Early-life adversity induces social anxiety and cognitive deficits alongside neurobiological changes in rats

Mood disorders such as anxiety often originate early in life, yet rodent models of early-life adversity are typically assessed only in adulthood using a limited array of behavioral assays. Here we show how neonatal isolation affects social behavior, learning and memory, neuron structure, and blood metabolites in Long Evans rats (Rattus norvegicus). Juvenile isolated rats play less with unfamiliar peers but interact typically with cage mates, consistent with a social anxiety-like phenotype.

As adults, isolated rats show reduced cooperation and increased aggression, whereas traditional anxiety tests do not reveal increased generalized anxiety. Females show pronounced cognitive and motivational deficits. Isolation is also associated with reduced dendritic spine density in the medial prefrontal cortex, sex-specific neuronal changes in the dorsolateral septum, and shifts in glucose and amino acid metabolism.

Together, these findings reveal selective, sex-dependent consequences of early-life social deprivation across behavioral, neural, and metabolic domains. We would like to thank the University of Lethbridge Animal Care Staff for diligent care of our subjects. We thank the University of Lethbridge for the use of the Magnetic Resonance Facility (Lethbridge, AB, Canada), which provided access to and training on the 700 MHz Bruker Avance III HD NMR spectrometer.

We would like to thank Amit Khundari for their assistance with behavioral analysis and testing. This research was funded in part by the University of Lethbridge Research Fund awarded to RJM and JRH, the Natural Science and Engineering Research Council (NSERC) NSERC-DG awarded to RJM (RGPIN-2020-06929), the Canada Foundation for Innovation awarded to ANI (30215), and the Canada Research Chairs Program awarded to ANI (CRC-2018-00023). JRH received funding from NSERC (CGS-D), BH and HS received funding from the Chinook Research Award, and VR and HS received funding from Alberta Innovates.

Present address: Department of Psychology, St. Francis Xavier University, Antigonish, NS, Canada Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, Lethbridge, AB, Canada Jackson R. Slobodian, Vannessa Urlacher, Erin Cantwell, Alex A.

Tong, Jessica Annor-Bediako, Barron Hastie, Andrew N. McDonald Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, AB, Canada Southern Alberta Genome Sciences Centre, University of Lethbridge, Lethbridge, AB, Canada Correspondence to Jackson R. The authors declare no competing interests.