Glycogen depletion in astrocytes induces sex-dimorphic remodeling of astrocytic and synaptic structures with concomitant anxiety-like behaviors and maternal care deficits.

Background: Maternal care is an instinctive social behavior indispensable for survival and gene transmission. Postpartum maternal behavior is profoundly affected by mother's emotional state via incompletely elucidated complex mechanisms including metabolic regulation. Brain glycogen, primarily located in astrocytes, is a potent modulator for brain plasticity and provides neuroprotection against bioenergetic insults. The regulation of brain glycogen is of relevance to hormonal control that might be linked to sex-dimorphic responses in mental health. The present study aims to investigate the involvement of glycogen in the sex differences of brain structural plasticity, and to characterize the impacts on affective and maternal behaviors in both sexes.

Methods: Male and female brain-type glycogen phosphorylase knock-in (Pygb-KI) mice were generated to exhaust glycogen in astrocytes in both sexes. Metabolomics, seahorse and relative assay kits were utilized to detect the changes in downstream metabolites to assess the effects of astrocytic glycogen depletion on energy metabolism. Virus-labeling, immunostaining combined with sholl analysis were performed to explore the morphological changes in astrocytes, neurons and dendrite spines. In addition, affective behaviors were assessed using the open field and elevated plus maze tests to quantify anxiety-like phenotypes, and the tail suspension test to evaluate depressive-like components of behavior. Maternal care was analyzed through pup retrieval assays and nest-building behavior, while offspring development was tracked via survival rates and ultrasonic vocalizations. Expression of hormonal receptors was identified via qPCR and immunofluorescence staining.

Results: Pygb-KI mice exhibited glycogen deficiency in astrocytes in both sexes, causing disrupted energy metabolic patterns, particularly in glycolysis. Subsequently, we observed in female-specific decreases in area, branching, and length of astrocytes and loss of mature dendritic spines in neurons. This sex-dimorphic phenotype was in accordance with the phenomenon that Pygb-KI females displayed anxiety-like behaviors in adulthood, irrespective of the virgin or lactating stage. Assessment of maternal behaviors revealed that Pygb-KI lactating mice displayed maternal care obstacles, and offspring nursed by Pygb-KI dams showed reduced survival rate and social deficits during development. Estradiol signaling was attenuated while glucocorticoid signaling was elevated in Pygb-KI females during the lactation stage.

Conclusion: Our findings demonstrate that astrocytic glycogen depletion induces female-specific disruption of structural plasticity in astrocytes and synapses, with these morphological alterations correlating with sex-dimorphic abnormalities in anxiety-like and maternal behaviors. These results reveal a sexually dimorphic mechanism whereby astrocytic glycogen loss selectively impairs structural plasticity in females, thereby underscoring the critical role of glycogen homeostasis in female-specific neurobehavioral adaptations essential for species survival.