Serotonin and the neurobiology of anxious states

C H A P T E R

29 Serotonin and the neurobiology of anxious states Adam J. Lawther1, Matthew W. Hale1, Christopher A. Lowry2,* 1

School of Psychology and Public Health, La Trobe University, Bundoora, VIC, Australia; 2Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder, CO, United States *Corresponding author.

I. INTRODUCTION A. Aims and scope of the chapter Anxiety in humans is an emotion, usually associated with increased autonomic and behavioral arousal, and an increase in vigilance and avoidance behavior (American Psychological Association, 2018; LeDoux & Pine, 2016; Lowry, Johnson, Hay-Schmidt, Mikkelsen, & Shekhar, 2005; Lowry & Hale, 2010). Anxious states have been modeled in nonhuman animals as the expression of defensive behaviors in response to threat (Blanchard, 2017; Blanchard & Blanchard, 2008). These behaviors are dependent on the distal or proximal nature of a real or perceived threat (i.e., the defensive distance), are highly adaptive, and serve to minimize exposure to threat. In preclinical models, defensive behaviors are controlled by a distributed and interconnected network of brain regions (Hale, Shekhar, & Lowry, 2012), and it is hypothesized that dysregulation of homologous networks in humans gives rise to anxiety disorders, such as agoraphobia, generalized anxiety disorder (GAD), panic disorder, separation anxiety disorder, social anxiety disorder, and specific phobia (Lang, McTeague, & Bradley, 2014; Sylvester et al., 2012). Serotonergic systems are important modulators of the brain regions involved in the control of anxious states in humans and anxiety-related defensive behaviors in nonhuman animals, although the precise mechanisms of control require further investigation. This chapter has four aims: (1) to define anxious states and anxietyrelated behavior in humans and how these behaviors can be modeled by assessment of anxiety-related behavior in preclinical animal models; (2) to highlight the opposing roles of serotonin on anxiety-related behavior and the integration of both appetitive and aversive signaling in key serotonergic nuclei; (3) to outline

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several key brain regions involved in the control of anxiety-related behavior and the effect of serotonin signaling within these regions; and (4) to demonstrate that serotonergic signaling within this network moderates distinct processes contributing to expression of anxiety-related behavior.

II. DEFINITIONS OF ANXIOUS STATES AND ANXIETY-RELATED BEHAVIOR Although the terms “fear” and “anxiety” are often used interchangeably, evidence demonstrates that people distinguish between the facial expressions of fear and anxiety (Perkins, Inchley-Mort, Pickering, Corr, & Burgess, 2012), suggesting these emotional states are at least partly distinct. Expressions elicited in response to a description of an ambiguous threat, for example, increased eye darting and scanning, are labeled as “anxiety” by participants naı¨ve to the described situation (Perkins et al., 2012). In contrast, expressions elicited in response to a description of an unambiguous threat are labeled as “fear” by participants naı¨ve to the described situation (Perkins et al., 2012). These findings are consistent with the suggestion that anxiety-related behaviors arise in situations where the potential threat is uncertain or ambiguous (Blanchard & Blanchard, 2008; LeDoux & Pine, 2016; Lowry et al., 2005), whereas fear-related behaviors are responses to proximal or unambiguous threat (Blanchard & Blanchard, 2008; LeDoux & Pine, 2016). Importantly, human behaviors that arise from anxiogenic stimuli, such as increased avoidance and increased risk assessment, and behaviors that arise from fearful stimuli, such as freezing and defensive attack, can also be modeled in animals (Blanchard, 2017).

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FIGURE 29.1 Anxious and fear states in humans can be modeled in nonhuman animals as the expression of defensive behaviors in response to distal or proximal threat, respectively, and the neuronal circuits that control these behaviors can be studied in the laboratory. For an animal that perceives a distal threat, an adaptive strategy is the expression of anxiety-related defensive behavioral responses, i.e., behaviors that serve to avoid the potential threat, such as open-area avoidance, avoidance of brightly lit spaces (in the case of nocturnal animals), or social avoidance. However, in the presence of a proximal threat, an adaptive strategy is the expression of fear-related defensive behavioral responses, in order to cope with the threat. Depending on the context, animals can adopt a proactive coping strategy, e.g., flight/escape or defensive aggression, or a reactive coping strategy, e.g., freezing or submission.

Recent consideration has been given to emotionally linked terminology to describe behavior in animals that cannot self-report internal states, such as anxiety or fear (LeDoux & Pine, 2016). With this in mind, we use the terms “anxiety-related behavior” and “fearrelated behavior” to distinguish the expression of behaviors in response to a potential or imminent threat, respectively (Fig. 29.1), from the internal emotional states of anxiety and fear. With these limitations in mind, we use “anxiety-related behavior” to refer to any behavior employed to avoid exposure to potential threat. In contrast, we use “fear-related behavior” to refer to any behavior employed to cope with a proximal, unavoidable threat. Depending on the environmental context, both anxiety- and fear-related behaviors can be adaptive behavioral strategies. Within this framework, preclinical models of anxiety-related behavior include avoidance behavior (i.e., open-arm avoidance in the elevated plus-maze [EPM], centerzone avoidance in the open-field, light avoidance in a light/dark box for nocturnal animals) and vigilance behavior, such as increased scanning of the environment (Blanchard, 2017). Fear-related behaviors include active coping strategies and passive coping strategies

(Koolhaas, 2008). Active coping strategies allow an animal to maintain some level of control over the outcome of interaction with an immediate threat, such as defensive fighting or flight responses in a resident-intruder paradigm, or swimming or climbing in the forced swim test (FST). Passive coping strategies relinquish control to the immediate threat, and include freezing or submission in the resident-intruder paradigm, immobility in the FST, or learned helplessness behaviors (Koolhaas, de Boer, Coppens, & Buwalda, 2010). When an organism is exposed to an imminent or proximal threat in time or space, rather than a potential or distal one, an adaptive behavioral strategy is the expression of fear-related behavior. In other words, the organism needs to behave to cope in situations with a high probability of an aversive outcome. Anxiety-related behavioral responses frequently involve a conflict between approach and avoidance; this conflict arises in situations involving a degree of uncertainty about the likely outcomes of any behavioral strategies. However, most environments contain the potential for both appetitive and aversive outcomes, resulting in a conflict between approach and avoidance behavior. The key component of approacheavoidance

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FIGURE 29.2 Illustration of a model of approacheavoidance conflict. In a highly predictable environment, the individual is faced with a straightforward behavioral strategy, i.e., approach appetitive stimuli, or avoid aversive stimuli. However, complex environments often contain the potential for both rewarding and aversive outcomes. Therefore, approach or avoidance will be influenced by the perceived outcome probability of a given behavioral strategy. As the perceived probability of aversive outcomes increases, so does the expression of avoidance behavior. As the perceived probability of appetitive outcomes increases, so does approach behavior. Adapted, with permission from Lowry & Hale (2010).

conflict is uncertainty as to the outcome of any given behavioral strategy when both appetitive and aversive outcomes are possible. Classically, approacheavoidance conflict has been conceptualized as “anxiety-like behavior” in the laboratory, and these behaviors are sensitive to drugs that modify anxious states in humans (Olivier, Vinkers, & Olivier, 2013). In addition to uncertainty, the relative strength of appetitive and aversive stimuli moderate the expression of anxiety-related behavior. Appetitive value influences approach behavior, i.e., an animal is more likely to approach a large food reward over a small food reward. Aversive value influences avoidance behavior; for example, rats show reduced open-field exploration in high- versus low-light conditions (Bouwknecht et al., 2007). In situations of uncertainty, the behavioral strategy (approach/avoid) will be a trade-off between appetitive and aversive value (Fig. 29.2). For example, if food is abundant and an animal’s appetite is satiated, the aversive value of predation will be stronger than the appetitive value of food and the animal can wait for times of reduced predation risk to access food (facilitation of anxiety-related behavior). Conversely, if food is scarce, the appetitive value of food becomes stronger and may overpower the aversive value of potential predation, resulting in increased risk-taking behavior (inhibition of anxietyrelated behavior).

III. ASSOCIATION BETWEEN SEROTONIN AND ANXIETY AND ANXIETY-RELATED DEFENSIVE BEHAVIORAL RESPONSES Gene
environment interactions are important determinants of anxious states in humans and the expression of anxiety-related defensive behavioral responses in nonhuman animals. The serotonin transporter (SERT) regulates serotonin signaling by rapidly transporting extracellular serotonin into the presynaptic terminal. This transporter is the primary target of selective serotonin reuptake inhibitors (SSRIs), which are among the frontline pharmacological treatments for anxiety disorders in humans (Nutt, 2005). Allelic variation in the SERT-linked polymorphic region (5-HTTLPR) results in differential expression of SERT and serotonin reuptake efficiency (Lesch et al., 1996). The 5-HTTLPR is typically categorized into short (S: lower SERT expression) and long (L: higher SERT expression) alleles, although multiple subvariants exist within these categories (Nakamura, Ueno, Sano, & Tanabe, 2000). Importantly, people with the SS genotype are more susceptible to the development of anxiety disorders following adverse early life experiences (Liu et al., 2018; Talati et al., 2017). Although further research is needed, this evidence is consistent with a role for serotonergic modulation of anxious states in humans.

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While population-based studies demonstrate a link between serotonergic signaling and anxious states, these studies are confounded by variability in life experience and genetic heterogeneity. Inbred rodent strains offer tight control over these factors, and modern gene editing technologies have improved understanding of how genes controlling serotonergic signaling affect anxietyrelated behavioral responses in these animals. The Tph2 gene encodes the tryptophan hydroxylase 2 (TPH2) protein, the brain-specific isoform of the ratelimiting enzyme in the biosynthesis of serotonin (Walther et al., 2003). Polymorphisms in the Tph2 gene are associated with changes in anxiety-related behavior in animals (Michalikova, van Rensburg, Chazot, & Ennaceur, 2010; Russo et al., 2018) and anxious states in humans (Chi et al., 2013; Laas et al., 2017). For example, a viral knock-in of a humanized TPH2 mutation (R439H) in mice causes substantial reduction of serotonin synthesis in both heterozygous and homozygous animals and results in increased light avoidance in the lightedark box test, compared to controls (Beaulieu et al., 2008). While these data suggest that decreased serotonin synthesis results in an increase in anxiety-related behavior, the role of serotonin in the control of anxious states and anxiety-related defensive behavioral responses is complex. For example, Tph2 knockout mice are devoid of brain serotonin, yet do not display increased anxiety-related behavior (AngoaPerez et al., 2012; Mosienko et al., 2012). Functional anatomical studies further implicate serotonergic systems in the control of anxiety-related behavior (for review, see Hale et al., 2012). For example, tests of approach/avoidance conflict increase activation of serotonin neurons, measured using activitydependent gene expression (e.g., c-Fos), including the EPM test (Grahn et al., 2018; Lawther et al., 2015, 2018), the open-field test (Bouwknecht et al., 2007), and treatment with anxiogenic dugs in the home cage environment (Abrams et al., 2005). Furthermore, the anxiolytic effects of chronic SSRI exposure in mice are associated with changes in c-Fos expression in distinct subregions of the dorsal raphe nucleus (DR; Payet et al., 2018). While these studies demonstrate a role for serotonin systems in the expression of anxiety-related behavioral responses, they lack the control needed to understand the precise mechanisms involved. Modern gene editing techniques allow precise temporal and target-specific control over these systems. These approaches have established a direct role for serotonergic signaling in the control of these behaviors. In order to understand the complex and opposing roles of serotonergic signaling on anxious states in humans and anxiety-related defensive behavioral responses in nonhuman animals, we first need to briefly consider anatomical organization of the serotonergic

raphe nuclei, as well as the complex patterns of afferent/efferent innervation of these nuclei.

IV. FUNCTIONAL SUBSETS OF SEROTONERGIC NEURONS The dorsal and median raphe nuclei (DR and MnR, respectively) provide the majority of serotonergic forebrain innervation and contain functionally and anatomically distinct subregions (Fig. 29.3A; for review, see Hale & Lowry, 2011; Lowry, 2002), which are in part determined by developmental lineage (Jensen et al., 2008; Okaty et al., 2015). Recent reviews suggest that the serotonergic MnR and caudal third of the DR (B8 and B6, respectively) project preferentially to the septohippocampal system, while the midrostrocaudal and rostral DR (B7) project preferentially to the extended amygdala, striatum, and cortex (Commons, 2015, 2016). Adding to the complexity of serotonergic forebrain projections, viral-based tracing studies demonstrate a clear topographic organization of serotonergic neurons across the anterioreposterior and dorsale ventral axes of the DR. For example, serotonergic neurons in the dorsal parts of the DR project preferentially to subcortical targets, such as the amygdala complex, and serotonergic neurons in the ventral parts of the DR preferentially target cortical regions (Ren et al., 2018). This complexity is further reflected in the regions innervating the serotonergic raphe neurons (Weissbourd et al., 2014), and these complex patterns of afferent/ efferent innervation likely underlie the diverse and, in some cases, opposing roles attributed to serotonergic function.

V. CONTROL OF SOCIAL BEHAVIOR BY SEROTONERGIC NEURONS IN THE DR The role of serotonergic systems in the control of anxiety-related behaviors is complex, and serotonin can facilitate or inhibit anxiety-related behavior, depending on the environmental or neurobiological context. To illustrate the opposing roles of serotonergic signaling on behavior, we will use the effects of stressinduced changes in serotonergic signaling on sociability as an example. Serotonergic signaling from the DR can promote social approach, as well as social avoidance. Chronic social defeat stress (CSDS) decreases the excitability of serotonergic neurons in the DR (Challis et al., 2013) and results in an adaptive increase of social avoidance (Challis et al., 2013). During the sensory contact phase, a period necessary for the behavioral effects of CSDS,

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FIGURE 29.3 Serotonergic neurons throughout the dorsal and median raphe nuclei are organized into topographically and functionally distinct subregions. (A) Topographically and functionally distinct subregions of the dorsal and median raphe nuclei include the rostral dorsal raphe nucleus, dorsal part (DRD) and rostral dorsal raphe nucleus, ventral part (DRV) (left panel), the midrostrocaudal DRD and DRV (directly beneath the DRD) and dorsal raphe nucleus, ventrolateral part (DRVL; middle panel), and the dorsal raphe nucleus, caudal part (DRC) and dorsal raphe nucleus, interfascicular part (DRI) at the more caudal level (right panel), as well as the MnR more ventrally. Serotonergic neurons from these regions project broadly throughout the central nervous system. These neurons provide the majority of serotonergic innervation to the forebrain, including the basolateral amygdala BLA, bed nucleus of the stria terminalis (BNST), habenula (Hb), medial prefrontal cortex (mPFC), nucleus accumbens (NAcb), and periaqueductal gray (PAG). Photomicrographs show the DR of a male rat at three rostrocaudal levels; e7.46 mm, e8.18 mm, and e8.54 mm from bregma. Scale bar, 200 mm. (B) Serotonergic signaling promotes behavioral adaptation through actions with in the mPFC, social behavior through actions with in the NAcb, aversive memory formation through actions with in the BLA, behavioral inhibition through actions with in the PAG, approach and avoidance behavior through actions with in the BNST, and can potentiate and inhibit aversive signaling from the LHb. Abbreviations: BNST, bed nucleus of the stria terminalis; BLA, basolateral amygdala; DR, dorsal raphe nucleus; Hb, habenula; mPFC, medial prefrontal cortex; NAcb, nucleus accumbens; PAG, periaqueductal gray.

inhibition of DR gamma aminobutyric acid (GABA)ergic neurons prevents subsequent decreases in sociability (Challis et al., 2013), while activation of these neurons during sensory contact mimics the effects of CSDS in undefeated mice (Challis, Beck, & Berton, 2014). Moreover, deep brain stimulation of the medial prefrontal cortex (mPFC) in CSDS-exposed mice restores, i.e., increases, DR serotonergic activity and sociability (Veerakumar et al., 2014), suggesting that serotonin signaling inhibits development of CSDS-induced social avoidance. In contrast, exposure to inescapable shock (IS) stress increases DR serotonergic neuron activation (Christianson et al., 2008; Kubala, Christianson, Kaufman,

Watkins, & Maier, 2012), increases serotonin release in targets of the DR (Amat et al., 2001; Dolzani et al., 2016), and results in decreased social interaction when assessed 24 h later in a model of learned helplessness. Importantly, inhibition of DR serotonergic neurons by local activation of 5-HT1A inhibitory autoreceptors prevents IS-induced reductions in social behavior (Christianson et al., 2008, 2010), suggesting that activation of serotonergic neurons in the DR increases anxiety-like defensive behavioral responses and impairs sociability. However, photoactivation of DR serotonergic neurons also promotes sociability and social preference (Walsh et al., 2018). Together, this shows that the CSDS

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paradigm promotes social avoidance through decreases in serotonergic signaling (Challis et al., 2013), whereas uncontrollable stress promotes social avoidance through increases in serotonergic activity (Christianson et al., 2010). This evidence demonstrates that serotonin signaling can enhance social approach and social avoidance behavior. If the hypothesis that serotonergic signaling bidirectionally moderates approacheavoidance conflict is correct, then different populations of serotonergic neurons should respond to appetitive and aversive cues.

VI. APPETITIVE AND AVERSIVE STIMULI ALTER SEROTONERGIC NEURON ACTIVITY Serotonergic neurons respond to multiple aspects of appetitive and aversive information. Evidence shows that populations of serotonergic neurons are activated in response to aversive environments and outcomes, whereas others are activated in response to appetitive stimuli (Cohen, Amoroso, & Uchida, 2015; Li et al., 2016). Earlier work in nonhuman primates established the involvement of putative serotonergic DR neurons in processing reward information (Nakamura, Matsumoto, & Hikosaka, 2008). Neurons in the DR respond to reward-predicting cues and respond differentially to the actual reward size; that is, some neurons respond to receipt of small rewards, while others respond to receipt of large rewards (Nakamura et al., 2008). Further work demonstrated that some DR neurons increase activity upon presentation of rewardpredicting cues and upon receipt of the reward, while other DR neurons decrease activity in response to cues predicting no-reward (Bromberg-Martin, Hikosaka, & Nakamura, 2010; Inaba et al., 2013). Activity in these neurons is moderated by the temporal proximity of the reward (Inaba et al., 2013). While these observations suggest the specific involvement of serotonergic neurons in reward processing, electrophysiological identification of serotonergic neurons during in vivo recording is not always reliable (Allers & Sharp, 2003), and, therefore, further research is required to confirm the serotonergic or nonserotonergic phenotype of the DR neurons studied in these paradigms. More recent studies demonstrate involvement of genetically identified serotonergic neurons in the DR in processing multiple aspects of both appetitive and aversive stimuli. For example, DR serotonergic neurons increase firing rates in response to reward- or punishment-predicting cues and predicted, but not omitted, outcomes (Cohen et al., 2015; Miyazaki et al., 2018), suggesting these neurons are not signaling prediction error. Furthermore, reward- or punishment-

responsive DR serotonergic neurons increased tonic firing rate during reward or punishment blocks, suggesting they encode appetitive and aversive values over short and long timescales (Cohen et al., 2015). An elegant series of experiments by Li et al. (2016) using in vivo Ca2þ imaging of DR serotonergic neurons showed that these neurons respond to diverse reward types, including social, sex, food, and sucrose rewards. Moreover, these neurons respond with increased tonic firing in anticipation of appetitive outcomes and phasic firing following receipt of appetitive stimuli, and encode the appetitive value of the outcome (Li et al., 2016). These findings suggest that DR serotonergic neurons signal general, rather than specific, appetitive value. Together, this evidence demonstrates that serotonergic neurons in the DR integrate and signal information about appetitive and aversive stimuli in a probability- and value-dependent manner. This information is necessary for balancing the overall appetitive and aversive value of diverse stimuli within multiple contexts and is critical to the successful implementation of defensive behavioral strategies intended to minimize risk and maximize reward.

VII. SEROTONIN ALTERS ACTIVITY OF CIRCUITS THAT CONTROL ANXIETYRELATED AND FEAR-RELATED DEFENSIVE BEHAVIORAL RESPONSES In this section, we will introduce several interconnected brain regions involved in the control of anxious states in humans and anxiety-related defensive behavioral responses in nonhuman animals. These regions include the prefrontal cortex (PFC), nucleus accumbens (NAcb), amygdala complex, bed nucleus of the stria terminalis (BNST), lateral habenula (LHb), and the periaqueductal gray (PAG). We will highlight the association between these regions and the expression of anxiety- and fear-related defensive behavioral responses, as well as the influence of serotonergic innervation on activity in these regions (Fig. 29.3B; for review, see Hale & Lowry, 2011).

A. The PFC as a nodal structure modulating anxiety- and fear-related defensive behavioral responses The medial prefrontal cortex (mPFC) is involved in the top-down regulation of appetitive and aversive drive, as well as the expression and suppression of anxiety- and fear-related defensive behavioral responses (for review, see McCullough, Morrison, & Ressler, 2016). The prelimbic cortex (PrL) is required for

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expression of conditioned behavior, while the infralimbic (IL) cortex suppresses these behaviors (Warren et al., 2016). For example, IL activation potentiates fear extinction, while inactivation of the IL impairs this process (Do-Monte, Manzano-Nieves, Quin˜ones-Laracuente, Ramos-Medina, & Quirk, 2015; Kim, Cho, Augustine, & Han, 2016). While the IL suppresses learned fear-related behaviors (Sierra-Mercado, Padilla-Coreano, & Quirk, 2011), the PrL promotes the expression of conditioned fear (for review, see Quirk & Mueller, 2008; Sierra-Mercado et al., 2011). Furthermore, inhibition of the vmPFC during escapable stress abolishes the protective effects of stressor controllability (Amat et al., 2005). Meanwhile, neurons in the mPFC encode aversive and appetitive signals (Monosov & Hikosaka, 2012). Recordings from macaque neurons during a gambling task demonstrated that the mPFC encodes choice-related predicted and outcome value (Strait, Blanchard, & Hayden, 2014). In humans, the mPFC is involved in assigning outcome value in a gambling task (Vassena, Krebs, Silvetti, Fias, & Verguts, 2014), and the value (intensity) of positive, but not negative, emotions (Winecoff et al., 2013). In rats, pharmacological inhibition of mPFC neurons following operant food conditioning reduces food seeking (Warren et al., 2016). Together, this evidence demonstrates a role for the mPFC in processing appetitive value and controlling the expression and suppression of learned behavior. Serotonergic neurons in the DR share reciprocal connections with the mPFC (for review, see Puig & Gulledge, 2011). Serotonergic neurons send efferent projections to the mPFC, primarily from the midrostrocaudal DRD (Van Bockstaele, Biswas, & Pickel, 1993). In turn, the mPFC, particularly the PrL and IL cortices, provides substantial innervation along the rostrocaudal extent of the DR (Goncalves, Nogueira, Shammah-Lagnado, & Metzger, 2009). The PrL provides direct excitatory and indirect inhibitory projections to the DR, preferentially targeting GABA neurons in the rostral DR and serotonergic neurons in the caudal DR (Challis & Berton, 2015). Electrical stimulation of the mPFC increases serotonin release in the DR and mPFC (Celada, Puig, Casanovas, Guillazo, & Artigas, 2001) and limbic forebrain structures (Juckel, Mendlin, & Jacobs, 1999), further highlighting the bidirectional connectivity of these regions.

B. The nucleus accumbens as a nodal structure mediating anxiety-related defensive behavioral responses The NAcb is classically associated with reward and addiction, but is also involved in the expression of appetitive and aversive states (for review, see McDevitt &

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Graziane, 2018) and social behavior (Dolen, 2015). The NAcb can be divided into a core region (NAcC) associated with motor function and a shell region (NAcSh) associated with reward processing and motivated behavior (Alheid & Heimer, 1988). Serotonergic innervation from the DR is present throughout the NAcb (Brown & Molliver, 2000; Van Bockstaele et al., 1993) and forms excitatory, as well as inhibitory, synapses (Van Bockstaele & Pickel, 1993). Local activation of GABAA receptors in the rostral NAcSh increases feeding, whereas local activation of GABAA receptors in the caudal NAcSh increases defensive treading (Reynolds & Berridge, 2001). Interestingly, photoactivation of dynorphinergic cells in the dorsal NAcSh induces place preference and increases operant self-stimulation, while photoactivation of these cells in the ventral NAcSh has the opposite effect (Al-Hasani et al., 2015), showing that the NAcSh can promote appetitive as well as aversive states. Moreover, 5-HT2A and 5-HT2C receptors colocalize with dynorphinergic neurons throughout the NAcb (Ward & Dorsa, 1996), suggesting serotonin may also have opposing functions on behavioral output regulated by this group of neurons. Finally, 5-HT1B receptor activation in the NAcb appears necessary for the neurophysiological changes required for social conditioned place preference (Dolen, Darvishzadeh, Huang, & Malenka, 2013).

C. The bed nucleus of the stria terminalis as a nodal structure mediating anxiety-related defensive behavioral responses The bed nucleus of the stria terminalis (BNST) is a stress responsive and highly heterogeneous region of the extended amygdala complex, containing at least 16 distinct subregions, and can either promote or inhibit avoidance behavior (for review, see Daniel & Rainnie, 2016; Jennings et al., 2013; Kim et al., 2013). Serotonin innervation is present throughout the rostrocaudal extent of the BNST (Linley, Olucha-Bordonau, & Vertes, 2017) and can inhibit, as well as excite, different neuronal populations through actions on the 11 different serotonin receptor subtypes expressed in this region (Bota, Sporns, & Swanson, 2012; Guo, Hammack, Hazra, Levita, & Rainnie, 2009; Hammack et al., 2009). Interestingly, optogenetic activation of serotonergic terminals in the BNST can result in both increased (Marcinkiewcz et al., 2016) and decreased (Garcia-Garcia et al., 2017) anxietyrelated defensive behavioral responses as measured by EPM open-arm avoidance, consistent with the opposing roles of both serotonin and the BNST in the expression of anxiety-related behavior. Together, this evidence demonstrates that serotonergic signaling in the BNST can promote either approach or avoidance behavior, suggesting

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that different subsets of serotonergic raphe neurons may enhance either behavior.

D. The amygdala as a nodal structure mediating anxiety-related and fear-related defensive behavioral responses The amygdala is a limbic forebrain structure associated with anxiety disorders in people and anxiety- and fear-related defensive behavioral responses in nonhuman animals. This structure contains a number of distinct subnuclei with complex afferenteefferent innervation patterns (for review, see Asan, Steinke, & Lesch, 2013). Serotonin fibers innervate all amygdala subnuclei and all serotonergic receptor subtypes are expressed within this complex (Linley et al., 2017). The basolateral (BLA) and central (CeA) nuclei of the amygdala show increased activation following EPM exposure (Jacinto, Cerqueira, & Sousa, 2016; Lawther et al., 2018; Sorregotti et al., 2018). Optogenetic activation of axon terminals of glutamatergic neurons projecting from the BLA to the CeA increases open-arm time in the EPM and center time in the OFT, whereas inhibition of these terminals increases avoidance behavior (Tye et al., 2011), suggesting that glutamatergic BLAeCeA microcircuits inhibit avoidance behavior. Meanwhile, exposure to aversive stimuli increases extracellular serotonin concentrations in the BLA (Baratta et al., 2016), and intra-BLA infusion of serotonin enhances inhibitory avoidance in the elevated T-maze (ETM) in a 5-HT2C receptoredependent manner (Vicente & Zangrossi, 2012), suggesting that 5-HT2C receptor signaling in the BLA promotes anxiety-related defensive behavioral responses (Christianson et al., 2008). However, NPY-expressing inhibitory interneurons in the BLA also express the excitatory 5-HT2C receptor (Bonn, Schmitt, Lesch, Van Bockstaele, & Asan, 2013), and NPY interneurons in the BLA appear to be anxiolytic (Truitt, Johnson, Dietrich, Fitz, & Shekhar, 2009), suggesting the effect of serotonin signaling on BLA-mediated defensive behavior is cell type specific.

E. The lateral habenula as a nodal structure mediating anxiety- and fear-related defensive behavioral responses The LHb is an evolutionarily conserved bilateral epithalamic structure located beneath the third ventricle in the caudal thalamus, common to all vertebrates, and involved in the expression of defensive behavior (Mizumori & Baker, 2017; Zahm & Root, 2017). The LHb is primarily glutamatergic but can exert strong indirect inhibitory effects through activation of the GABAergic rostromedial tegmental nucleus (RMTg)

(Brown et al., 2017). The LHb is reciprocally connected to many brain regions involved in the control of anxious states and anxiety- and fear-related defensive behavioral responses, including the DR and MnR (Metzger, Bueno, & Lima, 2017; Sego et al., 2014). The LHb can directly activate serotonergic DR neurons and indirectly inhibit them through activation of GABAergic interneurons (Metzger et al., 2017), or through activation of GABAergic neurons in the RMTg (Metzger et al., 2017; Zhang et al., 2018). Conversely, inhibition of the DR by local GABA injection decreases LHb serotonin metabolism and reduces activation of these neurons (57% inhibited/13% excited). However, photoinhibition of serotonergic DR neurons enhances LHb c-Fos expression and serotonergic DR neurons block presynaptic excitation of LHb neurons (Shabel, Proulx, Trias, Murphy, & Malinow, 2012; Zhang et al., 2018). Neurons in the LHb have been suggested to encode antireward information (Matsumoto & Hikosaka, 2007), a notion strongly supported by their potent indirect inhibitory effects on reward-encoding ventral tegmental area (VTA)/substantia nigra (SN) dopaminergic neurons through activation of GABAergic neurons in the RMTg (Brown et al., 2017). In humans, the LHb is activated following negative feedback for incorrect predictions and when positive feedback is omitted for correct predictions in a motion prediction task (Ullsperger & von Cramon, 2003). In rhesus monkeys, LHb neurons show robust activity in response to cues predicting punishment in a probability-dependent manner (Matsumoto & Hikosaka, 2009). Interestingly, while these neurons are inhibited in response to cues predicting reward, they respond equally to 100% probability of punishment and 0% probability of reward, showing that these cells encode the probability of aversive outcomes and the absence of reward (Matsumoto & Hikosaka, 2009), as opposed to just the value of aversive stimuli. Inhibition or activation of the LHb implicates this nucleus in the control of anxiety-related defensive behavioral responses. For example, electrolytic ablation of the LHb decreases open-arm avoidance while facilitating escape behavior in the ETM, while activation of the LHb by direct injection of kainic acid shows the opposite effect (Pobbe & Zangrossi, 2008), suggesting that LHb signaling can affect approach/avoidance and escape behaviors. Ethanol withdrawal increases avoidance behavior in the EPM and OFT (Kang et al., 2017), effects blocked and mimicked by chemogenetic inhibition or activation of the LHb, respectively (Kang et al., 2017). Exposure to either chronic unpredictable stress or anxiogenic drugs increases avoidance behavior in the EPM (Gill, Ghee, Harper, & See, 2013; Jacinto, Mata, Novais, Marques, & Sousa, 2017), effects blocked by LHb ablation (Jacinto et al., 2017) and inhibition (Gill et al., 2013). Interestingly, inactivation of the LHb

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VIII. SEROTONIN SIGNALING MODULATES DISTINCT PROCESSES CONTRIBUTING TO THE EXPRESSION OF ANXIETY

does not affect avoidance behavior in control animals (Gill et al., 2013; Jacinto et al., 2017), suggesting that LHb signaling is critical for stress-induced increases in defensive behavior, but not the expression of normal defensive behavior. Together, this evidence demonstrates bidirectional connectivity between the LHb and serotonergic neurons in the DR and MnR. This evidence also highlights a role for the LHb in aversive signaling and the expression of anxiety- and fear-related defensive behavioral responses and suggests that serotonergic signaling can activate and inhibit the LHb.

F. The periaqueductal gray as a nodal structure mediating anxiety- and fear-related defensive behavioral responses The dorsal periaqueductal gray (dPAG) has been implicated in the control of escape behavior (Graeff, Guimaraes, De Andrade, & Deakin, 1996). The dPAG is activated during panic- or escape-like responses, as determined using induction of immediate-early gene expression (Lamprea et al., 2002; Silveira, Zangrossi, de Barros Viana, Silveira, & Graeff, 2001). Manipulation of this region is used to model human panic anxiety (Graeff, 1994; Jenck, Moreau, & Martin, 1995). Indeed, pharmacological inhibition of the dPAG using the benzodiazepine midazolam (de Bortoli et al., 2008), GABAA receptor agonists (Bueno, Zangrossi, Nogueira, Soares, & Viana, 2005; de Menezes et al., 2008), or GABAB receptor agonists (Bueno et al., 2005) impairs panic-like and escape responses. Meanwhile, electrical stimulation (Jenck et al., 1995), pharmacological activation (Zanoveli, Netto, Guimaraes, & Zangrossi, 2004), or disinhibition (Graeff, Brandao, Audi, & Schutz, 1986) of the dPAG potentiates escape behavior. Serotonergic neurons from the dorsal raphe nucleus, ventrolateral part (DRVL) project to the dPAG (Stezhka & Lovick, 1997), and activation of 5-HT1A or 5-HT2 receptors in the dPAG reduces the excitability of the dPAG and reduces panic-like responses (for review, see Graeff et al., 1996). This suggests that serotonin signaling in the dPAG acts to decrease output of this region and inhibit panic-like behavior.

VIII. SEROTONIN SIGNALING MODULATES DISTINCT PROCESSES CONTRIBUTING TO THE EXPRESSION OF ANXIETY- AND FEAR-RELATED DEFENSIVE BEHAVIORAL RESPONSES IN A TARGET-SPECIFIC MANNER Serotonin signaling in the BNST moderates approach/avoidance behavior. For example, optogenetic activation of serotonergic terminals in the dlBNST

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increases center time in the OFT and open-arm entries in the EPM, without affecting locomotion, in a 5-HT1A heteroreceptoredependent manner (Garcia-Garcia et al., 2017). Conversely, optogenetic activation of serotonergic terminals in the BNST increases open-arm avoidance in the EPM and increases feeding latency in the novelty-suppressed feeding (NSF) test in a 5-HT2C receptoredependent manner (Marcinkiewcz et al., 2016). Interestingly, activation of this aversive serotonergic circuit in the fear-potentiated startle test did not affect acquisition, but enhanced recall to both cue and context (Marcinkiewcz et al., 2016), suggesting that serotonin in the BNST enhances learned, but not innate, freezing behavior. Together, this evidence suggests that serotonergic signaling in the BNST can promote or inhibit the expression of anxiety- and fear-related defensive behavioral responses in a serotonin receptor subtype-dependent manner. Serotonergic signaling in the BLA enhances aversive memory acquisition. Exposure to inescapable stress, but not exposure to escapable stress, enhances serotonin release in the BLA during the juvenile social exploration test of anxiety and facilitates social avoidance in a 5-HT2C receptoredependent manner (Christianson et al., 2010). In animals without prior stress exposure, agonism of 5-HT2C receptors in the BLA enhances shock-induced freezing without affecting avoidance learning (Strong et al., 2011), suggesting 5-HT2C receptors in the BLA enhance aversiveness. Moreover, upregulation of 5-HT2C receptors in the BLA by chronic immobilization stress enhances long-term memory formation, as measured by cue-induced freezing 24 h postacquisition (Baratta et al., 2016). Interestingly, this effect is blocked by BLA 5-HT2C receptor antagonism immediately following acquisition, and by photoinhibition of the BLA-projecting serotonergic neurons during acquisition (Baratta et al., 2016). Together, these data suggest that 5-HT2C receptor activation in the BLA during exposure to aversive stimuli mediates associations to negative outcomes, while activation of these receptors poststimulus enhances aversive memory formation, contributing to the development of an avoidant phenotype. Serotonergic signaling in the NAcb promotes sociability. CSDS results in an adaptive increase of social avoidance, and results in decreased excitability in serotonergic neurons in the DRD/DRV (Challis et al., 2013). Moreover, optogenetic inhibition of DRV GABAergic neurons during postdefeat sensory contact results in a resilient phenotype (Challis et al., 2013), while photoactivation of glutamatergic vmPFC terminals in the DR promotes a susceptible phenotype, through DR GABAergic neuron activation (Challis et al., 2014). Interestingly, photostimulation of serotonergic terminals in the NAcb promotes sociability in the juvenile social exploration test in a 5-HT1B receptor-dependent manner

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(Walsh et al., 2018). This may suggest that mPFCmediated decreases in DRD/DRV serotonergic signaling following social defeat promotes increased anxietyrelated behavior, potentially through downregulation and/or reduced activation of 5-HT1B receptors in the NAcb. It is interesting that the CSDS paradigm promotes social avoidance by decreasing serotonergic signaling (Challis et al., 2013), whereas uncontrollable stress promotes social avoidance by increasing serotonergic activity (Christianson et al., 2010). These data suggest that a socially avoidant phenotype can be induced by decreases in appetitive signaling or by increases in aversive signaling arising from serotonergic DR neurons, and that social approach behavior is mediated by serotonergic signaling in the NAcb. Serotonergic signaling in the dPAG promotes behavioral inhibition. Pharmacological activation of the DR reliably increases escape latency and increases latency to enter the open-arm of the ETM (Pobbe & Zangrossi, 2005; Sena et al., 2003). These effects are reversed by inhibition or selective lesion of serotonergic DR neurons (Pobbe & Zangrossi, 2005; Sena et al., 2003), and by intra-dPAG administration of a selective 5-HT2A/C receptor antagonist (Pobbe & Zangrossi, 2010). Moreover, these apparent anxiogenic/panicolytic effects are mimicked by chemical stimulation of the LHb (Pobbe & Zangrossi, 2008) in a dPAG 5-HT2A/C receptordependent manner (Pobbe & Zangrossi, 2010). This suggests that the effect of serotonergic signaling in the dPAG on avoidance/escape behavior is moderated, at least in part, by aversive signals from the LHb. However, this fails to explain the apparent panicolytic effects of activating the LHb-DR-dPAG circuit. An alternative explanation is that, in the absence of reward/ punishment-predicting cues, serotonin signaling in the dPAG decreases effort output, i.e., it is not worth the energy cost to either approach or avoid. Therefore, removing the “no-reward” signal from the LHb to the DR, or blocking 5-HT2A/C receptors in the dPAG, increases effort in the absence of clear appetitive or aversive cues. This hypothesis is further supported by research showing that optogenetic activation of glutamatergic mPFC axon terminals in the LHb strongly increases immobility in the FST (Warden et al., 2012). While this can be interpreted as an increase in depressive-like behavior, it can equally be interpreted as the adaptive conservation of energy (Molendijk & de Kloet, 2015) in the presence of “no-reward”signals from the LHb to the DR. Furthermore, optogenetic activation of the DR serotonergic neurons promotes waiting for a food reward rather than exploring alternatives, an effect strongest when the probability of reward is high but timing of delivery is uncertain (Miyazaki et al., 2018), further implicating the serotonergic DRVL in promoting behavioral inhibition. This idea suggests

that DRVL serotonergic neurons may be one important component of Gray’s proposed behavioral inhibition system (Gray & McNaughton, 2000). While speculative, serotonergic DR-dPAG signaling may moderate adaptive approach/avoidance behavior in a cost/benefitdependent manner by conserving energy when the probability of rewarding outcomes is low and promoting waiting when the probability is high. Serotonin signaling in the PFC moderates impulsivity and behavioral adaptation. Serotonin signaling in the PFC bidirectionally modifies neural activity and output of this region (for review, see Puig & Gulledge, 2011). In the common marmoset, selective lesion of serotonergic terminals in the PFC (Clarke et al., 2004, 2005; Rygula et al., 2015) substantially impairs reversal learning. In zebrafish, selective lesion of cortical serotonergic terminals impairs adaptive avoidance learning to shockpredicting cues without affecting unconditioned freezing (Amo et al., 2014). In rats, 5-HT1A receptor agonists administered to the mPFC reduce impulsivity (Carli, Baviera, Invernizzi, & Balducci, 2006). This evidence suggests that PFC serotonin signaling contributes to behavioral adaptation in both rewarding and aversive contexts. Serotonin signaling in the LHb moderates appetitive and aversive states. Serotonin signaling can potentiate, as well as inhibit, output from the LHb (for review, see Tchenio, Valentinova, & Mameli, 2016). In vitro electrophysiology evidence shows that activation of 5-HT2/3 receptors potentiates glutamatergic transmission from the LHb (Xie et al., 2016; Zuo et al., 2016), while activation of 5-HT1B receptors inhibits presynaptic glutamatergic inputs to this region (Hwang & Chung, 2014). Furthermore, photoactivation of excitatory entopeduncular nucleus terminals in the LHb in vivo promotes place aversion, while bath application of serotonin in vitro inhibits photoactivation of these terminals (Shabel et al., 2012). Rats exposed to chronic unpredictable mild stress show a decrease in sucrose preference and increased immobility in the FST (Zhang et al., 2018). In these rats, photoactivation of serotonergic DR afferents in the LHb reinstates normal levels of sucrose preference and FST mobility through actions on 5-HT1B receptors (Zhang et al., 2018). Finally, intra-LHb administration of the 5-HT2C receptor agonist, Ro60-0175, reduces sucrose preference and increases immobility in the FST (Han et al., 2015). While more research is needed in order to understand the behavioral effects of serotonergic signaling in the LHb, these data suggest that activation of 5-HT2C receptors in the LHb promotes passive coping and anhedonia. Meanwhile, 5-HT1B receptor activation has the opposite effect, consistent with the hypothesis that serotonin exerts opposed control over appetitive and aversive states.

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IX. CONCLUSIONS AND FUTURE DIRECTIONS Overall, evidence suggests that serotonin signaling directs behavior based on the relative strength of appetitive and aversive signals filtered through serotonergic neurons. Then, outcome-related serotonergic signaling promotes behavioral adaptation and future threat appraisal through functional alterations in serotonin receptor expression profiles. Serotonin signaling modulates discrete neural functions involved in the adaptive expression of anxiety- and fear-related defensive behavioral responses. These include behavioral adaptation (mPFC), aversive memory formation and consolidation (BLA), approach/avoidance behavior (BNST), sociability (NAcb), behavioral inhibition (dPAG), and aversive signaling from the LHb (Fig. 29.3B). Current gene, viral, and conditional activation/inhibition techniques have substantially improved our understanding of the way in which serotonin signaling can coordinate and shape diverse behaviors over long and short timescales. However, given that the evidence suggests the possibility of parallel and overlapping serotonergic systems are involved in appetitive and aversive signaling, future studies will need to target these separate systems independently. The recently developed robust activity-dependent marking system (RAM; Sorensen et al., 2016) combined with other virally based technologies should enable identification of independent serotonergic neurons involved in the processing of aversive and appetitive behavior. When paired with chemogenetic or optogenetic actuators, this approach should enable improved understanding of how serotonergic systems exert opposed control over many diverse physiological functions and behavioral states.

Acknowledgments We are grateful to Zachary D. Barger for proofreading the manuscript. This work was supported by the National Institute of Mental Health (grant number 1R21MH116263).

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IV. SEROTONIN AND BEHAVIOURAL CONTROL