Genotype- and Age-Dependent Differences in Ultrasound Vocalizations of SPRED2 Mutant Mice Revealed by Machine Deep Learning.

Juvenile manifestation of ultrasound communication deficits in the neuroligin-4 null mutant mouse model of autism

The hypothalamic pituitary adrenal (HPA) axis responds to environmental perturbations to maintain homeostasis. Pregnancy demands extensive modifications in HPA axis function to prepare for increased energy and metabolic demands required to meet the needs of mother and offspring. Short-term effects of pregnancy on the HPA axis have been shown, but data is lacking regarding the long-term effects in middle-aged female mice no longer breeding. Since changes of the HPA axis are further found with age, in this study, we examined both parity- and age-related interactions on the HPA axis in female mice. Wildtype C57bl/6N females were divided into nulliparous young (NY) (3-6 mo) and nulliparous middle-aged (NM) or multiparous retired-breeder middle-aged (RBM) (8-10 mo) groups. RBM mice were killed at least 4 weeks after their last litter was weaned. Control mice were euthanized directly out of the home cage and experimental groups were euthanized at 0 min, 30 min, or 90 min recovery (n=8-10/ group) after 2h of multi-modal stress (MMS; restraint, noise, shaker, light). (Paraventricular nucleus of the hypothalamus (PVN) neuronal activity was quantified by c-FOS immunoreactivity (-ir), and plasma corticosterone (CORT) levels were measured by radioimmunoassay. Corticotropin releasing hormone (CRH) mRNA was assayed by in situ hybridization. Two-way ANOVA showed effects of age (p<0.0248), parity (p<0.0021), time (p<0.0001), and interaction (p<0.0009) on CORT levels. Specifically, basal CORT levels were reduced in NM/RBM versus NY mice. In all groups, CORT levels were significantly elevated by MMS. There was no difference between CORT levels immediately after MMS in NY or NM groups, but CORT levels after 30- and 90- min recovery from MMS remained elevated in NM, indicating reduced negative feedback with age. Additionally, RBM plasma CORT was further reduced in all time groups versus NM, accompanied by a return to baseline CORT after 90 min recovery, suggesting a parity-dependent effect on the HPA axis. Changes in CORT levels were correlated with c-FOS-ir. MMS increased PVN c-FOS-ir in all groups compared to controls and c-FOS-ir in NM was significantly greater than PVN c-FOS of RBM. Further, while c-FOS-ir in the NY females was reduced to baseline 30 min after MMS, the return to baseline was more gradual in NM. No effect of parity or age was seen in Crh mRNA. Collectively, our findings show that activation of the HPA axis in females involves interactions between age- and parity- dependent function. Our findings further show activation and inhibition of the HPA axis in females involving long-term changes that occur after pregnancy, which may increase risk for stress- or postpartum- related disorders. Supported by NIDDK 1-R01 DK105826

A social recognition test for female mice reveals behavioral effects of developmental chlorpyrifos exposure

Gonadal hormones play a key role in the establishment, activation, and regulation of the hypothalamic–pituitary–adrenal (HPA) axis. By influencing the response and sensitivity to releasing factors, neurotransmitters, and hormones, gonadal steroids help orchestrate the gain of the HPA axis to fine-tune the levels of stress hormones in the general circulation. From early life to adulthood, gonadal steroids can differentially affect the HPA axis, resulting in sex differences in the responsivity of this axis. The HPA axis influences many physiological functions making an organism’s response to changes in the environment appropriate for its reproductive status. Although the acute HPA response to stressors is a beneficial response, constant activation of this circuitry by chronic or traumatic stressful episodes may lead to a dysregulation of the HPA axis and cause pathology. Compared to males, female mice and rats show a more robust HPA axis response, as a result of circulating estradiol levels which elevate stress hormone levels during non-threatening situations, and during and after stressors. Fluctuating levels of gonadal steroids in females across the estrous cycle are a major factor contributing to sex differences in the robustness of HPA activity in females compared to males. Moreover, gonadal steroids may also contribute to epigenetic and organizational influences on the HPA axis even before puberty. Correspondingly, crosstalk between the hypothalamic–pituitary–gonadal (HPG) and HPA axes could lead to abnormalities of stress responses. In humans, a dysregulated stress response is one of the most common symptoms seen across many neuropsychiatric disorders, and as a result, such interactions may exacerbate peripheral pathologies. In this review, we discuss the HPA and HPG axes and review how gonadal steroids interact with the HPA axis to regulate the stress circuitry during all stages in life.

Immune-toxicity effects of scorpion venom on the hypothalamic pituitary adrenal axis during rest and activity phases in a rodent model

Clinical literature indicates there may be a therapeutic use of cannabidiol (CBD) for stress-related disorders. Preclinical literature remains conflicted regarding the underlying neurobehavioral mechanisms, reporting mixed effects of CBD (increased, decreased, or no effect) on anxiety- and fear-related behaviors. Preclinical data demonstrated that CBD modulates hypothalamus-pituitary-adrenal (HPA) axis gene expression; it is unknown whether CBD changes HPA axis responsivity and how this relates to altered behavior. We aimed to evaluate whether acute or chronic CBD administration would alter physiological and behavioral measures of HPA axis responsivity in male or female mice. C57BL/6 mice of both sexes were injected with vehicle or CBD (30mg/kg, i.p.) daily for 26days. Plasma corticosterone (CORT) levels were evaluated following dexamethasone suppression and adrenocorticotropin hormone stimulation tests after acute and chronic CBD exposure. After chronic CBD, mice were tested for anxiety-like behavior using an elevated plus maze (EPM) and associative fear learning and memory using a trace fear conditioning (FC) protocol. Compared to vehicle, CBD induced a state of HPA axis hyperactivation, an effect which was significant in males; it also normalized anxiety-like behavior in female mice classified as having HPA axis hypofunction and primed all female mice for enhanced conditioned responding. Significant sex differences were also detected: females had greater plasma CORT levels and HPA axis responsivity than males, exhibited less EPM anxiety-like behavior, and were more responsive during FC. CBD potentiated physiological and behavioral markers of HPA axis function and normalized anxiety-like behavior in a sex-specific manner. This observation has implications for cannabinoid-based drug development targeting individuals with stress-related disorders involving HPA axis hypofunction pathology.

Sexually Dimorphic Patterns of Episomal rAAV Genome Persistence in the Adult Mouse Liver and Correlation With Hepatocellular Proliferation

Comprehensive Study for Breast Cancer Using Deep Learning and Traditional Machine Learning

Advancements in Deep Learning Algorithms is a comprehensive exploration of the cutting-edge developments in deep learning, a subset of artificial intelligence that has revolutionized the way machines learn from data. This book starts with the basics, introducing the reader to the fundamental concepts and terminologies of deep learning, before delving into the core algorithms that form the backbone of this field, including neural networks, convolutional neural networks (CNNs), recurrent neural networks (RNNs), and generative adversarial networks (GANs). It further explores advanced architectures and techniques such as attention mechanisms, deep reinforcement learning, federated learning, and autoencoders, providing a deep dive into the mechanisms that enable machines to mimic human-like learning processes. The book also addresses critical aspects of data handling and preprocessing, optimization and regularization techniques, and the practical applications of deep learning in various industries, highlighting real-world case studies. Additionally, it discusses the challenges, ethical considerations, and future implications of deploying deep learning technologies. With an eye towards recent trends and the future directions of deep learning, this book aims to equip researchers, practitioners, and enthusiasts with the knowledge to understand and leverage the potential of deep learning in solving complex problems. Keywords: Deep Learning, Neural Networks, Convolutional Neural Networks (CNNs), Recurrent Neural Networks (RNNs), Generative Adversarial Networks (GANs), Attention Mechanisms, Deep Reinforcement Learning, Federated Learning, Autoencoders, Data Preprocessing, Optimization Techniques, Artificial Intelligence, Industry Applications, Ethical Considerations, Future Directions.

Adrenocorticotropin (ACTH) and corticosterone secretion by perifused pituitary and adrenal glands from rodents exposed to 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD)

Disclosure: C. Ratner: Cecilia Ratner is emplyoed at Lundbeck A/S. V. Nielsen: Vibeke Nielsen is employed at Lundbeck A/S. M. Lubas: Michal Lubas is employed at Lundbeck A/S. M. Grupe Frost: Morten Grupe Frost is employed at Lundbeck A/S. A. Asuni: Ayodeji Asuni is employed at Lundbeck A/S.Elevated systemic glucocorticoid levels often result from exogenous glucocorticoid therapy, certain endocrine disorders such as Cushing’s syndrome and Cushing’s disease or in some psychiatric disorders with hypothalamic pituitary adrenal (HPA) axis overactivity including certain types of depression. In the present study, we aimed to assess how different treatment paradigms of chronic excess of glucocorticoids influence the dynamics of the HPA axis in a mouse model of exogenous corticosterone (CORT) treatment. CORT was administered to male C57Bl6/J mice for a duration of 21 days using three different treatment paradigms: Via the drinking water (80µg/ml), by subcutaneous pellet (7.5mg over 21 days) or by a combination of water (26.7µg/ml) and pellet (5mg over 21 days). Body weight was recorded throughout the study. Blood was sampled on day 7 and day 15 in the early light phase and just before lights out for CORT measurements. Mice were sacrificed on day 24 and pituitary glands were collected for gene expression analysis.To assess the reactivity of the HPA axis a separate cohort of mice treated with CORT pellets were subjected to acute restraint stress for 30 min on day 25 (4 days after end of CORT treatment). CORT treatment led to significantly lower body weight in some groups at select time points, but all groups showed trends toward lower body weight compared to control mice. All three types of CORT treatment resulted in increased plasma CORT levels in the early light phase on day 7 and day 15 compared to controls, while dark phase plasma CORT was similar between all groups. Overall, CORT levels were similar between the three treatment paradigms, but the water CORT group showed larger variability. CORT treatment reduced pituitary corticotropin releasing hormone receptor 1 (CRHR1) mRNA levels with no effect on proopiomelanocortin or glucocorticoid receptor mRNA levels. Treatment with CORT in the water reduced the vasopressin 1b receptor mRNA levels, which may be due to lower overall water intake. CORT treatment by subcutaneous pellets completely blocked the reactivity of the HPA axis to acute restraint stress. Overall, the three CORT treatment paradigms gave rise to similar results. The pellet treatment may be advantageous to obtain less variability in the model due to differences in water intake. CORT treatment gave rise to changes in the HPA axis including a significant downregulation of CRHR1, which may contribute to the lack of responsivity to acute stressorsPresentation: Sunday, July 13, 2025

Myostatin signaling governs neonatal longitudinal muscle growth and neuromuscular contractures in a sex-dependent manner, identifying a potential avenue for contracture treatment and underscoring the need to consider sex as a biological variable in the pathophysiology of acquired neuromuscular disorders.

Myostatin signaling governs neonatal longitudinal muscle growth and neuromuscular contractures in a sex-dependent manner, identifying a potential avenue for contracture treatment and underscoring the need to consider sex as a biological variable in the pathophysiology of acquired neuromuscular disorders.

Magnesium deficiency induces anxiety and HPA axis dysregulation: Modulation by therapeutic drug treatment

Glucocorticoid receptors (GR) in the paraventricular nucleus of the hypothalamus (PVN) are important regulators of negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Previous evaluation of endogenous PVN GR function in adult mice demonstrated that mice with loss of GR exon 3 in the PVN (Sim1Cre-GRe3Δ) have a hyperactive HPA axis, growth impairment and metabolic disruptions. Here, we hypothesized that lack of negative feedback inhibition of the HPA axis through PVN GR, as demonstrated through loss of PVN GR early in life, will have developmental-stage-specific consequences. Immunofluorescence revealed that Sim1Cre-GRe3Δ mice display PVN GR loss as early as post-natal day 2 compared to control mice. Sim1Cre-GRe3Δ mice compared to controls also displayed increased corticotropin-releasing hormone (CRH) mRNA in the PVN at post-natal day 10, as shown by in situ hybridization. Corticosterone radioimmunoassay revealed that the disruptions in PVN GR and CRH expression led to elevated basal corticosterone secretion in male Sim1Cre-GRe3Δ mice by early adolescence and increased stress-induced (restraint) corticosterone secretion in late adolescence into adulthood. In comparison, female Sim1Cre-GRe3Δ mice did not display corticosterone disruption until adulthood. Circadian rhythmicity of corticosterone secretion was normal for male and female mice at all age groups regardless of genotype with one exception. In late adolescence, female Sim1Cre-GRe3Δ mice had disrupted circadian corticosterone secretion due to significantly elevated circulating levels at nadir. We conclude that PVN GR function matures at an earlier developmental time point in male than in female mice and thus leads to later differential stress responsiveness between sexes.