Overall, these findings highlight the dynamic changes occurring in dopaminergic neurotransmission in the cortex at adolescence and suggest that such changes may play a role in the functional maturation of the cortex. A–c Developmental changes in expression of mRNA transcripts and proteins in the dopamine and stress signaling pathways in the human PFC. Human cortical DR1 mRNA and protein do not attain adult levels until late adolescence/early adulthood (Fig. 2) (Rothmond et al. 2012; Weickert et al. 2007). The midbrain dopaminergic neural circuitry consists of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA), and dopamine-responsive neurons in the PFC, nucleus accumbens (NAc), hippocampus, entorhinal cortex, amygdala, and striatum (Fig. 1). Additional studies reveal ERβ expression in the dorsal raphe nucleus (DRN) of male and female mice (Alves et al., 1998). This activation stimulates the protein tyrosine kinase/mitogen-activated protein kinase (Boonyaratanakornkit and Edwards, 2007) and occurs through interactions with the metabotropic glutamate receptors (Tonn Eisinger et al., 2018). This can occur through a process called transcriptional cross-talk, where signaling happens via protein–protein interaction between receptors (Göttlicher et al., 1998). Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5α-dihydrotestosterone (5α-DHT) by the cytoplasmic enzyme 5α-reductase. Androgens such as testosterone have also been found to bind to and activate membrane androgen receptors. A few studies indicate that the testosterone derivative estradiol might play an important role in male aggression. The masculinization of the brain is not just mediated by testosterone levels at the adult stage, but also testosterone exposure in the womb. The reflexive testosterone increases in male mice is related to the male's initial level of sexual arousal. Addiontally, genetic techniques used to block hippocampal neurogenesis in transgenic mice were shown to impair memory acquisition and retention on the water maze , and similar results were obtained using a lentiviral technique to reduce neurogenesis in rats . For example, rats that engaged in the hippocampus-dependent Morris water maze had more neurogenesis in the dentate gyrus than did rats engaging in a cued version of the water maze that is hippocampus independent 139,140,141. On the other hand, environmental enrichment increases hippocampal neurogenesis and improves performance on hippocampus-dependent tasks 136,137,138. Similarly, decreased performance on spatial memory tasks correlates with decreased adult neurogenesis among aged rodents 8,134,135. It has long been known that the hippocampus plays a critical role in spatial memory formation 128,129,130, and so it is not surprising that most work testing the function of hippocampal neurogenesis has involved testing rodents in spatial memory tasks . Biological sex, a category that generally includes male, female, and intersex, classifies organisms based on anatomical, reproductive, and genetic characteristics. Many of us think of hormones as chemical messengers that arrive during puberty to govern our reproductive development. Food and Drug Administration issued a black box warning for TRT due to the increased risk of cardiovascular events, like ischemic stroke or myocardial infarction . In contrast, transdermal options—such as gels and patches—provide more stable hormone levels and are linked to the lowest cardiovascular risk. This is attributed to the increased access to hormonal supplements via online shops, increased awareness around presentation of hypogonadism, and marketing of TRT for cosmetic indications or as an anti-aging supplement. Table 1 summaries the role of androgen in various neurological disorders. Studies have shown that epileptiform discharges, specifically from the temporal lobe, can influence the hypothalamic-pituitary-adrenal axis and produce symptoms secondary to sex-hormone imbalance. Men taking testosterone replacement must be carefully monitored for prostate cancer. There are times when low testosterone is not such a bad thing. Affected women may experience low libido, reduced bone strength, poor concentration or depression. Testosterone may prove to be an effective treatment in female sexual arousal disorders, and is available as a dermal patch. In addition, a continuous increase in vaginal sexual arousal may result in higher genital sensations and sexual appetitive behaviors. There is a time lag effect when testosterone is administered, on genital arousal in women. Androgens may modulate the physiology of vaginal tissue and contribute to female genital sexual arousal. Testosterone levels follow a circadian rhythm that peaks early each day, regardless of sexual activity. Adult neurogenesis occurs in most mammalian species studied to date 14,15, but the amount of neurogenesis declines with increasing age and, because of this, the functional significance of adult neurogenesis in humans remains controversial . Determining the neural mechanisms by which new memories are formed is a fundamental question in the field of neurobiology, and the study of adult neurogenesis has provided exciting new insights that directly address this question 1,2. Most evidence indicates that androgens selectively enhance the survival of newly generated neurons, while having little effect on cell proliferation.
