased numbers of ∆fosB+ cells in the medial amygdala and periaqueductal gray, and increased numbers in the prefrontal cortex and somatosensory cortex, compared to vehicle. Our results demonstrate that microglia regulate maternal behavior in adult females, possibly by shifting patterns of activity in the maternal brain network.

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Fig. 1: BLZ945 treatment led to rapid depletion of microglia in the adult female rat brain.
Fig. 2: Microglia depletion in adult nulliparous females accelerated maternal sensitization, increased maternal behavior, and reduced threat appraisal behavior.
Fig. 3: Microglia depletion prior to maternal sensitization altered ∆fosB expression across maternally relevant brain regions.
Fig. 4: Microglia depletion altered ∆fosB correlation patterns in the maternal brain network during maternal sensitization.

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Funding

Funding

National Institute of Mental Health grant (R21 MH117482-02) to BL and KML; National Science Foundation grant (2114381) to BL and KML; CND was supported by National Institute of Neurological Disorders and Stroke (T32NS105864).

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Author notes

  1. These authors contributed equally: Benedetta Leuner, Kathryn M. Lenz.

Authors and Affiliations

  1. Neuroscience Graduate Program, The Ohio State University, Columbus, OH, USA

    Courtney N. Dye

  2. Department of Psychology, The Ohio State University, Columbus, OH, USA

    Dominic Franceschelli, Benedetta Leuner & Kathryn M. Lenz

  3. Department of Neuroscience, The Ohio State University, Columbus, OH, USA

    Benedetta Leuner & Kathryn M. Lenz

  4. Institute of Behavioral Medicine Research, The Ohio State University, Columbus, OH, USA

    Kathryn M. Lenz

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  1. Courtney N. Dye
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  2. Dominic Franceschelli
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CND performed experiments, analyzed the data, and wrote and edited the manuscript. DF contributed to behavior analysis. BL and KML conceptualized and supervised the experiments and wrote and edited the manuscript.

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Correspondence to Kathryn M. Lenz.

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Dye, C.N., Franceschelli, D., Leuner, B. et al. Microglia depletion facilitates the display of maternal behavior and alters activation of the maternal brain network in nulliparous female rats. Neuropsychopharmacol. 48, 1869–1877 (2023). https://doi.org/10.1038/s41386-023-01624-1

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