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

TL;DR

Glycogen depletion in astrocytes causes female-specific changes in brain structure and behavior, including anxiety and poor maternal care.

Contribution

This study reveals a sex-specific role of astrocytic glycogen in structural brain plasticity and maternal behavior.

Findings

Female Pygb-KI mice showed reduced astrocyte area, branching, and dendritic spine loss.

Glycogen depletion in astrocytes correlates with anxiety-like behaviors and maternal care deficits in females.

Offspring of Pygb-KI dams had reduced survival rates and social communication deficits.

Abstract

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.

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.

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.

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.

The online version contains supplementary material available at 10.1186/s13293-025-00723-6.

Glycogen deficiency in astrocytes correlates with glycolysis decrement in Pygb-KI mice.

Pygb-KI mice display female-specific decreases in area, branching, and length in astrocytes, and loss of mature dendritic spines in pyramidal neurons.

Glycogen depletion in astrocytes shows a female-biased association with anxiety-like behaviors, whereas depressive-like phenotypes remain unaffected across sexes.

Glycogen depletion in astrocytes is associated with maternal care obstacles, reduced survival rate and social communication ability of offspring, and disruptive hormonal signaling pathways in lactating mice.

Glycogen depletion in astrocytes triggers female-restricted remodeling of astrocytic and synaptic structures which correlate with exclusively female behavioral impairments.

The online version contains supplementary material available at 10.1186/s13293-025-00723-6.

Maternal care is a sex-dimorphic behavior that is necessary for survival and reproduction in species. At present, postpartum anxiety, depression as well as maternal care obstacles have become serious social problems that have garnered increasing public attention. It’s known that metabolic disorders in the brain are closely associated with mental illnesses. Brain glycogen serves as the largest on-demand energy source within the brain, predominantly stored in astrocytes and acts as a necessary component for synaptic formation and plasticity. Whether brain glycogen metabolism contributes to sex differences in emotional and maternal behaviors is unknown. Here, by generating a glycogen depletion model via a transgenic brain-type glycogen phosphorylase knock-in (Pygb-KI) method, we observed glycolysis decrement in both sexes. Furthermore, female-specific decreases in area, branching, and length in astrocytes, as well as loss of mature dendritic spines in pyramidal neurons were observed compared to male mice. Additionally, female Pygb-KI mice displayed anxiety-like behaviors in both virgin and reproductive periods. We also discovered maternal care deficits, reduced survival rate and social communication ability in pups, and dysregulations in neuronal hormonal signaling pathways in Pygb-KI lactating mice. These results may provide a perspective that targeting astrocytic glycogen metabolism may supply effective therapeutics for addressing postpartum anxiety and maternal behavioral deficits in clinical settings. But additional work is needed to investigate how astrocytic glycogen depletion triggers the neuronal plasticity and maternal behavioral phenotypes in females.

The online version contains supplementary material available at 10.1186/s13293-025-00723-6.

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