A Variant C178T in the Regulatory Region of the Serotonin Receptor Gene<i>HTR3A</i>Modulates Neural Activation in the Human Amygdala

Iidaka, Tetsuya; Ozaki, Norio; Matsumoto, Atsushi; Nogawa, Junpei; Kinoshita, Yoko; Suzuki, Tatsuyo; Iwata, Nakao; Yamamoto, Yoshiyuki; Okada, Tomohisa; Sadato, Norihiro

doi:10.1523/jneurosci.5261-04.2005

Cited by 73 publications

(65 citation statements)

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“…An allelic variant of a SNP in the human HTR3A gene, C178T, is associated with increased 5-HT3-R expression in vitro (Niesler et al, 2001). Individuals carrying this variant exhibit lower scores for anxiety-related traits such as harm avoidance (Melke et al, 2003) and reduced amygdala and PFC activity in response to threatening stimuli as measured by fMRI (Iidaka et al, 2005). This interesting source of gene variation in the serotonin system warrants further study.…”

Section: -Ht3 Receptorsmentioning

confidence: 99%

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Holmes

2008

Neuroscience & Biobehavioral Reviews

243

166

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The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research.

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Section: -Ht3 Receptorsmentioning

confidence: 99%

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Holmes

2008

Neuroscience & Biobehavioral Reviews

243

166

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“…visual presentation of threatening facial expressions Heinz et al, 2005;Pezawas et al, 2005; see also Iidaka et al, 2005).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Selective attention to threat versus reward: Meta-analysis and neural-network modeling of the dot-probe task

Frewen

Dozois

Joanisse

et al. 2008

Clinical Psychology Review

175

160

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Two decades of research conducted to date has examined selective visual attention to threat and reward stimuli as a function of individual differences in anxiety using the dot-probe task. The present study tests a connectionist neural-network model of meta-analytic and key individual study results derived from this literature. Attentional bias for threatening and reward-related stimuli is accounted for by connectionist model implementation of the following clinical psychology and affective neuroscience principles: 1) affective learning and temperament, 2) state and trait anxiety, 3) intensity appraisal, 4) affective chronometry, 5) attentional control, and 6) selective attention training. Theoretical implications for the study of mood and anxiety disorders are discussed.Key Words: Dot-Probe Task, Selective Attention, Threat, Reward, Anxiety, Depression, Connectionism, Neural Network, Amygdala. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPTSelective Attention for Reward & Threat 3 Selective Attention to Threat versus Reward: Meta-analysis and Neural-Network Modeling of the Dot-Probe TaskTheoretical constructs and research methodologies derived from cognitive psychology figure prominently in current emotion research, including investigations into the nature and function of anxiety. For example, cognitive researchers have been studying how individuals visually attend to threatening stimuli, and how between-subject variability in the functioning of attentional systems may correlate with individual differences in anxiety-related traits and disorders (e.g., Williams, Watts, MacLeod, & Matthews, 1997).Evolutionary models of emotion and attention hypothesize that nature may have programmed the visual-attention system to attend selectively to stimuli of biological significance, including both to cues of possible impending threat (e.g., predators), on the one hand, and to cues of potential reinforcement-reward value (e.g., food, mates), on the other (e.g., LeDoux, 1996;Panksepp, 1998;Rolls, 1999). Attentional mechanisms procuring the rapid detection of sources of potential environmental threat are therefore presumed to afford an obvious survival-facilitating mechanism (A. Mathews & Mackintosh, 1998;A. Mathews, Mackintosh, & Fulcher, 1997;. However, an equally integral attentional function to the biological fitness of organisms is to orient toward stimuli of potential reward-value in their environments (Panksepp, 1998;Rolls, 1999).It may be that reward-and threat-detection are performed by distinct attentional systems 1 . Specifically, threat detection attentional mechanisms may represent secondary interrupt programs that continuously perform a background analysis of stimuli regarding their likelihood of representing a source of danger, attaining foreground and conscious significance only to the extent that this analysis results in the detection of relatively significant sources of danger (e.g., LeDoux, 1996). Otherwise, the default and primary orientation of attention may be toward reward-relevant stimuli...

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“…5-HT3A receptor knockout mice showed increased fear learning (Bhatnagar et al 2004). Humans carriers of an allelic variant of a SNP in the HTR3A gene, C178T, which is associated with increased 5-HT3 receptor expression in vitro (Niesler et al 2001) show lower scores for anxiety-related traits and reduced amygdala activity in response to threatening stimuli (Melke et al 2003;Iidaka et al 2005). These results suggest that higher levels of 5-HT3 receptors may constrain aversive processing, while lower levels of 5-HT3 receptor may promote fear learning and anxiety, consistent with the idea that these receptors are mostly located in BLA inhibitory neurons and may act to reduce the excitability of BLA projection neurons .…”

Section: Dorsal Raphe Nuclei Projections To the Blamentioning

confidence: 99%

“…Activity through the 5HT-2 receptors promotes fear and decreases reward seeking (McCool et al 2014) and activity at 5HT-3A receptors decreases anxiety but increases food approach behavior (Melke et al 2003;Iidaka et al 2005;Barker et al 2014). In addition, 5HT-2C and 5HT-3 receptors seem to have opposite functions during learning tasks driven by either positive or negative valence.…”

Section: Org Downloaded Frommentioning

confidence: 99%

Input-specific contributions to valence processing in the amygdala

Correia

Goosens

2016

Learn. Mem.

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Reward and punishment are often thought of as opposing processes: rewards and the environmental cues that predict them elicit approach and consummatory behaviors, while punishments drive aversion and avoidance behaviors. This framework suggests that there may be segregated brain circuits for these valenced behaviors. The basolateral amygdala (BLA) is one brain region that contributes to both types of motivated behavior. Individual neurons in the BLA can favor positive over negative valence, or vice versa, but these neurons are intermingled, showing no anatomical segregation. The amygdala receives inputs from many brain areas and current theories posit that encoding of positive versus negative valence by BLA neurons is determined by the wiring of each neuron. Specifically, many projections from other brain areas that respond to positive and negative valence stimuli and predictive cues project strongly to the BLA and likely contribute to valence processing within the BLA. Here we review three of these areas, the basal forebrain, the dorsal raphe nucleus and the ventral tegmental area, and discuss how these may promote encoding of positive and negative valence within the BLA.The basic desire to seek reward and avoid punishment shapes virtually all of behavior, and the ability to discriminate between "good" and "bad" environmental cues is critical for guiding choices and maximizing survival. Thus, understanding the brain circuits that encode motivated behaviors is important because it contributes to our knowledge of how we learn, and it is also essential for understanding human disorders associated with abnormal processing of reward and danger (i.e., emotional disorders), such as anxiety, depression, addiction, and post-traumatic stress disorder (PTSD).The amygdala is one brain area implicated in motivated behaviors and the basolateral complex of the amygdala (BLA) receives information about diverse environmental stimuli from many brain regions. The BLA is thought to encode the association of predictive stimuli with both aversive and appetitive outcomes (Morrison and Salzman 2010;Barberini et al. 2012). Reward and punishment are reinforcers of opposite valence (positive versus negative), and these reinforcers typically lead to opposing behaviors (approach versus avoidance). Many theories have suggested that appetitive and aversive systems act in opponent fashion (Solomon and Corbit 1974;Daw et al. 2002). However, it is unclear how the BLA contributes to this. We do not yet understand the extent to which aversive and appetitive information is processed in parallel BLA circuits, or whether individual BLA neurons are involved in the regulation of both types of motivated behaviors.In this review, we propose several models by which functional segregation of valence can be achieved in the BLA. These models are based on studies describing how BLA neurons respond to reward and aversive stimuli. We then consider whether three major inputs, known to carry valenced information, support or conflict these models, and also discus...

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A Variant C178T in the Regulatory Region of the Serotonin Receptor GeneHTR3AModulates Neural Activation in the Human Amygdala

Cited by 73 publications

References 55 publications

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Selective attention to threat versus reward: Meta-analysis and neural-network modeling of the dot-probe task

Input-specific contributions to valence processing in the amygdala

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