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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.

Article

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.

Article

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.

Article

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.

Article

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.

Article

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.