Androgens play a pivotal role during development. These gonadal hormones and their receptors exert organizational actions that shape brain morphology in regions controlling the stress regulatory systems in a male-specific manner. Specifically, androgens drive sex differences in the hypothalamic/pituitary/adrenal (HPA) axis and corresponding hypothalamic neuropeptides. While studies have examined the role of estradiol and its receptors in sex differences in the HPA axis and associated behaviors, the role of androgens remains far less studied. Androgens are generally thought to modulate the HPA axis through the activation of androgen receptors (ARs). They can also impact the HPA axis through reduction to estrogenic metabolites that can bind estrogen receptors in the brain and periphery. Such regulation of the HPA axis stress response by androgens can often result in sex-biased risk factors for stress-related disorders, such as anxiety and depression. This review focuses on the biosynthesis pathways and molecular actions of androgens and their nuclear receptors. The impact of androgens on hypothalamic neuropeptide systems (corticotropin-releasing hormone, arginine vasopressin, oxytocin, dopamine, and serotonin) that control the stress response and stress-related disorders is discussed. Finally, this review discusses potential therapeutics involving androgens (androgen replacement therapies, selective AR modulator therapies) and ongoing clinical trials.

The clustered regularly interspaced short palindromic repeat (CRISPR)/Cas system is best known for its role in genomic editing. It has also demonstrated great potential in nucleic acid biosensing. However, the specificity limitation in CRISPR/Cas has created a hurdle for its advancement. More recently, nucleic acid aptamers known for their high affinity and specificity properties for their targets have been integrated into CRISPR/Cas systems. This review article gives a brief overview of the aptamer and CRISPR/Cas technology and provides an updated summary and discussion on how the two distinctive nucleic acid technologies are being integrated into modern diagnostic and therapeutic applications

Infections during pregnancy are associated with increased risk for adult neuropsychiatric disease, such as major depressive disorder, schizophrenia, and autism spectrum disorder. In mouse models of maternal immune activation (MIA), different toll‐like receptors (TLRs) are stimulated to initiate inflammatory responses in mother and fetus. The goal of this study was to determine sex‐dependent aspects of MIA using a TLR7/8 agonist, Resiquimod (RQ), on neurodevelopment. RQ was administered to timed‐pregnant mice on embryonic day (E) 12.5. At E15, maternal/fetal plasma cytokines were measured by enzyme‐linked immunosorbent assay (ELISA). Maternal cytokines interleukin (IL)‐6 and IL‐10 were higher while tumor necrosis factor (TNF)‐α and IL‐17 were lower in pregnant dams exposed to RQ. Fetal cytokines (E15) were altered at the same timepoint with fetal plasma IL‐6 and IL‐17 greater after RQ compared to vehicle, while IL‐10 and TNF‐α were higher in male fetuses but not female. Other timed‐pregnant dams were allowed to give birth. MIA with RQ did not alter the female to male ratio of offspring born per litter. Body weights were reduced significantly in both sexes at birth, and over the next 5 weeks. Offspring from RQ‐injected mothers opened their eyes 5 days later than controls. Similarly, female offspring from RQ‐injected mothers exhibited pubertal delay based on vaginal opening 2–3 days later than control females. On the behavioral side, juvenile and adult male and female MIA offspring exhibited less social‐like behavior in a social interaction test. Anhedonia‐like behavior was greater in MIA adult female mice. This study provides support for sex‐dependent influences of fetal antecedents for altered brain development and behavioral outputs that could be indicative of increased susceptibility for adult disorders through immune mechanisms. Future studies are needed to determine neural cellular and molecular mechanisms for such programming effects.

The ventromedial prefrontal cortex (vmPFC) regulates fear acquisition, fear extinction, mood, and HPA axis function. Multiple brain regions exhibit time‐of‐day dependent variations in learning, long term potentiation (LTP), and dendritic morphology. Glucocorticoids have been implicated in the regulation of dendritic structure in the context of stress. Glucocorticoids are also known to regulate molecular clock entrainment via upregulation of Per1 transcription. In the present study, C57BL/6 N mice were sacrificed at three distinct times of day (ZT3, ZT12, and ZT16, lights off at ZT12) and Per1 mRNA expression was measured in the infralimbic and prelimbic vmPFC subregions using droplet digital (dd) PCR after recovering from adrenalectomy or sham surgery for 10 days. Sham mice showed Per1 rhythmicity in both infralimbic (IL) and prelimbic (PL) cortex, with peak expression occurring at ZT12. Adrenalectomized mice showed reductions in Per1 amplitude at ZT12 in both IL and PL, suggesting that the vmPFC molecular clock is entrained by diurnal glucocorticoid oscillations. Thy1‐eGFP mice were used to visualize and quantify dendritic spine density on deep layer pyramidal dendrites at ZT 3, 12, and 16. Spine density in both PL and IL exhibited changes between the light (inactive) and dark (active) phases, with peak spine density observed at ZT16 and trough spine density observed at ZT3. These changes in spine density were restricted to changes in long thin and stubby type spines. To determine if changes in spine density is regulated by glucocorticoid oscillations, the 11β‐hydroxylase inhibitor metyrapone was administered 2 h prior to the onset of the active phase (ZT10) daily for 7 days. Metyrapone administration blocked both the diurnal peak of plasma corticosterone and peak spine densities in the IL and PL at ZT16. These results suggest that vmPFC molecular clock gene and dendritic spine diurnal rhythms depend on intact diurnal glucocorticoid oscillations.

Developmental programming, a permanent adaptation of the fetus/neonate to maternal environmental signals, underlies many adult physiological and psychiatric disorders. Prenatal stress induced by the synthetic glucocorticoid dexamethasone has been shown to increase anxiety‐ and depressive‐like behaviors and lead to hyperreactive neuroendocrine and autonomic nervous system (ANS) responses to stress in adult female offspring. Prenatal stressors can also cause maternal immune activation (MIA), impact mood/stress circuitry, and program neural development. One way to engage molecular immune signals is to activate toll‐like receptors (TLRs). Developmental changes have been seen following gestational exposure to lipopolysaccharide (LPS; TLR4), poly I:C (TLR3), and, most recently, TLR7 agonists resiquimod (RQ) or imiquimod (IMQ). Studies have identified changes in ANS function that may be tied to blood–brain barrier (BBB) changes in the paraventricular nucleus of the hypothalamus (PVN) that coincide with anxiety‐ /depressive‐like behaviors that manifest after fetal programming. These adult dysfunctions are a consequence of prenatal stressors and may have a common underlying mechanism related to the dysregulation of communication between the PVN and critical ANS centers in the brainstem. Studies in humans indicate that brainstem loci may be important centers of ANS regulation that can be targeted to attenuate major depressive disorder (MDD) symptoms in adults. Furthermore, data suggest that select immune and BBB characteristics in PVN and autonomic nuclei in the brainstem are critical targets for future studies, aligning with the hypothesis that immune signaling plays a major role in the development and expression of psychiatric disorders. The overarching goal of this review is to outline the cellular and physiological pathways by which prenatal stressors, mainly synthetic glucocorticoid exposure and MIA, produce long‐term, sex‐biased programming of adult behavior and ANS function relevant to physiological and psychiatric disorders.