Chapter Six - Effects of Estrogens on Central Nervous System Neurotransmission: Implications for Sex Differences in Mental Disorders

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Abstract

Nearly one of every five US individuals aged 12 years old or older lives with certain types of mental disorders. Men are more likely to use various types of substances, while women tend to be more susceptible to mood disorders, addiction, and eating disorders, all of which are risks associated with suicidal attempts. Fundamental sex differences exist in multiple aspects of the functions and activities of neurotransmitter-mediated neural circuits in the central nervous system (CNS). Dysregulation of these neural circuits leads to various types of mental disorders. The potential mechanisms of sex differences in the CNS neural circuitry regulating mood, reward, and motivation are only beginning to be understood, although they have been largely attributed to the effects of sex hormones on CNS neurotransmission pathways. Understanding this topic is important for developing prevention and treatment of mental disorders that should be tailored differently for men and women. Studies using animal models have provided important insights into pathogenesis, mechanisms, and new therapeutic approaches of human diseases, but some concerns remain to be addressed. The purpose of this chapter is to integrate human and animal studies involving the effects of the sex hormones, estrogens, on CNS neurotransmission, reward processing, and associated mental disorders. We provide an overview of existing evidence for the physiological, behavioral, cellular, and molecular actions of estrogens in the context of controlling neurotransmission in the CNS circuits regulating mood, reward, and motivation and discuss related pathology that leads to mental disorders.

Introduction

Nearly one of every five individuals aged 12 years old or older lives with certain types of mental disorders in the United States.1, 2 Mental illnesses, including substance use disorders such as drug addiction and opioid abuse, mood disorders, and eating disorders affect millions of people and are prominent public health threats due to their increasing prevalence, difficulty in prevention and treatment, and cost (hundreds of billions of US dollars are spent to care for the patients with mental disorders).3 Additionally, many mental disorders are associated with suicide attempts.4 Therefore, mental disorders take a heavy toll on public health and human lives with enormously high economic costs. We are in a drastic need of a better understanding of the underlying neurobiological mechanisms behind these disorders.

Several neural circuits within the central nervous system (CNS) regulate mood, reward, and motivation and are modulated by different types of stimuli that individuals respond to by exhibiting certain behaviors. These different types of reward stimuli that function as reinforcers to modulate reward circuits include natural rewards (e.g., food and sex) and nonnatural rewards (e.g., drug, alcohol, and money). Different types of rewards function as stimuli to provide pleasure, enjoyment, and arousal to individuals. While appropriate behavioral responses to reward are beneficial for survival, improper responses to reward, for example, dysregulation of neurotransmitters within the reward circuitry, could be detrimental. As an example, palatable foods high in calories are a strong reinforcer of neural circuits that control feeding behavior. Rogers and Smit termed compulsive seeking of natural food reward “food addiction,”5 which could lead an individual to develop certain eating disorders and obesity. Similarly, uncontrolled compulsive nonnatural reward seeking contributes to destructive substance overuse, potentially leading to substance addiction. Therefore, dysregulation of the CNS reward system serves as a biological factor contributing to the increased prevalence of substance use disorders and related addictions, as well as eating disorders and related obesity.

The reward system includes various brain anatomical regions and pathway structures in the CNS. The reward system is modulated by various neurotransmitters and neuromodulators, including dopamine (DA), serotonin (5HT), glutamate, and gamma-aminobutyric acid (GABA), and is influenced by circulating hormones, including satiety signals, adiposity signals, and stress hormones, to alter responses to various types of rewards.6 The neural structures of the reward system are similar across species.6 Animal species from Drosophila to humans share a core set of conserved genes.7 Accordingly, neural networks of the reward system also share conserved gene expression profiles across species.8 As animals evolved, different selection pressures likely acted on distinct brain regions.8 Males and females have dissimilar internal homeostatic states and physiological needs to maintain energy homeostasis9 and thus would have distinct responses to various types of reward stimuli. Due to specific societal niches occupied by each sex, selection pressures have had disparate impacts on underlying neural circuitry between the sexes. Although reward system structures are similar between males and females, functional modulation of shared circuitry by brain chemical messengers is different between the sexes10 (see Section 2). Additionally, sex hormones interact with these chemical messengers to alter functions between the sexes (see Section 3). Furthermore, there may be more anatomical structural and pathway differences in the CNS reward circuitry between males and females than initially realized. Therefore, it may become cumbersome to define discrete functional differences due to modulations vs intrinsic structural differences in brain circuitry between the sexes.

The CNS reward system drives the relationship between reward stimuli from the external environment and the internal state of individuals as regulated by homeostatic mechanisms. Motivation to gain reward stimuli from the external environment can change depending on internal physiological state of individuals and established associations between external stimuli and reward circuitry from prior contexts. Therefore, within the CNS, information of external stimuli and internal state of individuals converges in the regulatory control regions (such as the hypothalamus and the brainstem) and reward regions that integrate with one another to communicate needs vs costs and evaluate specific reward stimuli, as reciprocal feedback signals are sent between the regulatory control regions and reward regions. Maladjustment of neural circuits of the CNS reward system by either highly palatable foods or drugs of abuse is expected in both eating disorders and substance abuse disorders11 and is evidenced by their high comorbidity rates.12

In most of the available literature, areas of the CNS that drive hedonic regulation of food reward by palatable foods13 and areas that drive homeostatic control of feeding have been studied independently from one another. In actuality, the hedonic circuitry regulating reward responses and the homeostatic circuitry regulating feeding overlap and directly influence one another, depending on each other for proper functioning14, 15 (see Section 2.1). To successfully drive appropriate behavior to physiologically maintain whole-body metabolic homeostasis, integration of hedonic reward regions and homeostatic feeding regions with brain areas and neural circuits important for regulating emotion and decision making, along with motor circuits controlling execution of the behaviors, occurs to change feeding, energy expenditure, and foraging behavior (see Section 2.1). Such motivational responses due to modified reward circuits are beneficial and necessary for individuals to engage in specific behaviors in order to stay fit and survive. Eating palatable foods, engaging in sexual activity and reproductive behavior, and taking alcohol or other drugs, however, could change neurotransmitter function and neural activity and modify the reward system.16 While some of these changes could be beneficial, others may be detrimental.

It is noteworthy that cross-sensitization between different types of natural and nonnatural reward stimuli take place.17 For example, addiction to a natural reward and overuse of a nonnatural reward could strengthen each other, leading to comorbidity between eating disorders and substance use disorders.18 This cross-sensitization could be due to distinctive types of natural and nonnatural rewards converging on and activating common neural pathways. Even though distinct rewards may activate similar, overlapping anatomical brain structures, discrete neurochemical modulation may be involved. A better understanding of the reward system at both structural and molecular levels would contribute to our understanding of how different reward stimuli and substances modify reward circuits, leading to mental disorders such as depression, anxiety, and food and substance addictions. While many studies have demonstrated external effects modulating reward circuitry as a means to phenotypes of depression, anxiety, and other mental disorders, it is important to note that such effects occur both ways. Chronic stress can lead to increased anxiety and inhibit expectations of reward.19 People can be genetically predisposed to dysregulation of neurotransmitters involved in reward and limbic responses and therefore develop depression and anxiety. In fact, there are many dysregulations commonly linked to depression, not limited to but including monoamine, glutamate, neurotropic, and epigenetic dysregulation.20 Depression can increase the odds for becoming obesity and having obesity can increase the odds of developing depression.21 Responses to depression can either decrease or increase appetite, with brain regions associated with reward being more active to food cues in depressed appetite-increase patients compared to depressed appetite-decrease patients.22

The prevalence and types of mental disorders differ significantly between men and women. Fundamental sex differences are present in the development of eating disorders, obesity-related metabolic diseases, and substance use disorders. Abundant evidence has established that women are more frequently diagnosed with psychiatric illnesses, in particular eating disorders, anxiety, and depression, compared to men.23, 24 Indeed, the prevalence of eating disorders, depression, and anxiety is about threefold higher in women than in men.25, 26 Although eating disorders, such as anorexia nervosa and bulimia nervosa27, 28 and obesity,29 are more prevalent in women than in men, the incidence of metabolic disorders is more common in men than in women, potentially due to sex differences in fat distribution and energy metabolism.9, 30 While men are more likely to use various types of substances,31 women can become addicted more rapidly from casual drug use and tend to be more susceptible to some key phases of addiction, such as craving and relapse.32, 33, 34 Among mental disorders, mood disorders are the most strongly associated with suicidal attempts.4 Women have an increased risk of attempting suicide in the general population.35 Published studies in the literature have indicated that while men are at a greater risk of completing suicide than women, the prevalence of attempted suicide is significantly higher in women than in men among the US population.35 Although many factors contribute to the prevalence of mental disorders, it is noteworthy that the prevalence of mental disorders is especially high in women during reproductive years following puberty,36 suggesting that elevated and cyclic sex hormone estrogens could predispose women at reproductive ages to develop mental disorders. Furthermore, major drops in estrogen during menopausal or postpartum periods are also suggestive of an increased propensity for developing mental disorders.37, 38

It is not suppressing that sex differences exist in almost all aspects of reward- and motivation-related processes. Males and females perceive stimuli and process reward information in different ways and consequently carry out different behaviors based on their sex-specific roles. Specifically, males of many species play important roles in hunting and gathering, as well as territorial defense and protection, whereas females of many species play important roles in gestation, lactation, and caregiving.9 Therefore, in order to optimize fitness, males and females would need to respond in different ways to metabolic and psychological stressors. Accordingly, decision making and related behaviors in response to these external and internal pressures would need to be different. Therefore, different selection pressures due to the evolutionary origins of sex-specific reproductive roles and physiological needs of each sex have shaped physiological metabolic responses, psychological decision making, and other behavioral responses between males and females, in addition to neural circuitry. Consequential sex differences seen in susceptibility to psychiatric disorders such as addiction, eating disorders, and mood disorders, along with metabolic disorders, are also apparent.

Importantly, not all sex differences in physiology and behavior are due to differences in socioeconomic status or cultural experience. Sex chromosomes and sex hormones contribute to sex-specific brain differentiation and brain activation during development and adulthood (see Section 2) and distinct sex hormone actions between the sexes play critical roles in the CNS reward system (see Section 3). These sex differences suggest underlying dissimilarities in the brain reward circuitry.30, 39 Specifically, dysfunction of reward circuitry is heavily implicated in addiction to food and drugs. The potential mechanisms for sex differences in addiction processes and motivational behavior are not well understood. The initiative undertaken by the US National Institutes of Health (NIH) to take sex differences into account in biomedical research is relatively recent.40 Uniform investigations into understanding the sex differences in reward circuitry have yet to take place, particularly for mechanistic molecular studies regarding processes involved in CNS neurotransmission.

Estrogens are central to physiological regulation and pathological processes during health and disease in both sexes. This includes behavioral responses involving the CNS reward system, tested using both animal and human models.41 We aim to provide the readers with an overview of current knowledge surrounding sex differences in neural circuits of the reward system involving neurotransmission in the CNS. We discuss central estrogenic action in reward-related behavior based on key brain regions and neural pathways involving the neurotransmitters DA, 5HT, glutamate, GABA, and endocannabinoids, with some directly but others indirectly activated by estrogens. For examples of how these reward regions and pathways have been implicated in a variety of mental disorders including depression, see reviews 42, 43. It is important to note that many other neurotransmitters in the brain, such as norepinephrine,44 acetylcholine,45 histamine,46 and endogenous opioids,47 have been either directly or indirectly implicated in reward regulation and/or show sex differences. Additionally, androgens play vital roles in regulating the reward system48 and also are outside the scope of this chapter.

In this chapter, we first introduce the interconnected circuitry, including brain structures, neural pathways, and neurotransmitters. We review the studies that have investigated the roles of estrogens and their receptors in the regulation of activities and functions of neural pathways involved in reward processing. We then discuss current knowledge and questions about estrogenic actions in these pathways, and how these actions are involved in the regulation of reward, focusing on different brain regions and pathways of the reward circuit, involving various neurotransmitters, some directly but others indirectly activated by estrogens.

Although sex dimorphism is known for some circuits, it remains unknown in many other brain regions and pathways. Recent NIH policy promotes studies of animals and cells from both sexes and requests researchers to consider sex as a biological variable.40 However, uniform practices in studying sex differences are not always followed. For example, many times researchers may include both males and females in their studies without actually taking sex differences into account. Nevertheless, we can speculate that more sex differences will be reported as more uniform investigations utilizing both males and females in biomedical research take place. Such sex differences could be anatomical in structure and morphology, or functional sex differences due to different modulation of the same anatomical structures by sex hormones. This review highlights gaps in the literature due to a lack of examining sex differences and focuses on the effects of estrogens on reward-related brain functioning. In light of vulnerability to mental disorders, such as mood disorders, eating disorders, and substance use disorders among females, future studies should try to understand these sex differences.

Section snippets

Structurally Interconnected Circuitry

Recent studies highlight how brain regions and pathways traditionally studied in terms of discrete functions are currently known as interconnected circuits. For example, connections between metabolic, reward, emotional, and behavioral circuits are discussed with implications for comorbidity witnessed in mood and metabolic disorders.49, 50, 51, 52, 53, 54 Similarly, therapeutic implications for a better understanding of eating disorders and associated obesity, either hedonic or homeostatic

Overview of Effects of Estrogens on Neurotransmission-Mediated CNS Circuitry

Traditional neurotransmitters, such as DA, glutamate, GABA, and 5HT, and nontraditional neurotransmitters such as endocannabinoids, along with their receptors and transporters, are expressed in different brain regions that are interconnected parts of the reward system (Fig. 2), regulating mood- and reward-related behavior. The same neurotransmitters can be used in multiple pathways of the reward system. For example, DA can be used in mesolimbic and mesocortical pathways (see Section 3.2).

Conclusions

The culmination of human and animal studies from recent decades has revealed extensive sex differences in CNS neurotransmission and neural circuits in different species, many of which are regulated by estrogens. These studies have provided considerable mechanistic insight, underpinning essential differences in central neural circuit regulation of physiology and behavior involving various neurotransmitters between males and females. However, further work remains in order to reveal the cellular

Acknowledgments

This work was supported by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (DK090823), and the American Heart Association (16GRNT31110008) to H.S., and doctoral fellowship from the Department of Biology to K.N.K. and Q.Z.

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