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The Role of Microglia in Brain Aging: A Focus on Sex Differences  

Jeffrey S. Darling, Kevin Sanchez, Andrew D. Gaudet, and Laura K. Fonken

Microglia, the primary innate immune cells of the brain, are critical for brain maintenance, inflammatory responses, and development in both sexes across the lifespan. Indeed, changes in microglia form and function with age have physiological and behavioral implications. Microglia in the aged brain undergo functional changes that enhance responses to diverse environmental insults. The heightened sensitivity of aged microglia amplifies proinflammatory responses, including increased production of proinflammatory cytokines and chemokines, elevated danger signals, and deficits in debris clearance. Elevated microglia activity and neuroinflammation culminate in neuropathology, including increased risk for neurodegenerative diseases and cognitive decline. Importantly, there are sex differences in several age-related neuroinflammatory pathologies. Microglia coordinate sex-dependent development within distinct brain structures and behaviors and are, in turn, sensitive to sex-specific hormones. This implies that microglia may confer differential disease risk by undergoing sex-specific changes with age. Understanding how aging and sex influence microglial function may lead to targeted therapies for age- and sex-associated diseases and disorders.


Role of Sex Hormones on Pain  

Dayna L. Averitt, Rebecca S. Hornung, and Anne Z. Murphy

The modulatory influence of sex hormones on acute pain, chronic pain disorders, and pain management has been reported for over seven decades. The effect of hormones on pain is clearly evidenced by the multitude of chronic pain disorders that are more common in women, such as headache and migraine, temporomandibular joint disorder, irritable bowel syndrome, chronic pelvic pain, fibromyalgia, rheumatoid arthritis, and osteoarthritis. Several of these pain disorders also fluctuate in pain intensity over the menstrual cycle, including headache and migraine and temporomandibular joint disorder. The sex steroid hormones (estrogen, progesterone, and testosterone) as well as some peptide hormones (prolactin, oxytocin, and vasopressin) have been linked to pain by both clinical and preclinical research. Progesterone and testosterone are widely accepted as having protective effects against pain, while the literature on estrogen reports both exacerbation and attenuation of pain. Prolactin is reported to trigger pain, while oxytocin and vasopressin have analgesic properties in both sexes. Only in the last two decades have neuroscientists begun to unravel the complex anatomical and molecular mechanisms underlying the direct effects of sex hormones and mechanisms have been reported in both the central and peripheral nervous systems. Mechanisms include directly or indirectly targeting receptors and ion channels on sensory neurons, activating pain excitatory or pain inhibitory centers in the brain, and reducing inflammatory mediators. Despite recent progress, there remains significant controversy and challenges in the field and the seemingly pleiotropic role estrogen plays on pain remains ambiguous. Current knowledge of the effects of sex hormones on pain has led to the burgeoning of gender-based medicine, and gaining further insight will lead to much needed improvement in pain management in women.


Behavioral Neuroendocrinology of Female Aggression  

Natalia Duque-Wilckens and Brian C. Trainor

Aggressive behavior plays an essential role in survival and reproduction across animal species—it has been observed in insects, fish, reptiles, and mammals including humans. Even though specific aggressive behaviors are quite heterogeneous across species, many of the underlying mechanisms modulating aggression are highly conserved. For example, in a variety of species arginine vasopressin (AVP) and its homologue vasotocin in the hypothalamus, play an important role in regulating aggressive behaviorssuch as territorial and inter male aggression. Similarly in the medial amygdala, activation of a subpopulation of GABAergic neurons promotes aggression, while the prefrontal cortex exerts inhibitory control over aggressive behaviors. An important caveat in the aggression literature is that it is focused primarily on males, probably because in most species males are more aggressive than females. However, female aggression is also highly prevalent in many contexts, as it can affect access to resources such as mates, food, and offspring survival. Although it is likely that many underlying mechanisms are shared between sexes, there is sex specific variation in aggression, type, magnitude, and contexts, which suggests that there are important sex differences in how aggression is regulated. For example, while AVP acts to modulate aggression in both male and female hamsters, it increases male aggression but decreases female aggression. These differences can occur at the extent of neurotransmitter or hormones release, sensitivity (i.e., receptor expression), and/or molecular responses.


An Overview of Sexual Differentiation of the Mammalian Nervous System and Behavior  

Ashley Monks

There is growing appreciation for the numerous and often dramatic differences in the nervous system of males and females and the importance of these sex differences for behavioral traits. Sex differences in the nervous system and behavior result from a process of sexual differentiation that is carried out by the interplay of genetic, hormonal, and environmental factors throughout the life span. Although the preponderance of mechanistic study of mammalian sexual differentiation has occurred in traditional laboratory rodents, this field of study has benefitted from comparative studies, which highlight the diversity in sexual polymorphism in vertebrates and also point to strongly conserved mechanisms whereby these sexually differentiated traits develop.


Drosophila Reward Circuits  

John S. Hernandez, Tariq M. Brown, and Karla R. Kaun

The ability to sense and respond to a rewarding stimulus is a key advantage for animals in their natural environment. The circuits that mediate these responses are complex, and it has been difficult to identify the fundamental principles of reward structure and function. However, the well-characterized brain anatomy and sophisticated neurogenetic tools in Drosophila melanogaster make the fly an ideal model to understand the mechanisms through which reward is encoded. Drosophila find food, water, intoxicating substances, and social acts rewarding. Basic monoaminergic neurotransmitters, including dopamine (DA), serotonin (5-HT), and octopamine (OA), play a central role in encoding these rewards. DA is central to sensing, encoding, responding, and predicting reward, whereas 5-HT and OA carry information about the environment that influences DA circuit activity. In contrast, slower-acting neuromodulators such as hormones and neuropeptides play a key role in both encoding the pleasurable stimulus and modulating how the internal environment of the fly influences reward sensation and seeking. Recurring circuit motifs for reward signaling identified in Drosophila suggest that these key principles will help elucidate understanding of how reward circuits function in all animals.


Neuroendocrine Influences on Human Sexuality  

Ashlyn Swift-Gallant and S. Marc Breedlove

While prenatal sex hormones guide the development of sex-typical reproductive structures, they also act on the developing brain, resulting in sex differences in brain and behavior in animal models. Stemming from this literature is the prominent hypothesis that prenatal neuroendocrine factors underlie sex differences in human sexual orientation, to explain why most males have a preference for female sexual partners (gynephilia), whereas most females display a preference for male sexual partners (androphilia). Convergent evidence from experiments of nature and indirect markers of prenatal hormones strongly support a role for prenatal androgens in same-same sexual orientations in women, although this finding is specific to a subset of lesbians who are also gender nonconforming (“butch”). More gender-conforming lesbians (“femmes”) do not show evidence of increased prenatal androgens. The literature has been more mixed for male sexual orientation: some report evidence of low prenatal androgen exposure, while others report evidence of high androgen levels and many other studies find no support for a role of prenatal androgen exposure in the development of androphilia in males. Recent evidence suggests there may be subgroups of gay men who owe their sexual orientation to distinct biodevelopmental mechanisms, which could account for these mixed findings. Although this research is young, it is similar to findings from lesbian populations, because gay men who are more gender nonconforming, and report a preference for receptive anal sex, differ on markers of prenatal development from gay men who are more gender conforming and report a preference for insertive anal sex. This chapter concludes with future research avenues including assessing whether multiple biodevelopmental pathways underlie sexual orientation and whether neuroendocrine factors and other biological mechanisms (e.g., immunology, genetics) interact to promote a same-sex sexual orientation.


Neuroendocrine and Neuroimmune Mechanisms Regulating the Blood-Brain Barrier  

Divine C. Nwafor, Allison L. Brichacek, Sreeparna Chakraborty, Catheryne A. Gambill, Stanley A. Benkovic, and Candice M. Brown

The blood-brain barrier (BBB) is a dynamic structural interface between the brain and periphery that plays a critical function in maintaining cerebral homeostasis. Over the past two decades, technological advances have improved our understanding of the neuroimmune and neuroendocrine mechanisms that regulate a healthy BBB. The combination of biological sex, sex steroids, age, coupled with innate and adaptive immune components orchestrates the crosstalk between the BBB and the periphery. Likewise, the BBB also serves as a nexus within the hypothalamic-pituitary-adrenal (HPA) and gut-brain-microbiota axes. Compromised BBB integrity permits the entry of bioactive molecules, immune cells, microbes, and other components that migrate into the brain parenchyma and compromise neuronal function. A paramount understanding of the mechanisms that determine the bidirectional crosstalk between the BBB and immune and endocrine pathways has become increasingly important for implementation of therapeutic strategies to treat a number of neurological disorders that are significantly impacted by the BBB. Examples of these disorders include multiple sclerosis, Alzheimer’s disease, stroke, epilepsy, and traumatic brain injury.


Regulation of Gonadotropins  

Daniel J. Bernard, Yining Li, Chirine Toufaily, and Gauthier Schang

The gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), are glycoproteins produced by gonadotrope cells of the anterior pituitary gland. The two hormones act on somatic cells of the gonads in both males and females to regulate fundamental aspects of reproductive physiology, including gametogenesis and steroidogenesis. In males, LH stimulates testosterone production and sperm maturation. FSH also regulates spermatogenesis, though the importance of the hormone in this process differs across species. In females, FSH stimulates ovarian follicle maturation. Follicles are structures composed of oocytes surrounded by two types of somatic cells, granulosa and theca cells. FSH stimulates granulosa cells to proliferate and to increase their production of the aromatase enzyme. LH stimulates theca cells to make androgens, which are converted into estrogens by aromatase in granulosa cells. A surge of LH also stimulates ovulation of mature follicles. Gonadotropin-releasing hormone (GnRH) from the brain is the principal stimulator of gonadotropin synthesis and secretion from the pituitary. The sex steroids (androgens and estrogens) that are produced by the gonads in response to the gonadotropins feedback to the brain and pituitary gland. In the brain, these hormones usually slow the release of GnRH through a process called negative feedback, which in turn leads to decreases in FSH and LH. The steroids also modulate the sensitivity of the pituitary to GnRH in addition to directly regulating expression of the genes that encode the gonadotropin subunits. These effects are gene- and species-specific. In females, estrogens also have positive feedback actions in the brain and pituitary in a reproductive cycle stage-dependent manner. This positive feedback promotes GnRH and LH release, leading to the surge of LH that triggers ovulation. The gonadotropins are dimeric proteins. FSH and LH share a common α-subunit but have hormone-specific subunits, FSHβ and LHβ. The β subunits provide a means for differential regulation and action of the two hormones. In the case of FSH, there is a second gonadal feedback system that specifically regulates the FSHβ subunit. The gonads produce proteins in the transforming growth factor β (TGFβ) family called inhibins, which come in two forms (inhibin A and inhibin B). The ovary produces both inhibins whereas the testes make inhibin B alone. Inhibins selectively suppress FSH synthesis and secretion, without affecting LH. The pituitary produces additional TGFβ proteins called activins, which are structurally related to inhibins. Activins, however, stimulate FSH synthesis by promoting transcription of the FSHβ subunit gene. Inhibins act as competitive receptor antagonists, binding to activin receptors and blocking activin action, and thereby leading to decreases in FSH. Together, GnRH, sex steroids, activins, and inhibins modulate and coordinate gonadotropin production and action to promote proper gonadal function and fertility.


Transcriptomic Architecture of Reproductive Plasticity  

Susan C. P. Renn and Nadia Aubin-Horth

Several species show diversity in reproductive patterns that result from phenotypic plasticity. This reproductive plasticity is found for example in mate choice, parental care, reproduction suppression, reproductive tactics, sex role, and sex reversal. Studying the genome-wide changes in transcription that are associated with these plastic phenotypes will help answer several questions, including those regarding which genes are expressed and where they are expressed when an individual is faced with a reproductive choice, as well as those regarding whether males and females have the same brain genomic signature when they express the same behaviors, or if they activate sex-specific molecular pathways to output similar behavioral responses. The comparative approach of studying transcription in a wide array of species allows us to uncover genes, pathways, and biological functions that are repeatedly co-opted (“genetic toolkit”) as well as those that are unique to a particular system (“genomic signature”). Additionally, by quantifying the transcriptome, a labile trait, using time series has the potential to uncover the causes and consequences of expressing one plastic phenotype or another. There are of course gaps in our knowledge of reproductive plasticity, but no shortage of possibilities for future directions.


Pain and Its Modulation  

Asaf Keller

Sensory perceptions are inherently subjective, being influenced by factors such as expectation, attention, affect, and past experiences. Nowhere is this more commonly experienced than with the perception of pain, whose perceived intensity and emotional impact can fluctuate rapidly. The perception of pain in response to the same nociceptive signal can also vary substantially between individuals. Pain is not only a sensory experience. It also involves profound affective and cognitive dimensions, reflecting the activation of and interactions among multiple brain regions. The modulation of pain perception by such interactions has been most extensively characterized in the context of the “descending pain modulatory system.” This system includes a variety of pathways that directly or indirectly modulate the activity of neurons in the spinal dorsal horn, the second-order neurons that receive inputs directly from nociceptors. Less understood are the interactions among brain regions that modulate the affective and cognitive aspects of pain perception. Emerging data suggest that certain pain conditions result from dysfunction in pain modulation, suggesting that targeting these dysfunctions might have therapeutic value. Some therapies that are thought to target pain modulation pathways—such as cognitive behavior therapy, mindfulness-based stress reduction, and placebo analgesia—are safer and less expensive than pharmacologic or surgical approaches, further emphasizing the importance of understanding these modulatory mechanisms. Understanding the mechanisms through which pain modulation functions may also illuminate fundamental mechanisms of perception and consciousness.


Integration of Peripheral and Central Systems in Control of Ingestive and Reproductive Behavior  

Jill E. Schneider

During the evolution of animals, survival and reproduction depended upon mechanisms that maintained internal homeostasis in the face of environmental change. These environmental changes included fluctuations in ambient temperature, food availability, humidity, day length, and population density. Most, if not all, of these variables have effects on the availability of energy, and most vertebrate species have mechanisms that sense energy availability and adjust behavioral priorities accordingly. For example, when the availability of food and potential mating partners is stable and abundant, brain mechanisms often inhibit ingestive behavior, increase energy expenditure, and give priority to courtship and mating. In response to severe energy shortages, brain mechanisms are likely to stimulate foraging, food hoarding, and overeating. These same deficits often delay reproductive development or inhibit adult reproductive behavior. Such adaptations involve the integration of sensory signals with peripheral hormone signals and central effectors, and they are key to understanding health and disease, particularly obesity, eating disorders, and diabetes. The link between energy balance and reproduction recurs repeatedly, whether in the context of the sensory-somatic system, the autonomic nervous system, or the neuroendocrine cascades. Peripheral signals that are detected by receptors on vagal and splanchnic nerves are relayed to the caudal hindbrain. This brain area contains the effectors for peripheral hormone secretion and for chewing and swallowing, and this same brain area contains receptors for humoral and metabolic signals from peripheral circulation. The caudal hindbrain is therefore a strong candidate for integration of multiple signals that control the initiation of meals, meal size, energy storage, and energy expenditure, including the energy expended on reproduction. There are some differences between the reproductive and ingestive mechanisms, but there are also many striking similarities. There are still gaps in our knowledge about the nature and location of metabolic receptors and the pathways to their effectors. Some of the most promising research is designed to shed light on how hormonal signals might be enhanced or modulated by the peripheral energetic condition (e.g., the level of oxidizable metabolic fuels).