Sex Hormones and Cognition: Neuroendocrine Influences on Memory and Learning.

Sex differences in neurological disease exist in incidence, severity, progression, and symptoms and may ultimately influence treatment. Cognitive disturbances are frequent in neuropsychiatric disease with men showing greater cognitive impairment in schizophrenia, but women showing more severe dementia and cognitive decline with Alzheimer's disease. Although there are no overall differences in intelligence between the sexes, men, and women demonstrate slight but consistent differences in a number of cognitive domains. These include a male advantage, on average, in some types of spatial abilities and a female advantage on some measures of verbal fluency and memory. Sex differences in traits or behaviors generally indicate the involvement of sex hormones, such as androgens and estrogens. We review the literature on whether adult levels of testosterone and estradiol influence spatial ability in both males and females from rodent models to humans. We also include information on estrogens and their ability to modulate verbal memory in men and women. Estrone and progestins are common components of hormone therapies, and we also review the existing literature concerning their effects on cognition. We also review the sex differences in the hippocampus and prefrontal cortex as they relate to cognitive performance in both rodents and humans. There has been greater recognition in the scientific literature that it is important to study both sexes and also to analyze study findings with sex as a variable. Only by examining these sex differences can we progress to finding treatments that will improve the cognitive health of both men and women. © 2016 American Physiological Society. Compr Physiol 6:1295-1337, 2016.

Testosterone has antidepressant-like efficacy and facilitates imipramine-induced neuroplasticity in male rats exposed to chronic unpredictable stress.

Hypogonadal men are more likely to develop depression, while testosterone supplementation shows antidepressant-like effects in hypogonadal men and facilitates antidepressant efficacy. Depression is associated with hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and testosterone exerts suppressive effects on the HPA axis. The hippocampus also plays a role in the feedback regulation of the HPA axis, and depressed patients show reduced hippocampal neuroplasticity. We assessed the antidepressant-like effects of testosterone with, or without, imipramine on behavioral and neural endophenotypes of depression in a chronic unpredictable stress (CUS) model of depression. A 21-day CUS protocol was used on gonadectomized male Sprague-Dawley rats treated with vehicle, 1mg of testosterone propionate, 10mg/kg of imipramine, or testosterone and imipramine in tandem. Testosterone treatment reduced novelty-induced hypophagia following CUS exposure, but not under non-stress conditions, representing state-dependent effects. Further, testosterone increased the latency to immobility in the forced swim test (FST), reduced basal corticosterone, and reduced adrenal mass in CUS-exposed rats. Testosterone also facilitated the effects of imipramine by reducing the latency to immobility in the FST and increasing sucrose preference. Testosterone treatment had no significant effect on neurogenesis, though the combination of testosterone and imipramine increased PSA-NCAM expression in the ventral dentate gyrus. These findings demonstrate the antidepressant- and anxiolytic-like effects of testosterone within a CUS model of depression, and provide insight into the mechanism of action, which appears to be independent of enhanced hippocampal neurogenesis.

Enzymatic Depletion of the Polysialic Acid Moiety Associated with the Neural Cell Adhesion Molecule Inhibits Antidepressant Efficacy.

Antidepressant drugs are too often ineffective, the exact mechanism of efficacy is still ambiguous, and there has been a paucity of novel targets for pharmacotherapy. In an attempt to understand the pathogenesis of depression and subsequently develop more efficacious antidepressant drugs, multiple theories have been proposed, including the modulation of neurotransmission, the upregulation of neurogenesis and neurotrophic factors, normalizing hypothalamic-pituitary-adrenal reactivity, and the reduction of neuroinflammation; all of which have supporting lines of evidence. Therefore, an ideal molecular target for novel pharmaceutical intervention would function at the confluence of these theories. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) functions broadly, serving to mediate synaptic plasticity, neurogenesis, neurotrophic factor signaling, and inflammatory signaling throughout the brain; all of which are associated with the pathophysiology and treatment of depression. Moreover, the expression of PSA-NCAM is reduced by depression, and conversely enhanced by antidepressant treatment, particularly within the hippocampus. Here we demonstrate that selectively cleaving the polysialic acid moiety, using the bacteriophage-derived enzyme endoneuraminidase N, completely inhibits the antidepressant efficacy of the selective-serotonin reuptake inhibitor fluoxetine (FLX) in a chronic unpredictable stress model of depression. We also observe a corresponding attenuation of FLX-induced hippocampal neuroplasticity, including decreased hippocampal neurogenesis, synaptic density, and neural activation. These data indicate that PSA-NCAM-mediated neuroplasticity is necessary for antidepressant action; therefore PSA-NCAM represents an interesting, and novel, target for pharmacotherapy.

Androgen insensitive male rats display increased anxiety-like behavior on the elevated plus maze.

Male rats carrying the testicular feminization mutation (Tfm-affected males) are insensitive to androgens, resulting in a female-typical peripheral phenotype despite possession of inguinal testes that are androgen secretory. Androgen-dependent neural and behavioral processes may likewise show atypical sexual differentiation. Interestingly, these mutant rats display elevated serum corticosterone, suggesting a chronic anxiety phenotype and dysregulated hypothalamic-pituitary-adrenal axis. In order to understand if elevated anxiety-like behavior is a possible mediating variable affecting the display of certain androgen-dependent behaviors, we compared the performance of Tfm-affected males to wild type males and females in the elevated plus maze (EPM). Two well-established indicators of anxiety-like behavior in the EPM were analyzed: total percentage of time spent on the open arms, and the percentage of open arm entries. We also analyzed the total number of open arm entries. Interestingly, Tfm-affected males spent less percentage of time on the open arms than both males and females, suggesting increased anxiety-like behavior. Percentage of open arm entries and the total number of arm entries was comparable between the groups, indicating that the observed decrease in the percentage of time spent on the open arms was not due to a global reduction in exploratory behavior. These data, in contrast to earlier reports, thus implicate androgen receptor-mediated functions in the expression of anxiety behaviors in male rats. Given that anxiety is widely reported as a precipitating factor in depression, studying the role of the androgen receptor in anxiety may give insights into the pathogenesis of major depressive disorder.

Scheduled daily mating induces circadian anticipatory activity rhythms in the male rat.

Daily schedules of limited access to food, palatable high calorie snacks, water and salt can induce circadian rhythms of anticipatory locomotor activity in rats and mice. All of these stimuli are rewarding, but whether anticipation can be induced by neural correlates of reward independent of metabolic perturbations associated with manipulations of food and hydration is unclear. Three experiments were conducted to determine whether mating, a non-ingestive behavior that is potently rewarding, can induce circadian anticipatory activity rhythms in male rats provided scheduled daily access to steroid-primed estrous female rats. In Experiment 1, rats anticipated access to estrous females in the mid-light period, but also exhibited post-coital eating and running. In Experiment 2, post-coital eating and running were prevented and only a minority of rats exhibited anticipation. Rats allowed to see and smell estrous females showed no anticipation. In both experiments, all rats exhibited sustained behavioral arousal and multiple mounts and intromissions during every session, but ejaculated only every 2-3 days. In Experiment 3, the rats were given more time with individual females, late at night for 28 days, and then in the midday for 28 days. Ejaculation rates increased and anticipation was robust to night sessions and significant although weaker to day sessions. The anticipation rhythm persisted during 3 days of constant dark without mating. During anticipation of nocturnal mating, the rats exhibited a significant preference for a tube to the mating cage over a tube to a locked cage with mating cage litter. This apparent place preference was absent during anticipation of midday mating, which may reflect a daily rhythm of sexual reward. The results establish mating as a reward stimulus capable of inducing circadian rhythms of anticipatory behavior in the male rat, and reveal a critical role for ejaculation, a modulatory role for time of day, and a potential confound role for uncontrolled food intake.

Ontogeny of androgen receptor expression in spinal nucleus of the bulbocavernosus motoneurons and their target muscles in male mice.

The spinal nucleus of the bulbocavernosus (SNB) in rodents is a neuromuscular system consisting of lumbar motoneurons and the perineal muscles they innervate, the bulbocavernosus and levator ani. This system is present prenatally in both males and females but degenerates postnatally in females because of the lack of perinatal androgens. Whether androgens act on the motoneurons or muscles in the SNB system to promote survival is a longstanding question. Evidence in rats suggests androgens act primarily on the muscles in development, given that the muscles express androgen receptor (AR) before the critical period of androgen-dependent cell rescue, whereas motoneurons develop AR after this period. We now report, based on a novel AR-reporter mouse model, that AR is expressed in the bulbocavernosus muscles of C57/BL6(J) mice as early as embryonic day 15, while, based on AR-immunocytochemistry, SNB motoneurons do not express AR until postnatal day 4. These results indicate that the ontogeny of AR expression in the mouse SNB system resembles that found in rats, suggesting that androgens may also act on perineal muscles in mice to rescue the SNB system.

The testosterone two-step is really a minuet.

Newly developed genetic models indicate that estrogen receptors (ERs) alone mediate prenatal masculinization of the mouse brain to organize reproductive and territorial behaviors, while postnatal activation of androgen receptors (ARs) potentiates specific components of those behaviors. These results and others offer a model of how AR and ER pathways interact to fully masculinize the brain and behavior of male mice.

Time course of adult castration-induced changes in soma size of motoneurons in the rat spinal nucleus of the bulbocavernosus.

The spinal nucleus of the bulbocavernosus (SNB) innervates striated muscles, the bulbocavernosus and levator ani (BC/LA), which control penile reflexes. Castration results in shrinkage in the size of SNB somata and dendrites, as well as BC/LA muscle mass. However, there is no information about how quickly these regressive changes occur compared to the rapid effects of castration upon penile reflexes, which are greatly diminished a few days after surgery. Therefore we examined the time course of change in the size of SNB somata after castration of adult male rats. Males were sacrificed 2, 14, or 28 days after either castration or sham surgery and somata were measured in the SNB and in a control population of motoneurons, the retrodorsolateral nucleus (RDLN). BC/LA weight was reduced in castrates compared to intact males 14 and 28 days post surgery, but SNB somata were significantly smaller in castrates only at 28 days after surgery. As has been previously observed, castration did not affect soma size in the RDLN. These data indicate that SNB somata respond more slowly after castration than BC/LA mass or penile reflexes, suggesting that the size of SNB somata cannot account for the loss of penile reflexes. Androgenic effects on SNB somata may contribute to aspects of reproductive behavior that are not apparent in penile reflexes tested ex copula.

Partner preference and mount latency are masculinized in androgen insensitive rats.

The sexual motivation of male rats may be inferred from a preference to stay in proximity to estrous female partners, and also from a short latency to show mounting behavior. Here, partner preference was assessed in rats carrying the testicular feminization mutation (TFM), and compared to wild type (WT) males in one version of this paradigm, and WT females and males in another version. Additionally, mount latency was quantified in the TFMs and compared to WT males in order to assess arousal levels, as this has not been previously reported. When presented with a choice between proximity to an estrous or non-estrous female, WT males and TFMs demonstrated similar preferences for the estrous female. Estrous females, conversely, preferred to spend time with the WT male. In agreement with previous reports we observed several sexual performance deficits in the TFMs, but mount latencies were in the male range. Given that the TFMs reliably choose to spend time with the estrous female in the partner preference tests, and that they display normal arousal levels (reflected in masculinized mount latencies), the data suggest the motivation to engage in sexual behavior is masculine in the TFM rat and that possession of functional androgen receptors is not crucial in these behaviors.

Analysis of Foxp2 expression in the cerebellum reveals a possible sex difference.

Deletion of the gene Foxp2 affects ultrasonic vocalizations and induces morphological abnormalities in the Purkinje cell layer of the cerebellum in mice. Castration decreases the production of ultrasonic vocalizations in rats, but the mechanisms of androgenic regulation of ultrasounds are unknown. We explored a possible relationship between Foxp2 expression and androgens in the Purkinje cell layer of wild-type and androgen-insensitive male rats, as well as estrous and nonestrous female rats. Analyses of relative optical densities of Foxp2 immunoreactivity revealed significantly greater immunolabeling in the wild-type and testicular feminization mutation-affected male rats (which did not differ from each other) than in either the estrous or nonestrous female rats (which similarly did not differ from each other). These data suggest a sex difference in Foxp2 expression in the cerebellum.

Neural correlates of arousal-induced circadian clock resetting: hypocretin/orexin and the intergeniculate leaflet.

In Syrian hamsters, some procedures for stimulating behavioural arousal (e.g. running in a novel wheel and sleep deprivation by gentle handling with minimal activity) markedly phase-advance circadian rhythms when applied during the middle of the daily rest period, while other arousal procedures do not (e.g. physical restraint, caffeine and modafinil). The neural basis for this differential effect of arousal procedures on clock resetting is unknown. We used c-fos expression as a marker for neuronal activation to determine whether these arousal procedures differentially activate two nonphotic inputs to the circadian system, the thalamic intergeniculate leaflet (IGL; a proposed nonphotic gateway to the circadian clock) and the hypothalamic hypocretin system (which depolarizes arousal-related cell groups throughout the brain and innervates both the IGL and the peri-suprachiasmatic nucleus region). c-FOS in hypocretin-1-immunoreactive neurons, in hypothalamic nonhypocretin neurons and in the IGL was significantly increased by novel wheel running, gentle handling and physical restraint, but only weakly by systemic injections of modafinil (300 mg/kg) or caffeine (75 mg/kg), at doses that are strongly alerting. Spatial analysis revealed few regional differences in the percentage of cells double-labelled for hypocretin-1 and c-FOS following each treatment. These results suggest that activation of hypocretin neurons (as in the restraint condition) is not sufficient to induce phase shifts, and that gating of arousal effects on circadian clock phase may be downstream from the hypocretin system and from IGL neurons activated by these procedures.

Regional brainstem expression of Fos associated with sexual behavior in male rats.

This study utilized Fos expression to map the distribution of activated cells in brainstem areas following masculine sexual behavior. Males displaying both appetitive and consumatory sexual behaviors (Cop) were compared to animals prevented from copulation (NC) and to socially isolated (SI) animals. Following copulation, Fos was preferentially augmented in the caudal ventral medulla (CVM), a region mediating descending inhibition of penile reflexes, and which may be regulated by a forebrain circuit that includes the medial preoptic area (MPOA). Copulation-induced Fos was observed in the medial divisions of both the dorsal cochlear nucleus (DC) and trapezoid bodies (Tz), areas which are part of a circuit processing auditory information. In addition, the medullary linear nucleus (Li) displayed comparable amounts of Fos in Cop and NC as compared to the SI animals. Other regions of the pontomedullary reticular system, which may mediate sleep and arousal, did not exhibit Fos expression associated with consumatory sexual behavior. We suggest that Fos is associated with the inhibition of sexual behavior following ejaculation in the CVM, and that auditory information arising from the DC and Tz is combined with copulation-related sensory information in the subparafasicular nucleus and projected to the hypothalamus. In addition, equal amounts of Fos expression observed in the Li in both the Cop and NC animals suggests that this region is involved in sexual arousal. Overall, the data suggest that processing by brainstem nuclei directly contributes to the regulation of mating behavior in male rats.

Lumbar motoneuron fate in a mouse model of amyotrophic lateral sclerosis.

Onuf's nucleus, a collection of motoneurons within the spinal cord, is often spared in the neurodegenerative disorder amyotrophic lateral sclerosis. To assess whether these cells survive in a rodent model of this disease, motoneurons were counted in the spinal nucleus of the bulbocavernosus (an homologous structure to Onuf's), as well as in two other cell groups at the same level of the spinal cord, the dorsolateral nucleus and the retrodorsolateral nucleus. In mice displaying signs of neurodegeneration, both the dorsolateral and retrodorsolateral nuclei displayed significant motoneuron loss compared to controls; this cell loss was particularly exaggerated in the retrodorsolateral nucleus of animals displaying a rapid disease progression. However, no significant decline in motoneuron number was observed in the spinal nucleus of the bulbocavernosus, and the perineal muscle bulbocavernosus, which is innervated by this nucleus, appeared to be unaffected. This was in stark contrast to the thigh muscles, which displayed significant atrophy. Overall, these data indicate that the spinal nucleus of the bulbocavernosus is spared from degeneration in an animal model of amyotrophic lateral sclerosis, paralleling observations in patients suffering from this disease. Further study of this resistance to motoneuron loss may provide useful insights into the pathophysiology of the degenerative process.