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Urocortin-3 neurons in the perifornical area are critical mediators of chronic stress on female infant-directed behavior

Abstract

Infant avoidance and aggression are promoted by activation of the Urocortin-3 expressing neurons of the perifornical area of hypothalamus (PeFAUcn3) in male and female mice. PeFAUcn3 neurons have been implicated in stress, and stress is known to reduce maternal behavior. We asked how chronic restraint stress (CRS) affects infant-directed behavior in virgin and lactating females and what role PeFAUcn3 neurons play in this process. Here we show that infant-directed behavior increases activity in the PeFAUcn3 neurons in virgin and lactating females. Chemogenetic inhibition of PeFAUcn3 neurons facilitates pup retrieval in virgin females. CRS reduces pup retrieval in virgin females and increases activity of PeFAUcn3 neurons, while CRS does not affect maternal behavior in lactating females. Inhibition of PeFAUcn3 neurons blocks stress-induced deficits in pup-directed behavior in virgin females. Together, these data illustrate the critical role for PeFAUcn3 neuronal activity in mediating the impact of chronic stress on female infant-directed behavior.

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Fig. 1: PeFA Urocortin-3 neuronal activation levels in response to foreign pups depends on physiological context.
Fig. 2: Inhibition of PeFAUcn3 neurons enhances alloparental behavior in virgin female mice.
Fig. 3: Chronic restraint stress dampens alloparental behavior in virgin female mice.
Fig. 4: Chronic restraint stress does not induce changes in parental behavior in lactating females.
Fig. 5: Chronic restraint leads to contrasting molecular changes between virgin and lactating females with parenting.
Fig. 6: PeFAUcn3 inhibition ameliorates parenting deficits in stressed virgin females.

Code availability

Custom Matlab code for analysis of photometry data is available at github.com/babdelme/Autrylab_photometry. MERFISH image analysis scripts are available at github.com/ZhuangLab/MERFISH-analysis.

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Acknowledgements

AEA was supported by a NARSAD Young Investigator Award and a Pathway to Independence Award (NIH R00HD085188). BA was supported by a diversity supplement to AEA’s NIH award (R00HD085188-S1) and a Tishman Scholarship. DB-M was supported by a Pathway to Independence Award (NIH R00HD092542). We thank Catherine Dulac for intellectual input and project support at Harvard University. We thank Stacey Sullivan for assistance with the transfer of data and mice from Harvard University to Albert Einstein College of Medicine. We thank Krysten Garcia for histology assistance. We thank Giovanni Podda for guidance on the photometry analysis. We thank Kostantin Dobrenis, Vladimir Mudragel, and Mariah Marrero for guidance on Axioscan usage. We thank Kevin Fisher for assistance with image export and analysis. We thank all the members of the Autry lab for input on manuscript preparation.

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BA and AEA designed and performed experiments, analyzed, and plotted data, and interpreted data and wrote the paper. RA supported animal experiments and analyzed data. DB-M performed and analyzed the single cell sequencing and MERFISH experiments. IC analyzed and plotted data.

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Correspondence to Anita E. Autry.

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Abdelmesih, B., Anderson, R., Bambah-Mukku, D. et al. Urocortin-3 neurons in the perifornical area are critical mediators of chronic stress on female infant-directed behavior. Mol Psychiatry 28, 483–496 (2023). https://doi.org/10.1038/s41380-022-01902-2

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  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-022-01902-2

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