Biology subjects

Baumgartner, N. E.

Publications and source records attributed to Baumgartner, N. E..

5 recordsLinked to original sources

bioRxiv2026

The lateral septum orchestrates state-dependent modulation of associative threat memory dynamics across the ovarian hormone cycle

Cycling ovarian hormones orchestrate neural states that greatly impact brain function and guide behavior. Here, we discover that cued threat memory processes are regulated across the mouse estrous cycle in a state-dependent manner. We show that low hormone states lead to overexpression of threat memory in females. However, high hormone states confer protection against this overexpression via state-dependent recruitment and reengagement of the lateral septum (LS) to the memory ensemble. Chemogenetic manipulations confirmed the LS as necessary and sufficient to suppress female memory overexpression. Single nucleus sequencing revealed a novel LS neuron population, defined by coexpression of neurotensin and somatostatin, selectively recruited to the female memory ensemble during high hormone states. This estradiol-sensitive population exhibits a female bias in projection strength to the nucleus accumbens and displays unique calcium dynamics associated with state-dependent memory suppression. Altogether, we uncover a sexually divergent neural mechanism whereby cycling ovarian hormones modulate memory expression.

neuroscience↗

bioRxiv2023

Sex differences in avoidance behavior and cued threat memory dynamics in mice: Interactions between estrous cycle and genetic background

Anxiety disorders are the most prevalent mental illnesses worldwide, exhibit high heritability, and affect twice as many women as men. To evaluate potential interactions between genetic background and cycling ovarian hormones on sex differences in susceptibility to negative valence behaviors relevant to anxiety disorders, we assayed avoidance behavior and cued threat memory dynamics in gonadally-intact adult male and female mice across four common inbred mouse strains: C57Bl/6J, 129S1/SVlmJ, DBA/2J, and BALB/cJ. Independent of sex, C57Bl/6J mice exhibited low avoidance but high threat memory, 129S1/SvlmJ mice high avoidance and high threat memory, DBA/2J mice low avoidance and low threat memory, and BALB/cJ mice high avoidance but low threat memory. Within-strain comparisons revealed reduced avoidance behavior in the high hormone phase of the estrous cycle (proestrus) compared to all other estrous phases in all strains except DBA/2J, which did not exhibit cycle-dependent behavioral fluctuations. Robust and opposing sex differences in threat conditioning and extinction training were found in the C57Bl/6J and 129S1/SvlmJ lines, whereas no sex differences were observed in the DBA/2J or BALB/cJ lines. C57Bl/6J males exhibited enhanced acute threat memory, whereas 129S1/SvlmJ females exhibited enhanced sustained threat memory, compared to their sex-matched littermates. These effects were not mediated by estrous cycle stage or sex differences in active versus passive defensive behavioral responses. Our data demonstrate that core features of behavioral endophenotypes relevant to anxiety disorders, such as avoidance and threat memory, are genetically driven yet dissociable and can be influenced further by cycling ovarian hormones.

animal behavior and cognition↗

bioRxiv2023

Sex differences in socioemotional behavior and changes in ventral hippocampal transcription across aging in C57Bl/6J mice

Socioemotional health is positively correlated with improved cognitive and physical aging. Despite known sex differences in socioemotional behaviors and trajectory of aging, the interactive effects between sex and aging on socioemotional outcomes are poorly understood. We performed the first comprehensive assessment of sex differences in socioemotional behaviors in C57Bl/6J mice across aging. Compared to males, females exhibited decreased anxiety-like behavior and social preference, but increased social recognition. With age, anxiety-like behavior, cued threat memory generalization, and social preference increased in both sexes. To investigate potential neural mechanisms underlying these behavioral changes, we analyzed transcriptional neuropathology markers in ventral hippocampus and found age-related changes in genes related to activated microglia, angiogenesis, and cytokines. Sex differences emerged in timing, direction, and magnitude of these changes, independent of reproductive senescence in aged females. Interestingly, female-specific upregulation of autophagy-related genes correlated with age-related behavioral changes selectively in females. These novel findings reveal critical sex differences in trajectories of ventral hippocampal aging that may contribute to sex- and age-related differences in socioemotional outcomes.

neuroscience↗

bioRxiv2022

History of previous midlife estradiol treatment permanently alters interactions of brain insulin-like growth factor-1 signaling and hippocampal estrogen synthesis to enhance cognitive aging in a rat model of menopause

Across species, including humans, elevated levels of brain estrogen receptor (ER) are associated with enhanced cognitive aging even in the absence of circulating estrogens. In rodents, short-term estrogen treatment--such as that commonly used in the menopausal transition--results in long-term increases in levels of ER in the hippocampus, leading to enhanced memory long after termination of estrogen treatment. However, mechanisms by which increased levels of brain ER enhances cognitive aging remain unclear. Here we show that in the hippocampus, insulin-like growth factor-1 (IGF-1)--which can activate ER via ligand-independent mechanisms--requires concomitant synthesis of brain-derived neuroestrogens to phosphorylate ER via MAPK signaling, ultimately resulting in enhanced memory. In a rat model of menopause involving long-term ovarian hormone deprivation, hippocampal neuroestrogen activity decreases, altering IGF-1 activity and resulting in impaired memory. However, this process is reversed by short-term estradiol treatment. Forty-days of estradiol exposure following ovariectomy results in maintenance of neuroestrogen levels that persist beyond the period of hormone treatment, allowing for continued interactions between IGF-1 and neuroestrogen signaling, elevated levels of hippocampal ER, and ultimately enhanced memory. Collectively, results demonstrate that short-term estradiol use following loss of ovarian function has long-lasting effects on hippocampal function and memory by dynamically regulating cellular mechanisms that promote activity of ER in the absence of circulating estrogens. Translational impacts of these findings suggest lasting cognitive benefits of short-term estrogen use near menopause and highlight the importance of hippocampal ER--independent from the role of circulating estrogens--in regulating memory in aging females. Significance statementDeclines in ovarian hormones following menopause coincide with increased risk of cognitive decline. Due to potential health risks, current recommendations are that menopausal estrogen therapy be limited to a few years. Long-term consequences for the brain and memory of this short-term midlife estrogen therapy are unclear. Here, in a rodent model of menopause, we determined mechanisms by which short-term midlife estrogen exposure can enhance hippocampal function and memory with cognitive benefits and molecular changes enduring long after termination of estrogen exposure. Our model indicates long-lasting benefits of maintaining hippocampal estrogen receptor function in the absence of ongoing estrogen exposure and suggests potential strategies for combating age-related cognitive decline.

neuroscience↗

bioRxiv2021

Previous estradiol treatment during midlife maintains transcriptional regulation of memory-related proteins by ERα in the hippocampus in a rat model of menopause

Previous midlife estradiol treatment, like continuous treatment, improves memory and results in lasting increases in hippocampal levels of estrogen receptor (ER) and ER-dependent transcription in ovariectomized rodents. We hypothesized that previous and continuous midlife estradiol act to specifically increase levels of nuclear ER, resulting in transcriptional regulation of proteins that mediate estrogen effects on memory. Ovariectomized middle-aged rats received estradiol or vehicle capsule implants. After 40 days, rats initially receiving vehicle received another vehicle capsule (Vehicle). Rats initially receiving estradiol received either another estradiol (Continuous Estradiol) or a vehicle (Previous Estradiol) capsule. One month later, hippocampal genes and proteins were analyzed. Continuous and previous estradiol increased levels of nuclear, but not membrane or cytosolic ER and had no effect on Esr1. Continuous and previous estradiol impacted gene expression and/or protein levels of mediators of estrogenic action on memory including ChAT, BDNF, and PSD-95. Findings demonstrate a long-lasting role for hippocampal ER as a transcriptional regulator of memory following termination of previous estradiol treatment in a rat model of menopause.

neuroscience↗