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Avoidance of harm and anxiety: A role for the nucleus accumbens

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... The smallest group (~ 20%) comprises the heterogeneous non-spiny or sparsely spinous stellate cortical cells. All are GABAergic inhibitory neurons, and until recently it was thought that their axons are confined to the grey matter, they only communicate with other cells locally: interneurons (Letinic, et al., 2002). ...
... First, it has been shown via functional magnetic resonance imaging (fMRI) studies using blood oxygenation level dependent (BOLD) signals, that active avoidance increased BOLD signal within the Nac (Delgado, et al., 2009;Levita, et al., 2012), whereas inhibitory avoidance was associated with a deactivation in this region in humans (Levita, et al., 2012). ...
... First, it has been shown via functional magnetic resonance imaging (fMRI) studies using blood oxygenation level dependent (BOLD) signals, that active avoidance increased BOLD signal within the Nac (Delgado, et al., 2009;Levita, et al., 2012), whereas inhibitory avoidance was associated with a deactivation in this region in humans (Levita, et al., 2012). ...
Thesis
Mammals, including rodents show a broad range of defensive behaviors as a mean of coping with threatful stimuli including freezing and avoidance behaviors. Several studies emphasized the role of the dorsal medial prefrontal cortex (dmPFC) in encoding the acquisition as well as the expression of freezing behavior. However the role of this structure in processing avoidance behavior and the contribution of distinct prefrontal circuits to both freezing and avoidance responses are largely unknown. To further investigate the role of dmPFC circuits in encoding passive and active fear-coping strategies, we developed in the laboratory a novel behavioral paradigm in which a mouse has the possibility to either passively freeze to an aversive stimulus or to actively avoid it as a function of contextual contingencies. Using this behavioral paradigm we investigated whether the same circuits mediate freezing and avoidance behaviors or if distinct neuronal circuits are involved. To address this question, we used a combination of behavioral, neuronal tracing, immunochemistry, single unit and patch clamp recordings and optogenetic approaches. Our results indicate that (i) dmPFC and dorsolateral and lateral periaqueductal grey (dl/lPAG) sub-regions are activated during avoidance behavior, (ii) a subpopulation of dmPFC neurons encode avoidance but not freezing behavior, (iii) this neuronal population project to the dl/lPAG, (iv) the optogenetic activation or inhibition of this pathway promoted and blocked the acquisition of conditioned avoidance and (v) avoidance learning was associated with the development of plasticity at dmPFC to dl/lPAG synapses. Together, these data demonstrate for the first time that activity-dependent plasticity in a subpopulation of dmPFC cells projecting to the dl/lPAG pathway controls avoidance learning.
... Active/Inhibitory avoidance training was adapted from previous reports conducting active avoidance in an operant setting (Fernando et al., 2013(Fernando et al., , 2015McCullough et al., 1993;Sokolowski et al., 1994), and based on a task used in humans, as described by Levita et al. (2012). ...
... Therefore, identifying the neural substrates underlying the basic behavior may improve our understanding of disorders characterized by such disturbances. To this end, activity within the human ventral striatum, which includes the NAc, has been associated with active avoidance (Delgado et al., 2009;Jensen et al., 2003;Levita et al., 2012). These studies illustrate that NAc activity is increased during the formation of an association between a particular instrumental action and its avoidance outcome (Delgado et al., 2009), as well as during performance of an active avoidance response (Jensen et al., 2003;Levita et al., 2012). ...
... To this end, activity within the human ventral striatum, which includes the NAc, has been associated with active avoidance (Delgado et al., 2009;Jensen et al., 2003;Levita et al., 2012). These studies illustrate that NAc activity is increased during the formation of an association between a particular instrumental action and its avoidance outcome (Delgado et al., 2009), as well as during performance of an active avoidance response (Jensen et al., 2003;Levita et al., 2012). Although these studies did not have the spatial resolution necessary to disambiguate potential activation differences between ventral striatal subregions, they are consistent with the present finding that this region is necessary for instrumental active avoidance. ...
... Active and passive avoidance have also been associated with distinct neural pathways (Gozzi et al., 2010;Levita et al., 2012;Eldar et al., 2016;Tovote et al., 2016;Yu et al., 2016;Fadok et al., 2017). Animal models have identified neurons in the CeA responsible for switching behavioral responses to a threatening stimulus from freezing to overt approach-action (Gozzi et al., 2010;Moscarello and LeDoux, 2013;Fadok et al., 2017). ...
... This stage allows for freezing biases to be differentially evoked according to the type of response required for avoidance. Situations may require active avoidance (initiation of withdrawal behavior) or passive avoidance (inhibition of an approach response that results in non-engagement with the threatening stimulus), and these response modes are dissociable neurally (Gozzi et al., 2010;Levita et al., 2012;Eldar et al., 2016;Tovote et al., 2016;Yu et al., 2016;Fadok et al., 2017). Differential biases can be contrasted by using a task incorporating decisions of both types, and behavioral models incorporating both aversive value and switch costs. ...
Article
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Acutely challenging or threatening situations frequently require approach-avoidance decisions. Acute threat triggers fast autonomic changes that prepare the body to freeze, fight or flee. However, such autonomic changes may also influence subsequent instrumental approach-avoidance decisions. Since defensive bodily states are often not considered in value-based decision-making models, it remains unclear how they influence the decision-making process. Here, we aim to bridge this gap by discussing the existing literature on the potential role of threat-induced bodily states on decision making and provide a new neurocomputational framework explaining how these effects can facilitate or bias approach-avoid decisions under threat. Theoretical accounts have stated that threat-induced parasympathetic activity is involved in information gathering and decision making. Parasympathetic dominance over sympathetic activity is particularly seen during threat-anticipatory freezing, an evolutionarily conserved response to threat demonstrated across species and characterized by immobility and bradycardia. Although this state of freezing has been linked to altered information processing and action preparation, a full theoretical treatment of the interactions with value-based decision making has not yet been achieved. Our neural framework, which we term the Threat State/Value Integration (TSI) Model, will illustrate how threat-induced bodily states may impact valuation of competing incentives at three stages of the decision-making process, namely at threat evaluation, integration of rewards and threats, and action initiation. Additionally, because altered parasympathetic activity and decision biases have been shown in anxious populations, we will end with discussing how biases in this system can lead to characteristic patterns of avoidance seen in anxiety-related disorders, motivating future pre-clinical and clinical research.
... Structural variations of neural regions implicated in fear and avoidance responses have been well documented in the pathophysiology of anxiety disorders [10] and may play an important role in treatment response. Utilizing fear conditioning and avoidance models, studies have identified several neural regions involved in fear circuitry and behaviors, including the ventromedial prefrontal cortex (PFC), nucleus accumbens (NAcc), and limbic areas (e.g., amygdala, hippocampus, and insula) [11][12][13]. The amygdala plays an important role in the perception, learning, and early extinction of threat [14], whereas the ventromedial PFC is thought to play a significant part in the retention of fear extinction [15] as well as the ability to use adaptive regulation strategies to attenuate aversive responses to threat [16]. ...
... The amygdala plays an important role in the perception, learning, and early extinction of threat [14], whereas the ventromedial PFC is thought to play a significant part in the retention of fear extinction [15] as well as the ability to use adaptive regulation strategies to attenuate aversive responses to threat [16]. Researchers have also shown that the NAcc plays a role in the etiology and maintenance of aberrant fear avoidance behaviors among individuals with anxiety [11,17], and the degree of NAcc activation modulates positive associations between anxiety levels and responses to fear-evoking stimuli [18]. ...
Article
Structural variations of neural regions implicated in fear responses have been well documented in the pathophysiology of anxiety and may play an important role in treatment response. We examined whether gray matter volume of three neural regions supporting fear and avoidance responses [bilateral amygdala, nucleus accumbens (NAcc), and ventromedial prefrontal cortex (PFC)] predicted cognitive-behavioral therapy (CBT) and selective serotonin reuptake inhibitor (SSRI) treatment outcome in two independent samples of patients with anxiety disorders. Study 1 consisted of 81 adults with anxiety disorders and Study 2 included 55 children and adolescents with anxiety disorders. In both studies, patients completed baseline structural MRI scans and received either CBT or SSRI treatment. Clinician-rated interviews of anxiety symptoms were assessed at baseline and posttreatment. Among the adult sample, greater pre-treatment bilateral NAcc volume was associated with a greater reduction in clinician-rated anxiety symptoms pre-to-post CBT and SSRI treatment. Greater left NAcc volume also predicted greater decreases in clinician-rated anxiety symptoms pre-to-post CBT and SSRI treatment among youth with current anxiety. Across studies, results were similar across treatments, and findings were maintained when adjusting for patient’s age, sex, and total intracranial brain volume. We found no evidence for baseline amygdala or ventromedial PFC volume serving as treatment predictors across the two samples. Together, these findings provide promising support for the role of NAcc volume as an objective marker of anxiety treatment improvement that spans across development. Future studies should clarify the specific mechanisms through which NAcc volume exerts its therapeutic effects.
... Increased striatal response and reduced fronto-striatal connectivity during peer feedback has been linked to impaired recall of positive feedback in adolescents with social anxiety (27), suggesting that fronto-striatal mechanisms may bias learning in anxiety. This bias may then contribute to avoidance, as research has identified a fronto-striatal circuit that controls anxious avoidance behaviors in mice (28) and striatal response during avoidance correlates with anxiety in adult humans (29). Despite work implicating the VS (30 33), amygdala (34 36), and prefrontal cortex (PFC) (36 38) in risk for anxiety, the role of anxiety on neural functioning during approach-avoidance conflict in adolescents is still poorly understood (11,39). ...
... In rodents, the striatum is necessary for scaling fear to degree of threat (67) and amygdala-striatal and fronto-striatal circuits control avoidant behavior (28,68). In human adults, degree of VS responding during avoidance is dependent on anxiety (29). The considerable development of amygdala-VS and fronto-striatal connections in adolescence may help explain both the emergence of anxiety and the refinement of motivated behavior. ...
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Background: Anxiety disorders often emerge in adolescence and are associated with risk aversion. Risk aversion is at odds with the typical adolescent propensity for heightened sensation-seeking and can interfere with learning and contribute to further anxiety development. Methods: We investigated the neural and behavioral correlates of risk avoidance in 137 diverse early adolescents (MAge=11.3, SDAge=1.41; 61 girls) during a decision-making task involving risk-taking and cognitive control during fMRI. Voluntary cautious choice was compared to successful response inhibition to isolate the neural systems underlying risk avoidance and identify their relation to risk-taking and anxiety in adolescents. Results: Risk-taking frequency was not related to anxiety severity; however, higher anxious youth spent relatively longer making voluntary cautious choices than inhibiting when instructed. All youth showed widespread neural activation in decision-making and salience network regions when making cautious choices. Greater recruitment of the left inferior frontal gyrus during cautious choice was associated with greater risk-taking in high anxious youth and greater risk avoidance in low anxious youth, while greater striatal connectivity during cautious choice was associated with heightened risk-taking in those with low anxiety and risk avoidance in those with high anxiety. Conclusions: Relative to non-anxious adolescents, anxious adolescents take longer to make decisions in the face of approach-avoidance conflict and demonstrate unique brain-behavior associations during decision-making. Together, results from this study identify a unique role of fronto-striatal circuitry in risky decision-making among adolescents who struggle with anxiety.
... To address this, we examined how the PL and IL enable expression of opposing forms of signaled avoidance using an aversive go/ no-go task, wherein rats were well trained to discriminate between different auditory cues and shift between instigation and suppression of actions. This active/inhibitory avoidance task was patterned after those used in studies with humans, revealing activation of corticolimbic circuitry in situations requiring response initiation or inhibition to avoid negative consequences (Schlund et al., 2011(Schlund et al., , 2016Levita et al., 2012). Moreover, performance of this task in rats is dependent on neural activity within different subregions of the NAc, a main target of mPFC outputs (Piantadosi et al., 2018). ...
... Active/inhibitory avoidance training was similar to that reported by Piantadosi et al. (2018) and based on a paradigm used in humans, as described by Levita et al. (2012). Animals trained on the full version of the task (active/inhibitory avoidance) and on the single-cue active avoidance variation began training shortly after arrival at the colony, whereas those allocated to the active/inhibitory reward-seeking experiment received surgery before training. ...
Article
Flexible initiation or suppression of actions to avoid aversive events is crucial for survival. The prelimbic (PL) and infralimbic (IL) regions of the medial prefrontal cortex (mPFC) have been implicated in different aspects of avoidance and reward-seeking, but their respective contribution in instigating versus suppressing actions in aversive contexts remains to be clarified. We examined mPFC involvement in different forms of avoidance in rats well trained on different cued lever-press avoidance tasks. Active/inhibitory avoidance required flexible discrimination between auditory cues signaling foot-shock could be avoided by making or withholding instrumental responses. On a simpler active avoidance task, a single cue signaled when a lever press would avoid shock. PL inactivation disrupted active but not inhibitory avoidance on the discriminative task while having no effect on single-cued avoidance. In comparison, IL inactivation broadly impaired active and inhibitory avoidance. Conversely, on a cued appetitive go/no-go task, both IL and PL inactivation impaired inhibitory but not active reward-seeking, the latter effect being diametrically opposite to that observed on the avoidance task. These findings highlight the complex manner in which different mPFC regions aid in initiating or inhibiting actions in the service of avoiding aversive outcomes or obtaining rewarding ones. IL facilitates active avoidance but suppress inappropriate actions in appetitive and aversive contexts. In contrast, contextual valence plays a critical role in how the PL is recruited in initiating or suppressing actions, which may relate to the degree of cognitive control required to flexibly negotiate response or motivational conflicts and override prepotent behaviors.
... Rodent and human studies employing these active avoidance tasks have converged on three critical neural structures: the medial prefrontal cortex (mPFC), the amygdala, and the striatum [28,30,35,[37][38][39][40]. The mPFC is implicated in top-down control of emotion and decision-making and is thought to modulate subcortical structures such as the central and basolateral amygdala [29,41,42] and the ventral and dorsal striatum T.M. Ball and L.A. Gunaydin [12,[43][44][45] that are implicated in valence processing and defensive behaviors including active avoidance [39,46,47]. Indeed, greater synchrony between mPFC and both the amygdala and striatum predicts effective avoidance learning [30]. ...
... However, little is known mechanistically about passive avoidance behavior at the circuit level, likely because it is difficult to identify neural correlates in the absence of a behavior. In addition, few studies have directly compared active and passive avoidance behavior to identify similarities and differences in neural mechanisms (though see [45,60] for paradigms that facilitate this comparison). ...
Article
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Avoiding stimuli that predict danger is required for survival. However, avoidance can become maladaptive in individuals who overestimate threat and thus avoid safe situations as well as dangerous ones. Excessive avoidance is a core feature of anxiety disorders, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). This avoidance prevents patients from confronting maladaptive threat beliefs, thereby maintaining disordered anxiety. Avoidance is associated with high levels of psychosocial impairment yet is poorly understood at a mechanistic level. Many objective laboratory assessments of avoidance measure adaptive avoidance, in which an individual learns to successfully avoid a truly noxious stimulus. However, anxiety disorders are characterized by maladaptive avoidance, for which there are fewer objective laboratory measures. We posit that maladaptive avoidance behavior depends on a combination of three altered neurobehavioral processes: (1) threat appraisal, (2) habitual avoidance, and (3) trait avoidance tendency. This heterogeneity in underlying processes presents challenges to the objective measurement of maladaptive avoidance behavior. Here we first review existing paradigms for measuring avoidance behavior and its underlying neural mechanisms in both human and animal models, and identify how existing paradigms relate to these neurobehavioral processes. We then propose a new framework to improve the translational understanding of maladaptive avoidance behavior by adapting paradigms to better differentiate underlying processes and mechanisms and applying these paradigms in clinical populations across diagnoses with the goal of developing novel interventions to engage specific identified neurobehavioral targets.
... http://dx.doi.org/10.1101/498337 doi: bioRxiv preprint first posted online Dec. 17, 2018; Recently, a role for the nucleus accumbens (NAc), the main anatomical constituent of the ventral striatum (VS), is emerging in the context of anxiety (Gunaydin and Kreitzer, 2016;Levita et al., 2012) interconnected with the NAc function in behavioral adaptation (Haber and Behrens, 2014). In rodents, anxiety-like behaviors can be regulated by pharmacological (Heshmati et al., 2016;Lopes et al., 2012) or genetic (Crofton et al., 2017;Feng et al., 2017;Shen et al., 2016;Zhao and Gammie, 2018) manipulation of NAc neurochemistry. ...
... Importantly, anxiety-like behaviors have also been related to variations in NAc mitochondrial function Van Der Kooij et al., 2018) and brain energy metabolism (Larrieu et al., 2017). A few studies have also highlighted NAc structural (Kühn et al., 2011) and functional (Goff et al., 2013;Levita et al., 2012) alterations in association with anxiety and depression in humans. However, there is virtually no information on the NAc/VS neurochemical profile, nor on its relationship with anxiety. ...
Preprint
Full-text available
Individual differences in anxiety provide a differential predisposition to develop neuropsychiatric disorders. The neurochemical underpinnings of anxiety remain elusive, particularly in deep structures, such as the nucleus accumbens (NAc) whose involvement in anxiety is being increasingly recognized. We examined the associations between the neurochemical profile of human NAc metabolites involved in neural excitation and inhibition and inter-individual variation in temperamental and situational anxiety. Twenty-seven healthy 20-30 years-old human males were phenotyped with questionnaires for state and trait anxiety (State-Trait Anxiety Inventory, STAI), social anxiety (Liebowitz Social Anxiety Scale), depression (Beck Depression Inventory, BDI) and fatigue (Mental and Physical State Energy and Fatigue Scales, SEF). Using proton magnetic resonance spectroscopy (1H-MRS) at 7 Tesla (7T), we measured metabolite levels for glutamate, glutamine, GABA and taurine in the NAc with. Salivary cortisol was also measured. Strikingly, trait anxiety was negatively associated with NAc taurine content. Perceived situational stress was negatively associated with NAc GABA, while positively with the Glu/GABA ratio. These findings were specific, as no correlation was observed between NAc taurine or GABA and other phenotypic variables examined (i.e., state anxiety, social anxiety, depression, or cortisol), except for a negative correlation between taurine and state physical fatigue. This first 7T study of NAc neurochemistry shows relevant metabolite associations with individual variation in anxiety traits and situational stress and state anxiety measurements. The novel identified association between NAc taurine levels and trait anxiety may pave the way for clinical studies aimed at identifying new treatments for anxiety and related disorders.
... The mechanism about how R-SDS increased anxiety and female preference in the same subpopulation remains elusive. It has been reported that dopamine signaling in nucleus accumbens promotes female preference in rodents, and dopamine and its receptors in nucleus accumbens have been associated with the level of anxiety in rodents and humans [21][22][23] . Interestingly, it has been reported that suppression of CREB activity in nucleus accumbens impairs R-SDS-induced social avoidance and heightened anxiety as measured by the EPM test [24][25][26] . ...
Article
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Repeated social defeat stress (R-SDS) induces multiple behavioral changes in mice. However, the relationships between these behavioral changes were not fully understood. In the first experiment, to examine how the social avoidance is related to R-SDS-impaired behavioral flexibility, 10-week-old male C57BL/6N mice received R-SDS followed by the social interaction test and the attentional set shifting task. R-SDS impaired attentional set shifting irrespective of the development of social avoidance. In the second experiment, to examine whether R-SDS affects sexual preference and how this behavioral change is related to the social avoidance and R-SDS-heightened anxiety, another group of 10-week-old male C57BL/6N mice were subjected to R-SDS followed by the social interaction test, the female encounter test and the elevated plus maze test. The anxiety was heightened in the defeated mice without social avoidance, but not in those which showed social avoidance. Furthermore, female preference was increased specifically in the defeated mice which showed heightened anxiety, but was not related to the level of social avoidance. Together, these results showed that attentional set shifting is more sensitive to R-SDS than social interaction, and that female preference is affected by R-SDS in association with heightened anxiety rather than the social avoidance.
... The PPE_low group mainly felt disgusted while watching the PP videos, which was accompanied by NAc deactivation. Although the NAc is often described as one part of the 'pleasure system' of the brain (for a review see Berridge & Kringelbach, 2015), this region is also involved in modulating responses to aversive events (e.g., Becerra et al., 2013;Carlezon & Thomas 2009;Levita et al., 2009Levita et al., , 2012Yuan et al., 2019). For example, Becerra et al. (2013) showed that pain onset ( The described functions of the NAc (aversion coding, avoidance/rejection) fit nicely to the differential degrees of NAc deactivation displayed by the two groups. ...
Article
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Background Millions of people enjoy watching videos of pimple treatments. The underlying neural mechanisms of this enjoyment have not been investigated so far. Method We administered a total of 96 video clips from three categories: Pimple Popping (PP), Water Fountains (WF), and Steam Cleaning (SC). The PP videos showed a pimple or blackhead that was opened to squeeze out the pus or sebum. The female participants (mean age: 24 years) were assigned to one of two groups: females who reported to enjoy watching PP (PPE_high; n = 38) and those with little enjoyment (PPE_low; n = 42). We analyzed brain activity in regions of interest (ROI) involved in the encoding of pleasure and aversion (e.g., nucleus accumbens (NAc), insula). Results The PPE_high group showed less deactivation of the NAc (ROI finding), more frontopolar activation (whole-brain finding), and stronger accumbens-insula coupling than the PPE_low group. Conclusions A specific pattern of brain activity and connectivity that involves the NAc and insula (coding of aversion/pleasure) and the frontopolar region (prediction of outcomes of motor decisions) is associated with the enjoyment of PP videos.
... It has been reported that trait anxiety and OCD risk are positively correlated with the volume of NAc (7,8). Functional neuroimaging reveals that the NAc activation correlates positively with the severity of human anxiety and obsessive-compulsive symptoms in OCD patients (9,10). More importantly, deep brain stimulation (DBS) targeting the NAc core has been found to improve obsessive-compulsive symptoms and decrease ratings of anxiety in patients suffering from treatment-resistant OCD or depression (11,12). ...
Article
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Significance Anxiety disorders and obsessive-compulsive disorder (OCD) are highly prevalent and debilitating psychiatric disorders commonly co-occurring in our stressful modern life. Yet the common effective therapeutic target is still unknown. Here we report that activation of the histaminergic afferent system, particularly the histamine H3 receptor, in the nucleus accumbens (NAc) core, a vital node in the limbic loop, inhibits glutamatergic synaptic transmission in the circuit from the prelimbic prefrontal cortex (PrL) to NAc and improves both anxiety- and obsessive-compulsive-like behaviors induced by restraint stress. Our results define a common glutamatergic PrL–NAc circuit involved in both anxiety- and obsessive-compulsive-like behaviors modulated by the H3 presynaptic heteroreceptor and pave a path for developing potential strategies for clinical treatment of anxiety and OCD.
... A critical role in stress response and anxiety has been attributed to the BNST in both rodent and human studies [3,54,55]. The NAc is a key component of the brain "reward" circuits [56][57][58] in emotional and motivated actions and its dysfunction has been strongly implicated in emotional disorders [59,60], especially in exerting a dominant influence on anxiety [10,61,62]. Although one study noted a projection from BNST to NAc [11], knowledge of the function of the link between the stress response neurocircuitry and reward circuitry not known. ...
Article
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The prevailing view is that parvalbumin (PV) interneurons play modulatory roles in emotional response through local medium spiny projection neurons (MSNs). Here, we show that PV activity within the nucleus accumbens shell (sNAc) is required for producing anxiety-like avoidance when mice are under anxiogenic situations. Firing rates of sNAcPV neurons were negatively correlated to exploration time in open arms (threatening environment). In addition, sNAcPV neurons exhibited high excitability in a chronic stress mouse model, which generated excessive maladaptive avoidance behavior in an anxiogenic context. We also discovered a novel GABAergic pathway from the anterior dorsal bed nuclei of stria terminalis (adBNST) to sNAcPV neurons. Optogenetic activation of these afferent terminals in sNAc produced an anxiolytic effect via GABA transmission. Next, we further demonstrated that chronic stressors attenuated the inhibitory synaptic transmission at adBNSTGABA → sNAcPV synapses, which in turn explains the hyperexcitability of sNAc PV neurons on stressed models. Therefore, activation of these GABAergic afferents in sNAc rescued the excessive avoidance behavior related to an anxious state. Finally, we identified that the majority GABAergic input neurons, which innervate sNAcPV cells, were expressing somatostatin (SOM), and also revealed that coordination between SOM- and PV- cells functioning in the BNST → NAc circuit has an inhibitory influence on anxiety-like responses. Our findings provide a potentially neurobiological basis for therapeutic interventions in pathological anxiety.
... Importantly, the NAc has also been implicated in coping behaviors. Use of active coping behaviors was associated with increases in NAc activity while passive coping was association with reductions in NAc activity (Levita et al., 2012). ...
Article
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It has been well recognized that exposure to stress can lead to the onset of psychosocial disorders such as depression. While there are a number of antidepressant therapies currently available and despite producing immediate neurochemical alterations, they require weeks of continuous use in order to exhibit antidepressant efficacy. Moreover, up to 30% of patients do not respond to typical antidepressants, suggesting that our understanding of the pathophysiology underlying stress-induced depression is still limited. In recent years inflammation has become a major focus in the study of depression as several clinical and preclinical studies have demonstrated that peripheral and central inflammatory mediators, including interleukin (IL)-1β, are elevated in depressed patients. Moreover, it has been suggested that inflammation and particularly neuroinflammation may be a direct and immediate link in the emergence of stress-induced depression due to the broad neural and glial effects that are elicited by proinflammatory cytokines. Importantly, individual differences in inflammatory reactivity may further explain why certain individuals exhibit differing susceptibility to the consequences of stress. In this review article, we discuss sources of individual differences such as age, sex and coping mechanisms that are likely sources of distinct changes in stress-induced neuroimmune factors and highlight putative sources of exaggerated neuroinflammation in susceptible individuals. Furthermore, we review the current literature of specific neural and glial mechanisms that are regulated by stress and inflammation including mitochondrial function, oxidative stress and mechanisms of glutamate excitotoxicity. Taken together, the impetus for this review is to move towards a better understanding of mechanisms regulated by inflammatory cytokines and chemokines that are capable of contributing to the emergence of depressive-like behaviors in susceptible individuals.
... Extinction is a distributed neural process involving the ventromedial prefrontal cortex (vmPFC), hippocampus, and amygdala (Quirk and Mueller, 2008). More recent evidence extends this network to include the nucleus accumbens (NAc) and related perceptual circuitry (Apergis-Schoute et al., 2014;Levita et al., 2012). Learning and plasticity in these regions underlie the creation and sustainment of extinction memories. ...
Article
Imagination is an internal simulation of real-life events and a common treatment tool for anxiety disorders; however, the neural processes by which imagination exerts behavioral control are unclear. This investigation tests whether and how imagined exposures to a threatening stimulus, conditioned in the real world, influence neural and physiological manifestations of threat. We found that imagined and real extinction are equally effective in the reduction of threat-related neural patterns and physiological responses elicited upon re-exposure to real-world threatening cues. Network connectivity during the extinction phase showed that imagined, like real, extinction engaged the ventromedial prefrontal cortex (vmPFC) as a central hub. vmPFC, primary auditory cortex, and amygdala activation during imagined and real extinction were predictive of individual differences in extinction success. The nucleus accumbens, however, predicted extinction success in the imagined extinction group alone. We conclude that deliberate imagination can attenuate reactions to threat through perceptual and associative learning mechanisms. Reddan et al. demonstrate that threat responses can be extinguished through imagined simulations of the conditioned stimuli. Like real extinction, imagined extinction engages the ventromedial prefrontal cortex, amygdala, and related perceptual cortices. Nucleus accumbens activity predicts an individual's ability to successfully extinguish via imagination.
... performance ( Heimberg et al., 1999 ) that, at high levels, 23 becomes social anxiety disorder (formerly known as social 24 phobia) ( Heimberg et al., 1999 ). 25 Identifying neurobiological factors related to individual 26 differences in temperamental and situational anxiety will ( Larrieu et al., 2017 ). A few stud-57 ies have also highlighted NAc structural ( Kühn et al., 2011 ) 58 and functional ( Goff et al., 2013;Levita et al., 2012 ) alter-59 ations in association with anxiety and depression in humans. 60 However, there is virtually no information on the NAc/VS 61 neurochemical profile, nor on its relationship with anxiety. ...
Article
Individual differences in anxiety provide a differential predisposition to develop neuropsychiatric disorders. The neurochemical underpinnings of anxiety remain elusive, particularly in deep structures, such as the nucleus accumbens (NAc) whose involvement in anxiety is being increasingly recognized. We examined the associations between the neurochemical profile of human NAc metabolites involved in neural excitation and inhibition and inter-individual variation in temperamental and situational anxiety. Twenty-seven healthy 20–30 years-old human males were phenotyped with questionnaires for state and trait anxiety (State-Trait Anxiety Inventory, STAI), social anxiety (Liebowitz Social Anxiety Scale), negative mood (Beck Depression Inventory, BDI) and fatigue (Mental and Physical State Energy and Fatigue Scales, SEF). Using proton magnetic resonance spectroscopy (¹H-MRS) at 7 Tesla (7T), we measured metabolite levels for glutamate, glutamine, GABA and taurine in the NAc. Salivary cortisol was also measured. Strikingly, trait anxiety was negatively associated with NAc taurine content. Perceived situational stress was negatively associated with NAc GABA, while positively with the Glu/GABA ratio. No correlation was observed between NAc taurine or GABA and other phenotypic variables examined (i.e., state anxiety, social anxiety, negative mood, or cortisol), except for a negative correlation between taurine and state physical fatigue. This first 7T study of NAc neurochemistry shows relevant metabolite associations with individual variation in anxiety traits and situational stress and state anxiety measurements. The novel identified association between NAc taurine levels and trait anxiety may pave the way for clinical studies aimed at identifying new treatments for anxiety and related disorders.
... Optogenetic activation of IL terminals in the nucleus accumbens (NAc) of rats following SNI (model of chronic neuropathic pain) is sufficient to suppress pain predictive cue (PPC)-avoidance, while chemogenetic inactivation of hSyn-expressing IL neurons reinstates PPC-avoidance (Schwartz et al., 2017). This would suggest that during maintenance of neuropathic pain, the IL projections to the NAc inhibit avoidance behavior, which is a key component in anxiety (Levita et al., 2012). ...
Article
Chronic pain and anxiety can be debilitating disorders and are often comorbid. There is significant overlap in the neural circuitry of pain and anxiety. Current treatments for these disorders are often ineffective and have negative side-effects, making further research into pain and anxiety circuitry crucial. The technique of optogenetics is propelling the possibilities for functional neuroanatomical research. With the use of light-activated proteins called opsins, optogenetics enables the switching on or off of a selective population of neurons, with precise temporal control. This manuscript reviews recent research that has employed optogenetic methodology to advance understanding of the neural circuitry of pain and anxiety and identify novel approaches for their improved treatment.
... Structural elements and functional activities in neuronal circuits including the nucleus accumbens are involved in reward memory versus fear memory (Fadok et al., 2010;Hikida et al., 2016;Ikemoto, 2007;Kochenborger et al., 2012;Russo et al., 2010;Thomas et al., 2002;Yang and Liang, 2014). The abnormality of the nucleus accumbens may lead to anxiety disorders (Anderson et al., 2018;Barrot et al., 2005;Fu et al., 2017;Heshmati et al., 2016;Levita et al., 2012). Some cellular processes and signaling molecules in the nucleus accumbens are presumably involved in anxiety and major depression (Bosch-Bouju et al., 2016;Feng et al., 2017;Francis and Lobo, 2017;Kim et al., 2008;Lim et al., 2012;Monk et al., 2008;Salamone et al., 2005;Si et al., 2018;Zhu et al., 2017). ...
Article
Anxiety is presumably driven by fear memory. The nucleus accumbens involves emotional regulation. Molecular profiles in the nucleus accumbens related to stress-induced fear memory remain elucidated. Fear memory in mice was induced by a paradigm of social defeat. Physical and psychological stress was delivered to an intruder that was attacked by an aggressive resident. Meanwhile, an observer experienced psychological stress by seeing aggressor attacks. The nucleus accumbens tissues from intruder and observer mice that appear fear memory and anxiety as well as control mice were harvested for analyses of mRNA and miRNA profiles by high throughput sequencing. In the nucleus accumbens of intruders and observers with fear memory and anxiety, genes encoding AdrRα, AChRM2/3, GluRM2/8, HrR1, SSR, BDNF and AC are upregulated, while genes encoding DR3/5, PR2, GPγ8 and P450 are downregulated. Physical and/or psychological stress leads to fear memory and anxiety likely by molecules relevant to certain synapses. Moreover, there are differential expressions in genes that encode GABARA, 5-HTR1/5, CREB3, AChRM2, RyR, Wnt and GPγ13 in the nucleus accumbens from intruders versus observers. GABAergic, serotonergic and cholinergic synapses as well as calcium, Wnt and CREB signaling molecules may be involved in fear memory differently induced by psychological stress and physical/psychological stress. The data from analyzing mRNA and miRNA profiles are consistent. Some molecules are validated by qRT-PCR and dual luciferase reporter assay. Fear memory and anxiety induced by the mixture of physical and psychological stress or psychological stress appear influenced by complicated molecular mechanisms in the nucleus accumbens.
... However, sex-specific neuroinflammatory effects of opioids in the reward neurocircuitry are not well-defined. Therefore, the present study explored the effects of chronic treatment with a prototypical opioid agonist, oxycodone, and withdrawal from oxycodone treatment, on sex-specific changes in neuroimmune responses in the prefrontal cortex (PFC) and nucleus accumbens (NAc), brain regions primarily associated with motivation, reward memory, compulsivity, and withdrawal phenotypes Volkow, 2010, 2016;Koya et al., 2006;Levita et al., 2012;Russo and Nestler, 2013). ...
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Opioid use disorder is a leading cause of morbidity and mortality in the United States. Increasing pre-clinical and clinical evidence demonstrates sex differences in opioid use and dependence. However, the underlying molecular mechanisms contributing to these effects, including neuroinflammation, are still obscure. Therefore, in this study, we investigated the effect of oxycodone exposure and withdrawal on sex- and region-specific neuroimmune response. Real-time PCR and multiplex cytokine array analysis demonstrated elevated neuroinflammation with increased pro-inflammatory cytokine levels, and aberrant oligodendroglial response in reward neurocircuitry, following withdrawal from chronic oxycodone treatment. Chronic oxycodone and withdrawal treated male mice had lower mRNA expression of TMEM119 along with elevated protein levels of pro-inflammatory cytokines/chemokines and growth factors (IL-1β, IL-2, IL-7, IL-9, IL-12, IL-15, IL17, M-CSF, VEGF) in the prefrontal cortex (PFC) as compared to their female counterparts. In contrast, reduced levels of pro-inflammatory cytokines/chemokines (IL-1β, IL-6, IL-9, IL-12, CCL11) was observed in the nucleus accumbens (NAc) of oxycodone and withdrawal-treated males as compared to female mice. No treatment specific effects were observed on the mRNA expression of putative microglial activation markers (Iba1, CD68), but an overall sex specific decrease in the mRNA expression of Iba1 and CD68 was found in the PFC and NAc of male mice as compared to females. Moreover, a sex and region-specific increase in the mRNA levels of oligodendrocyte lineage markers (NG2, Sox10) was also observed in oxycodone and withdrawal treated animals. These findings may open a new avenue for development of sex-specific therapeutics for opioid dependence by targeting region-specific neuroimmune signaling.
... Finally, H 2 O 15 PET revealed in apathetic PD patients a blunted response to money in the vmPFC, amygdala, striatum, and midbrain [40], which belong to a neural circuit involved in the representation of the reward prediction of stimuli and actions and the influence of the motivational value (positive or negative) on behavioral choice (approach or avoidance) [41]. ...
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Apathy, depression, and anxiety are among the most important non-motor signs of Parkinson’s disease (PD). This may be encountered at early stages of illness and represent a major source of burden. Understanding their pathophysiology is a major prerequisite for efficient therapeutic strategies. Anatomical and metabolic imaging studies have enabled a breakthrough by demonstrating that widespread abnormalities within the limbic circuits notably the orbitofrontal and anterior cingulate cortices, amygdala, thalamus, and ventral striatum are involved in the pathophysiology of depression, anxiety, and apathy in PD. Functional imaging has further shown that mesolimbic dopaminergic but also serotonergic lesions play a major role in the mechanisms of these three neuropsychiatric manifestations, which has direct therapeutic implications.
... Specifically, contextual fear conditioning has a highly influential role in avoidance learning, which is driven in part by the NAc. Avoidance behavior was not only found to visibly align with the activation and deactivation during both active and passive avoidance, but also relied on similar, functionally connected, bilateral regions of the brain, which included the caudate and dorsal anterior cingulate (Ernst et al., 2005;Levita et al., 2012). Indeed, this is supported by a more recent study that revealed that the functional connectivity of the dorsal lateral prefrontal cortex and NAc predicted the impact of treatment on anti-anxiety symptoms in repetitve transcranial magnetic stimulation (rTMS) treatment of depression (Haynes et al., 2018). ...
Article
Anxiety Disorders are prevalent and often chronic, recurrent conditions that reduce quality of life. The first-line treatments, such as serotonin reuptake inhibitors and cognitive behavioral therapy, leave a significant proportion of patients symptomatic. As psychiatry moves toward targeted circuit-based treatments, there is a need for a theory that unites the phenomenology of anxiety with its underlying neural circuits. The Alarm, Belief, Coping (ABC) theory of anxiety describes how neural circuits associated with anxiety interact with each other and domains of the anxiety symptoms, both temporally and spatially. The latest advancements in neuroimaging techniques offer the ability to assess these circuits in vivo. Using Neurosynth, a large open-access meta-analytic imaging database, the association between terms associated with specific neural circuits was explored within the ABC theory framework. Alarm-related terms were associated with the amygdala, anterior cingulum, insula, and bed nucleus of stria terminalis. Belief-related terms were associated with medial prefrontal cortex, precuneus, bilateral temporal poles and hippocampus. Coping-related terms were associated with the ventrolateral and dorsolateral prefrontal cortices, basal ganglia and anterior cingulate. Neural connections underlying the functional neuroanatomy of the ABC model were observed. Additionally, there was considerable interaction and overlap between circuits associated with the symptom domains. Further neuroimaging research is needed to explore the dynamic interaction between the functional domains of the ABC theory. This will pave the way for further understanding the neuroanatomical underpinnings of anxiety disorders and provide an evidence-based foundation for the development of targeted treatments, such as neuromodulation.
... Additionally, we identified vmPFC-NAcc connectivity in the subnetwork. NAcc is ascribed a central role in mediating the behavioral aspects of defensive responses in face of imminent threat, and active avoidance behavior in particular 103,106,114 . Thus, enhanced NAcc connectivity may suggest an increased preparation to execute acute defensive behaviors with threat imminence. ...
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Excessive expression of threat-anticipatory defensive responses is central in anxiety. Animal research indicates that anticipatory responses are dynamically organized by threat imminence and rely on conserved circuitry. Insight from translational work on threat imminence could guide mechanistic research mapping abnormal function in this circuitry to aberrant defensive responses in anxiety. Here, we initiate such research. Fifty pediatric anxiety patients and healthy-comparisons (33 females) completed a threat-anticipation task whereby cues signaled delivery of highly-painful (threat) or non-painful (safety) heat. Temporal changes in skin-conductance indexed defensive responding as function of threat imminence. Resting-state functional connectivity data were used to identify intrinsic-function correlates of anticipatory response within a specific functional network derived from translational research. Results indicate that anxiety was associated with greater increase in anticipatory response as threats became more imminent. Magnitude of increase in threat-anticipatory responses corresponded to intrinsic connectivity within a cortical-subcortical circuit; importantly, more severe anxiety was associated with greater connectivity between ventromedial prefrontal cortex and hippocampus and basolateral amygdala, a circuit implicated in animal models of anxiety. These findings link basic-translational and clinical research, highlighting aberrant intrinsic function in conserved defensive circuitry as potential pathophysiological mechanism in anxiety.
... It is made Piantadosi, Yeates, and Floresco, 2018). Our studies are the first to combine intermixed 201 active and inhibitory avoidance (Levita, Hoskin, and Champi, 2012) or reward-seeking 202 trials with increasing effort requirements throughout the task, requiring participants to 203 switch between withholding physical effort on inhibitory trials and deploying increasing 204 amounts of effort on active trials in each task. This design allows us to directly compare 205 performance on active and inhibitory trials in the context of increasing effort demands. ...
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We must often decide how much effort to exert or withhold to avoid undesirable outcomes or obtain rewards. In depression and anxiety, levels of avoidance tend to be excessive and reward-seeking is reduced. Yet outstanding questions remain about the links between motivated action/inhibition and anxiety and depression symptoms, and whether they differ between men and women. Here we examined the relationship between anxiety and depression symptoms and performance on effortful active and inhibitory avoidance (Study 1) and reward seeking (Study 2) in humans. Undergraduates and paid online workers ( N Avoid = 545, N Reward = 310; N Female = 368, N Male = 450, M Age = 22.58, Range Age = 17-62) were assessed on the Beck Depression Inventory (BDI-II) and the Beck Anxiety Inventory (BAI) and performed an instructed online avoidance or reward-seeking task. Participants had to make multiple presses on active trials and withhold presses on inhibitory trials to avoid an unpleasant sound (Study 1) or obtain points towards a monetary reward (Study 2). Overall, men deployed more effort than women in both avoidance and reward-seeking, and anxiety symptoms were negatively associated with active reward-seeking accuracy. Gender moderated the relationship between anxiety symptoms and inhibitory avoidance, such that women with higher anxiety showed reduced inhibitory avoidance accuracy. Anxiety symptoms predicted poorer active avoidance performance for those high in depression symptoms only. Our results illuminate effects of gender and symptom comorbidity in the relationship between mood disorder symptoms and the motivation to actively and effortfully respond to obtain positive and avoid negative outcomes. Significance statement We often need to take effortful action, or withhold action, to avoid unpleasant outcomes or obtain rewards. Depression and anxiety can impact these behaviours’ effectiveness, but the role of depression in avoidance and anxiety in reward-seeking is not well understood. Gender differences in avoidance and reward-seeking have also not been examined. Here, we present a task in which participants had to make or withhold button presses to avoid hearing an unpleasant sound or to obtain a reward. Men deployed more effort than women in avoidance, and women with higher levels of anxiety symptoms had lower inhibitory avoidance accuracy than men. Our results illuminate gender differences in how depressive and anxiety symptoms impact our ability to avoid threats and obtain rewards.
... Properly feeding one's mitochondria could even improve one's social rank-as suggested by a study on rats. In rats, just like in humans, motivation and social competition are regulated by the nucleus accumbens, a brain structure whose malfunctioning contributes to depression and anxiety (Bewernick et al., 2010;Chen, Rada, Bützler, Leibowitz, & Hoebel, 2012;Levita, Hoskin, & Champi, 2012). Anxious rats have lower concentrations of ATP (implying worse-functioning mitochondria) in their nucleus accumbens than less anxious ones, and they tend to become subordinate to them during social encounters (Hollis et al., 2015). ...
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Most of the energy we get to spend is furnished by mitochondria, minuscule living structures sitting inside our cells or dispatched back and forth within them to where they are needed. Mitochondria produce energy by burning down what remains of our meal after we have digested it, but at the cost of constantly corroding themselves and us. Here we review how our mitochondria evolved from invading bacteria and have retained a small amount of independence from us; how we inherit them only from our mother; and how they are heavily implicated in learning, memory, cognition, and virtually every mental or neurological affliction. We discuss why counteracting mitochondrial corrosion with antioxidant supplements is often unwise, and why our mitochondria, and therefore we ourselves, benefit instead from exercise, meditation, sleep, sunshine, and particular eating habits. Finally, we describe how malfunctioning mitochondria force rats to become socially subordinate to others, how such disparity can be evened off by a vitamin, and why these findings are relevant to us.
... In short, the tripartite circuit consisting of the hippocampus, medial prefrontal cortex (mPFC), and the amygdala, and the circuit's projection to the nucleus accumbens (NAcc), are well accepted to be responsible for the acquisition and expression of fear-related avoidance (Duvarci & Pare, 2014;Fendt & Fanselow, 1999;Janak & Tye, 2015;Killcross, Robbins & Everitt, 1997;Oleson, Gentry, Chioma, & Cheer, 2012;Ramirez, Moscarello, LeDoux & Sears, 2015;Sangha, Diehl, Bergstrom, & Drew, 2020). Similar to rodent models, neuroimaging studies in humans found that fear-related avoidance activates the human homolog of tripartite circuit, consisting of the hippocampus, amygdala, and ventral striatum, in addition to the thalamus and orbitofrontal cortex (Bolstad et al., 2013;Eldar, Hauser, Dayan, & Dolan, 2016;Jensen et al., 2003;Kim, Shimojo, & O'Doherty, 2006;Levita, Hoskin, & Champi, 2012;Mobbs et al., 2009;Schlund, Magee, & Hudgins, 2011). However, the neural circuits underlying CS-avoidance are largely unknown to date in both rodent and human models. ...
Article
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Avoiding stimuli that were previously associated with threat is essential for adaptive functioning, but excessive avoidance that persists in the absence of threat can turn dysfunctional and results in severe impairments. Fear and avoidance conditioning models have substantially contributed to the understanding of safety behaviors towards learnt fear stimuli. Safety behaviors are executed in the presence of a feared stimulus to prevent the upcoming threat and are well-established in laboratory models. Avoidance of learnt fear, i.e., avoidance of the feared stimulus itself, is typically initiated before the onset of a feared stimulus: individuals oftentimes avoid fear stimuli to prevent negative emotions evoked by them or ultimately the associated threat. Avoidance of learnt fear is surprisingly understudied despite of its prevalence in pathological anxiety. The current overview proposes potential behavioral mechanisms and neural circuits of avoidance of learnt fear in humans, and discusses findings and paradigms suitable for examining it. Specifically, higher-order conditioning, decision making paradigms, and context-cue conditioning investigate distinct forms of avoidance of learnt fear. We also discuss the clinical prospects and future directions of research in avoidance of learnt fear.
... The findings in animals are consistent with recent human brain imaging data suggesting that the amygdala, prefrontal cortex, and striatum are involved in avoidance learning Schlund et al., 2011;Levita et al., 2012;Schlund et al., 2013;Collins et al., 2014;Boeke et al., 2017). Indeed, in addition there is evidence from human research demonstrating that autonomic arousal decreases during avoidance learning (Lovibond et al., 2008;Delgado et al., 2009;Vervliet and Indekeu, 2015;Boeke et al., 2017). ...
Article
Resistant avoidance behaviors play a crucial role in the maintenance of anxiety disorders and are therefore central targets of therapeutic interventions. In the present study, the development of avoidance behavior was investigated in 24 healthy participants who repeatedly prematurely terminated the exposure to increasing interoceptive threat, i.e., the feeling of dyspnea induced by increasing inspiratory resistive loads that were followed by the ultimate threat, a short breathing occlusion. Physiological responses and subjective anxiety preceding terminations were compared to matched intervals of a matched control group (N=24) who completed the exposure. Initially, participants terminated during the ultimate threat, i.e., during occlusion. This first termination was preceded by a strong surge in autonomic arousal and reported anxiety. Startle reflex and the P3 component of event-related brain potentials to startle probes were strongly inhibited, indicating preparation for defensive action. With repetitive terminations, individuals successively terminated earlier, avoiding exposure to the occlusion. This avoidant behavior was accompanied by alleviated autonomic arousal as compared to the first termination. In addition, no indication of physiological response preparation was found implying that the avoidance behavior was performed in a rather habitual way. Matched controls did not show any indication of a defensive response surge in the matched intervals. In matched controls, no changes in physiological response patterns were detected while anxiety levels increased with repetitions. The present results shed new light on our understanding of the motivational basis of avoidance behavior and may help to refine etiological models, behavioral analysis and therapeutic strategies in treating anxiety disorders.
... To a certain extent, reduced functional communication of parahippocampus in this study may demonstrate that the capacity to control adverse memory breaks down after experiencing childhood trauma, increasing the tendency of HA personality. The HA personality, a trait associated with behavioral inhibition, plays a key role in the etiology and maintenance of aberrant avoidance behaviors in anxiety (36) and sub-clinical depression (37). Dynamic analyses provide additional information that is different from the static functional connectivity. ...
Article
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As one of the most studied resting-state functional networks, default mode network (DMN) is related to pathogenesis in neuropsychiatry. However, it is unclear whether changed DMN connectivity is transformed into vulnerability to psychopathology in adults who experienced childhood trauma, and what is the underlying genetic basis. Exploring the effect of DMN on environment-behavior pathway and the related genetic modulation mechanisms could further a better understanding of psychiatric pathogenesis and early prevention strategy. Two hundred and sixteen young adults with varying levels of early trauma indexed by the Childhood Trauma Questionnaire (CTQ) were recruited from the community. Static and dynamic functional connectivity based on DMN seeds and independent component analysis based on whole-brain voxels were combined to explore DMN alterations related to the CTQ score. Relationships between CTQ score, DMN connectivity, and behavioral scores were confirmed by mediation effect analysis. Imaging-genomic correlations were further used to identify risk genes whose expression was associated with the DMN changes. Dysregulated DMN connectivity was found both in seed-level and voxel-level analyses. Moreover, the functional disruption in the left temporal pole, right parahippocampal gyrus, and frontoparietal connectivity mediated the effects of childhood trauma on emotional behavior. The serotonin transporter gene was identified and might suggest the biological underpinning of the relationship between childhood trauma, DMN, and emotion regulation. Changed DMN may be useful as biomarkers to provide a powerful supplement to psychological evaluation related to childhood trauma. Combined with gene expression profiles, our findings advance a more integrative understanding of DMN alterations induced by childhood trauma, and clarify its implications for psychiatric pathogenesis and early prevention strategies.
... Additionally, we identified vmPFC-NAcc connectivity in the subnetwork. NAcc is ascribed a central role in mediating the behavioral aspects of defensive responses in face of imminent threat, and active avoidance in particular (Moscarello and Maren, 2018;Ramirez et al., 2015;Levita et al., 2012). Thus, enhanced NAcc connectivity may suggest an increased propensity to execute acute defensive behaviors with increasing threat imminence. ...
Article
Full-text available
Excessive expression of fear responses in anticipation of threat occurs in anxiety, but understanding of underlying pathophysiological mechanisms is limited. Animal research indicates that threat-anticipatory defensive responses are dynamically organized by threat imminence and rely on conserved circuitry. Insight from basic neuroscience research in animals on threat imminence could guide mechanistic research in humans mapping abnormal function in this circuitry to aberrant defensive responses in pathological anxiety. 50 pediatric anxiety patients and healthy-comparisons (33 females) completed an instructed threat-anticipation task whereby cues signaled delivery of painful (threat) or non-painful (safety) thermal stimulation. Temporal changes in skin-conductance indexed anxiety effects on anticipatory responding as function of threat imminence. Multivariate network analyses of resting-state functional connectivity data from a subsample were used to identify intrinsic-function correlates of anticipatory-response dynamics, within a specific, distributed network derived from translational research on defensive responding. By considering threat imminence, analyses revealed specific anxiety effects. Importantly, pathological anxiety was associated with excessive deployment of anticipatory physiological response as threat, but not safety, outcomes became more imminent. Magnitude of increase in threat-anticipatory physiological responses corresponded with magnitude of intrinsic connectivity within a cortical-subcortical circuit. Moreover, more severe anxiety was associated with stronger associations between anticipatory physiological responding and connectivity that ventromedial prefrontal cortex showed with hippocampus and basolateral amygdala, regions implicated in animal models of anxiety. These findings link basic and clinical research, highlighting variations in intrinsic function in conserved defensive circuitry as a potential pathophysiological mechanism in anxiety.
... The NAcc may therefore play a role in emitting and withholding responses to avoid harm. 45 Neuroticism and/or harm avoidance have also been linked to variations in several other brain regions, including the basal ganglia, dorsolateral prefrontal cortex, and cerebellum. [46][47][48][49][50] ...
Article
Background A number of recent investigations have focused on the neurobiology of obsessive–compulsive personality disorder (OCPD). However, there have been few reviews of this literature with no detailed model proposed. We therefore undertook a systematic review of these investigations, aiming to map the available evidence and investigate whether it is possible to formulate a detailed model of the neurobiology of OCPD. Methods OCPD can be considered from both categorical and dimensional perspectives. An electronic search was therefore conducted using terms that would address not only OCPD as a category, but also related constructs, such as perfectionism, that would capture research on neuropsychology, neuroimaging, neurochemistry, and neurogenetics. Results A total of 1059 articles were retrieved, with 87 ultimately selected for abstract screening, resulting in a final selection of 49 articles focusing on neurobiological investigations relevant to OCPD. Impaired executive function and cognitive inflexibility are common neuropsychological traits in this condition, and suggest that obsessive–compulsive disorder (OCD) and OCPD may lie on a continuum. However, neuroimaging studies in OCPD indicate the involvement of specific neurocircuitry, including the precuneus and amygdala, and so suggest that OCD and OCPD may have important differences. Although OCPD has a heritable component, we found no well-powered genetic studies of OCPD. Conclusion Although knowledge in this area has advanced, there are insufficient data on which to base a comprehensive model of the neurobiology of OCPD. Given the clinical importance of OCPD, further work to understand the mechanisms that underpin this condition is warranted.
... Neuroimaging studies of human active avoidance parallel rodent studies. Avoidance activates both the amygdala and the ventral striatum, and their activities are correlated (Delgado et al., 2009;Levita et al., 2012), consistent with BA activation of VS in rodents. The vmPFC, which is the human homologue of rodent IL (Bicks et al., 2015;Heilbronner et al., 2016) is also activated during avoidance (Boeke et al., 2017;Wendt et al., 2017), consistent with IL reduction of conditioned fear responses Bravo-Rivera et al., 2014). ...
Article
Traditional active avoidance tasks have advanced the field of aversive learning and memory for decades and are useful for studying simple avoidance responses in isolation; however, these tasks have limited clinical relevance because they fail to model key features of clinical avoidance. In contrast, platform-mediated avoidance (PMA) more closely resembles clinical avoidance because the response i) is associated with an unambiguous safe location, ii) is not associated with an artificial termination of the warning signal, and iii) is associated with a decision-based appetitive cost. Recent findings on the neuronal circuits of PMA have confirmed that amygdala-striatal circuits are essential for avoidance. However, in PMA the prelimbic cortex facilitates the avoidance response early during the warning signal, perhaps through disinhibition of the striatum. Future studies on avoidance need to account for additional factors such as sex differences and social interactions that will advance our understanding of maladaptive avoidance contributing to neuropsychiatric disorders.
... Excessive associative fear or the inability to suppress fear responses is associated with anxiety disorders and stress/trauma-related disorders such as PTSD. Brain imaging studies also implicate the nucleus accumbens in anxiety disorders by showing NAc activation in response to aversive stimuli and anxiety-dependent active avoidance behavior (Jensen et al., 2003;Levita et al., 2012). There may be some overlap in appetitive and aversive circuits within the NAc. ...
Article
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The nucleus accumbens (NAc), consisting of core (NAcC) and shell (NAcS) sub-regions, has primarily been studied as a locus mediating the effects of drug reward and addiction. However, there is ample evidence that this region is also involved in regulating aversive responses, but the exact role of the NAc and its subregions in regulating associative fear processing remains unclear. Here, we investigated the specific contribution of the NAcC and NAcS in regulating both fear expression and fear extinction in C57BL/6J mice. Using Arc expression as an indicator of neuronal activity, we first show that the NAcC is specifically active only in response to an associative fear cue during an expression test. In contrast, the NAcS is specifically active during fear extinction. We next inactivated each subregion using lidocaine and demonstrated that the NAcC is necessary for fear expression, but not for extinction learning or consolidation of extinction. In contrast, we demonstrate that the NAcS is necessary for the consolidation of extinction, but not fear expression or extinction learning. Further, inactivation of mGluR1 or ERK signaling specifically in the NAcS disrupted the consolidation of extinction but had no effect on fear expression or extinction learning itself. Our data provide the first evidence for the importance of the ERK/MAPK pathway as the underlying neural mechanism facilitating extinction consolidation within the NAcS. These findings suggest that the NAc subregions play dissociable roles in regulating fear recall and the consolidation of fear extinction, and potentially implicate them as critical regions within the canonical fear circuit.
... Dopamine receptor type-2 (D2R)-expressing cells in the NAc drive the avoidance of risk [19], and precisely timed phasic stimulation of NAc D2R cells instantaneously converts risk-preferring rats to risk-averse rats [27]. In humans, functional magnetic resonance imaging analyses have shown that hemodynamic changes within the NAc are associated with risk-avoidance behavior [28,29]. Although studies have confirmed that risk-related behavior is strongly correlated with NAc activity, the neuronal mechanisms underlying this behavior remain poorly understood. ...
Article
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A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk. In humans, a large proportion of mental disorders are accompanied by impairments in risk avoidance. One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1 ( DISC1 ), and animal models in which this gene has some level of dysfunction show emotion-related impairments. However, it is not known whether DISC1 mouse models have an impairment in avoiding potential risks. In the present study, we used DISC1-N terminal truncation ( DISC1-N TM ) mice to investigate risk avoidance and found that these mice were impaired in risk avoidance on the elevated plus maze (EPM) and showed reduced social preference in a three-chamber social interaction test. Following EPM tests, c-Fos expression levels indicated that the nucleus accumbens (NAc) was associated with risk-avoidance behavior in DISC1-N TM mice. In addition, in vivo electrophysiological recordings following tamoxifen administration showed that the firing rates of fast-spiking neurons (FS) in the NAc were significantly lower in DISC1-N TM mice than in wild-type (WT) mice. In addition, in vitro patch clamp recording revealed that the frequency of action potentials stimulated by current injection was lower in parvalbumin (PV) neurons in the NAc of DISC1-N TM mice than in WT controls. The impairment of risk avoidance in DISC1-N TM mice was rescued using optogenetic tools that activated NAc PV neurons. Finally, inhibition of the activity of NAc PV neurons in PV-Cre mice mimicked the risk-avoidance impairment found in DISC1-N TM mice during tests on the elevated zero maze. Taken together, our findings confirm an impairment in risk avoidance in DISC1-N TM mice and suggest that reduced excitability of NAc PV neurons is responsible.
... Thus, the tendency to seek varied and intense sensations and experiences and the willingness to take risks for the sake of such experiences [70] may be a general risk indicator for SU. The same commonality was observed for low anxiety, a finding that echoes previous reports on the relation between anxiety and harm-avoidance [71,72]. Low scores on harm avoidance reflect disinhibition and fearlessness [73] and have been associated with SU/abuse in adolescents and adults [74,75]. ...
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This study examined developmental patterns of co-occurrent alcohol, marijuana, and other illicit drugs use during adolescence and the associated preadolescent risk factors in a longitudinal sample of 926 boys from low-socioeconomic, urban neighborhoods. Latent growth mixture modeling revealed six developmental patterns: non-/low-alcohol and non-illicit drug users (61% sample) and five polysubstance user-groups varying in severity based on onset, frequency and type of substances used. In comparisons with non-/low-users, several preadolescent risk factors were associated with increasing severity of polysubstance use. Higher sensation-seeking and lower anxiety were associated with all user-groups. Low self-esteem and family-related risk factors differentiated all user-groups from later-onset users. Higher impulsivity and school problems characterized early-onset and frequent polysubstance users. Impulsive sensation-seekers with lower anxiety and self-esteem cumulated a larger number and higher severity of risk factors and were at risk of early-onset frequent polysubstance use, emphasising the importance of indicated prevention for these high-risk boys.
... The ventromedial prefrontal cortex (vmPFC) together with the ventral striatum comprise the ventral cortico-striatal loop (Haber and Knutson, 2010), which has been strongly implicated in approach and reward-seeking behaviors (Bartra et al., 2013;Chib et al., 2009;Delgado et al., 2000;Kable and Glimcher, 2007;Kim et al., 2007;Kim et al., 2011;O'Doherty, 2011). However, the ventral cortico-striatal loop has also been associated with active avoidance behavior (Kim et al., 2006;Levita et al., 2012), encoding successful avoidance particularly under contexts with a negative expected value (Palminteri et al., 2015). Unlike the ventral cortico-striatal loop, its dorsal counterpart including the dmPFC and the dorsal striatum is involved in avoiding punishment (Delgado et al., 2009;Palminteri et al., 2012;Pessiglione et al., 2006;Seymour et al., 2007;Shenhav and Buckner, 2014). ...
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A debate is still ongoing regarding whether approach and avoidance systems are distinguished from each other or a common and shared neural mechanism underlie both types of behavior. In this article, I will review some key neural substrates of approach and avoidance behaviors, focusing on the neural circuitries and the neurotransmitters associated with reward- and punishment-based learning and highlighting the inconsistencies between results found in support of dual vs. unified system views. I will then suggest that both approach and avoidance behaviors aim for a common goal of survival through maintaining bodily homeostasis. In parallel with the well-known heuristics called win-stay lose-shift strategy, the neural differences between approach and avoidance behaviors may arise from the differences between them in terms of the degree to which they utilize additional external information from the environment to update pre-existing behavioral strategy. In the end, an alternative model of approach and avoidance learning will be proposed, which is based on hierarchically organized allostatic regulatory control over homeostatic reflexes. This model can provide a useful theoretical framework to integrate the current findings on reward- and punishment-based learning, and to raise concrete and testable hypotheses for future studies.
... Studies of classical conditioning using both primate neurophysiology and fMRI methods suggest that reward-and punishment-related processing, including anticipation of financial rewards and punishments, are critically dependent on the nucleus accumbens and the SN/VTA (Bromberg-Martin et al., 2010;Carter et al., 2009;Delgado et al., 2008;Fiorillo et al., 2003;Jensen et al., 2003;Knutson et al., 2000Knutson et al., , 2001Levita et al., 2012;Matsumoto and Hikosaka, 2009;McClure et al., 2004;Olds and Milner, 1954;Schultz, 1997Schultz, , 1998Seymour et al., 2004Seymour et al., , 2007Shigemune et al., 2014;Zaghloul et al., 2009). Functional neuroimaging studies have shown that recruitment of SN/VTA and nucleus accumbens is associated with reward-motivated declarative learning (Adcock et al., 2006;Kuhl et al., 2010;Murayama and Kuhbandner, 2011;Wittmann et al., 2005Wittmann et al., , 2011. ...
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The neural circuitry mediating the influence of motivation on long-term declarative or episodic memory formation is delineated in young adults, but its status is unknown in healthy aging. We examined the effect of reward and punishment anticipation on intentional declarative memory formation for words using an event-related functional magnetic resonance imaging (fMRI) monetary incentive encoding task in twenty-one younger and nineteen older adults. At 24-hour memory retrieval testing, younger adults were significantly more likely to remember words associated with motivational cues than neutral cues. Motivational enhancement of memory in younger adults occurred only for recollection ("remember" responses) and not for familiarity ("familiar" responses). Older adults had overall diminished memory and did not show memory gains in association with motivational cues. Memory encoding associated with monetary rewards or punishments activated motivational (substantia nigra/ventral tegmental area) and memory-related (hippocampus) brain regions in younger, but not older, adults during the target word periods. In contrast, older and younger adults showed similar activation of these brain regions during the anticipatory motivational cue interval. In a separate monetary incentive delay task that did not require learning, we found evidence for relatively preserved striatal reward anticipation in older adults. This supports a potential dissociation between incidental and intentional motivational processes in healthy aging. The finding that motivation to obtain rewards and avoid punishments had reduced behavioral and neural influence on intentional episodic memory formation in older compared to younger adults is relevant to life-span theories of cognitive aging including the dopaminergic vulnerability hypothesis.
... A lesion study in gerbils (Wetzel et al. 1998) revealed that the right auditory cortex plays an important role in frequency-modulated discrimination learning. The lateralized activation of the right amygdala detected in our study is in line with observations during fear conditioning and avoidance learning (Coleman-Mesches and McGaugh 1995;LaBar et al. 1998;Baker and Kim 2004;Holschneider et al. 2006;Levita et al. 2012). Other studies suggested an involvement of the right amygdala in automatic emotional processes (which most likely plays a role in cueinstructed learning) and the left amygdala in conscious and cognitively controlled emotion processing (Dyck et al. 2011;LaBar et al. 1998;Phelps et al. 2001) including the posterior and basal amygdala. ...
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Chapter
Rigid motivational appraisals (i.e., demandingness) are core processes in emotional disorders. In this chapter, I suggest that rigid motivational appraisals result in disturbed emotions when they are based on embodied representations that recruit abnormal motivational states. I review studies that support the idea that rigid motivational appraisals involve the understanding of the significance of negative events based on simulations in a hyper-reactive mesolimbic dopamine motivational system. The concept of embodied rigid appraisals integrates research from human and nonhuman animal models in the support of rigid appraisals as a core process for emotional psychopathology. I suggest that embodied rigid appraisals are markers of behavioral inflexibility phenotype in response to stress that result in emotional disorders. Based on this understanding, the processes of development, maintenance, and the methods of change that target disturbed motivation and inflexible coping can be used to understand the development and change of rigid thinking.
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Humans and animals live in social relationships shaped by actions of approach and avoidance. Both are crucial for normal physical and mental development, survival, and well-being. Active withdrawal from social interaction is often induced by the perception of threat or unpleasant social experience and relies on adaptive mechanisms within neuronal networks associated with social behavior. In case of confrontation with overly strong or persistent stressors and/or dispositions of the affected individual, maladaptive processes in the neuronal circuitries and its associated transmitters and modulators lead to pathological social avoidance. This review focuses on active, fear-driven social avoidance, affected circuits within the mesocorticolimbic system and associated regions and a selection of molecular modulators that promise translational potential. A comprehensive review of human research in this field is followed by a reflection on animal studies that offer a broader and often more detailed range of analytical methodologies. Finally, we take a critical look at challenges that could be addressed in future translational research on fear-driven social avoidance.
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One strong survival instinct in animals is to approach things that are of benefit and avoid risk. In humans, a large portion of mental disorders are accompanied by cognition-related impairments including the inability to recognize potential risks. One of the most important genes involved in risk behavior is disrupted-in-schizophrenia-1 ( DISC1 ), and animal models where this gene has some dysfunction show cognitive impairments. However, whether DISC1 mice models have an impairment in avoiding potential risks is still not fully understood. In the present study, we used DISC1-N terminal truncation ( DISC1-N TM ) mice to study cognitive abilities related to potential risks. We found that DISC1-N TM mice were impaired in risk avoidance on the elevated plus maze (EPM) test, and showed impairment in social preference in a three-chamber social interaction test. Staining for c-Fos following the EPM indicated that the nucleus accumbens (NAc) was associated with risk avoidance behavior in DISC1-N TM mice. Meanwhile, in vivo electrophysiological recordings showed that firing rates of fast spiking neurons (FS) in the NAc significantly decreased in DISC1-N TM mice following tamoxifen administration. In addition, theta band power was lower when mice shuttled from the safe (closed) arms to the risky (open) arms, an effect which disappeared after induction of the truncated DISC1 gene. Furthermore, we found through in vitro patch clamp recording that the frequency of action potentials stimulated by current injection was lower in parvalbumin (PV) neurons in the NAc of DISC1-N TM mice than their wild-type littermates. Risk-avoidance impairments in DISC1-N TM mice were rescued using optogenetic tools that activated NAc PV neurons. Finally, we inhibited activitiy of NAc PV neurons in PV-Cre mice, which mimicked the risk-avoidance impairment found in the DISC1-N TM mice during tests on the elevated zero maze. Taken together, our findings confirmed a cognitive impairment in DISC1-N TM mice related to risk recognition and suggests that reduced excitability of NAc PV neurons may be responsible.
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The rodent ventral and primate anterior hippocampus have been implicated in approach-avoidance (AA) conflict processing. It is unclear, however, whether this structure contributes to AA conflict detection and/or resolution, and if its involvement extends to conditions of AA conflict devoid of spatial/contextual information. To investigate this, neurologically healthy human participants first learned to approach or avoid single novel visual objects with the goal of maximizing earned points. Approaching led to point gain and loss for positive and negative objects, respectively, whereas avoidance had no impact on score. Pairs of these objects, each possessing nonconflicting (positive-positive/negative-negative) or conflicting (positive-negative) valences, were then presented during functional magnetic resonance imaging. Participants either made an AA decision to score points (Decision task), indicated whether the objects had identical or differing valences (Memory task), or followed a visual instruction to approach or avoid (Action task). Converging multivariate and univariate results revealed that within the medial temporal lobe, perirhinal cortex, rather than the anterior hippocampus, was predominantly associated with object-based AA conflict resolution. We suggest the anterior hippocampus may not contribute equally to all learned AA conflict scenarios and that stimulus information type may be a critical and overlooked determinant of the neural mechanisms underlying AA conflict behavior.
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Is Pavlovian conditioning the same thing as Pavlovian conditioning? Though that question seems tautological, this article shows that it is not, because Pavlovian conditioning has at least three different meanings: Pavlovian conditioning is (1) a procedure, (2) the learning phenomenon observed in that same procedure and (3) the learning process explaining the phenomenon observed in that procedure. If we look at this third meaning from an evolutionary point of view, it seems extremely unlikely that a single Pavlovian conditioning process is responsible for learning in all procedures classified as Pavlovian conditioning -- a conclusion that supported by behavioral and neural data. In the end, it seems that it might be better to drop the term Pavlovian conditioning to designate a learning process and to stop the quest for a single process explaining all Pavlovian learning. Instead, it would be more fruitful to understand under which condition a particular model of Pavlovian learning holds. The same conclusion applies to other research field in the psychology of learning, notably operant conditioning and statistical learning.
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Tobacco exposure has been linked to neuroinflammation and adaptive/maladaptive changes in neurotransmitter systems, including in glutamatergic systems. We examined the effects of waterpipe tobacco smoke (WTS) on inflammatory mediators and astroglial glutamate transporters in mesocorticolimbic brain regions including the prefrontal cortex (PFC), nucleus accumbens (NAc) and ventral tegmental area (VTA). The behavioral consequences of WTS exposure on withdrawal-induced anxiety-like behavior were assessed using elevated plus maze (EPM) and open field (OF) tests. Male Sprague-Dawley rats were randomly assigned to 3 experimental groups: a control group exposed only to standard room air, a WTS exposed group treated with saline vehicle, and a WTS exposed group treated with ceftriaxone. WTS exposure was performed for 2 h/day, 5 days/week, for 4 weeks. Behavioral tests (EPM and OF) were conducted weekly 24 hr after WTS exposure, during acute withdrawal. During week 4, rats were given either saline or ceftriaxone (200 mg/kg i.p.) 30 min before WTS exposure. WTS increased withdrawal-induced anxiety, and ceftriaxone attenuated this effect. WTS exposure increased the relative mRNA levels for nuclear factor ĸB (NFĸB), tumor necrosis factor-α (TNF-α), and brain-derived neurotrophic factor (BDNF) in the PFC, NAc and VTA, and ceftriaxone treatment reversed these effects. In addition, WTS decreased the relative mRNA of nuclear factor erythroid 2 related factor 2 (Nrf2), glutamate transporter 1 (GLT-1) and cystine-glutamate transporter (xCT) in PFC, NAc and VTA, and ceftriaxone treatment normalized their expression. WTS caused neuroinflammation, alteration in relative mRNA glutamate transport expression, and increased anxiety-like behavior, and these effects were attenuated by ceftriaxone treatment.
Chapter
The neural basis of motivation is supported by brain systems that are integral in behaviors that maximize positively valued stimuli and minimize aversive stimuli. This article focuses on brain systems involved in minimization of aversive stimuli, which are extensively described by a substantial history of research on behaviors in nonhuman animals that are motivated by aversive stimuli. Such research strongly delineates a neural circuitry involving amygdala and striatum sub-nuclei that are modulated by regions of prefrontal cortex. Neuroimaging research on behaviors motivated by aversive stimuli in humans has confirmed the importance of homologous systems in humans, and allowed some understanding of the relation of these circuits to distinct behavioral responses and to clinical issues such as anxiety. We organize our review of this research around three important conceptual observations. First, active avoidance behaviors are distinguishable from passive avoidance behaviors in terms of both neural circuitry and motivational and affective consequences. Second, the perception of control over stimuli is critical for active avoidance behaviors, and influences brain systems for avoidance as well as subsequent behavior toward motivational stimuli. Third, avoidance behaviors may be adaptive in many situations but can become excessive or maladaptive in other situations. Knowledge about the neural circuitry underlying active avoidance provides an important path in understanding how avoidance behaviors are maintained and how they may change, and form a foundation for studying motivation and clinical issues such as anxiety.
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While conflict between incompatible goals has well-known effects on actions, in many situations the same action may produce harmful or beneficial consequences during different periods in a nonconflicting manner, e.g., crossing the street during a red or green light. To avoid harm, subjects must be cautious to inhibit the action specifically when it is punished, as in passive avoidance, but act when it is beneficial, as in active avoidance or active approach. In mice of both sexes performing a signaled action to avoid harm or obtain reward, we found that addition of a new rule that punishes the action when it occurs unsignaled delays the timing of the signaled action in an apparent sign of increased caution. Caution depended on task signaling, contingency, and reinforcement type. Interestingly, caution became persistent when the signaled action was avoidance motivated by danger but was only transient when it was approach motivated by reward. Although caution is represented by the activity of neurons in the midbrain, it developed independent of frontal cortex or basal ganglia output circuits. These results indicate that caution disrupts actions in different ways depending on the motivational state and may develop from unforeseen brain circuits.SIGNIFICANCE STATEMENT Actions, such as crossing the street at a light, can have benefits during one light signal (getting somewhere) but can be harmful during a different signal (being run over). Humans must be cautious to cross the street during the period marked by the appropriate signal. In mice performing a signaled action to avoid harm or obtain reward, we found that addition of a new rule that punishes the action when it occurs unsignaled, delays the timing of the signaled action in an apparent sign of increased caution. Caution became persistent when the signaled action was motivated by danger, but not when it was motivated by reward. Moreover, the development of caution did not depend on prototypical frontal cortex circuits.
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Deep brain stimulation (DBS) in the bed nucleus of the stria terminalis (BST), a region implicated in the expression of anxiety, shows promise in psychiatric patients, but its effects throughout the limbic system are largely unknown. In male Wistar rats, we first evaluated the neural signature of contextual fear (N = 16) and next, of the anxiolytic effects of high-frequency electrical stimulation in the BST (N = 31), by means of c-Fos protein expression. In non-operated animals, we found that the left medial anterior BST displayed increased c-Fos expression in anxious (i.e., context-conditioned) versus control subjects. Moreover, control rats showed asymmetric expression in the basolateral amygdala (BLA) (i.e., higher intensities in the right hemisphere), which was absent in anxious animals. The predominant finding in rats receiving bilateral BST stimulation was a striking increase in c-Fos expression throughout much of the left hemisphere, which was not confined to the predefined regions of interest. To conclude, we found evidence for lateralized c-Fos expression during the expression of contextual fear and anxiolytic high-frequency electrical stimulation of the BST, particularly in the medial anterior BST and BLA. In addition, we observed an extensive and unexpected left-sided c-Fos spread following bilateral stimulation in the BST.
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Despite the central status of avoidance in explaining the etiology and maintenance of anxiety disorders, surprisingly little behavioral research has been conducted on human avoidance. In the present paper, first we provide a brief review of the empirical literature on avoidance. Next, we describe the implications of research on derived relational responding and the transformation of functions for a contemporary behavioral account of avoidance, before providing several illustrative research examples of laboratory-based analogues of key clinical treatment processes. Finally, we suggest some challenges and opportunities that lie ahead for behavioral research on anxiety and avoidance.
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Adaptive functioning is thought to reflect a balance between approach and avoidance neural systems with imbalances often producing pathological forms of avoidance. Yet little evidence is available in healthy adults demonstrating a balance between approach and avoidance neural systems and modulation in avoidance neurocircuitry by vulnerability factors for avoidance. Consequently, we used functional magnetic resonance imaging (fMRI) to compare changes in brain activation associated with human avoidance and approach learning and modulation of avoidance neurocircuitry by experiential avoidance. fMRI tracked trial-by-trial increases in activation while adults learned through trial and error an avoidance response that prevented money loss and an approach response that produced money gain. Avoidance and approach cues elicited similar experience-dependent increases in activation in a fronto-limbic-striatal network. Positive and negative reinforcing outcomes (i.e., money gain and avoidance of loss) also elicited similar increases in activation in frontal and striatal regions. Finally, increased experiential avoidance and self-punishment coping was associated with decreased activation in medial/superior frontal regions, anterior cingulate, amygdala and hippocampus. These findings suggest avoidance and approach learning recruit a similar fronto-limbic-striatal network in healthy adults. Increased experiential avoidance also appears to be associated with reduced frontal and limbic reactivity in avoidance, establishing an important link between maladaptive avoidance coping and altered responses in avoidance neurocircuitry.
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Classical conditioning paradigms, such as trace conditioning, in which a silent period elapses between the offset of the conditioned stimulus (CS) and the delivery of the unconditioned stimulus (US), and delay conditioning, in which the CS and US coterminate, are widely used to study the neural substrates of associative learning. However, there are significant gaps in our knowledge of the neural systems underlying conditioning in humans. For example, evidence from animal and human patient research suggests that the hippocampus plays a critical role during trace eyeblink conditioning, but there is no evidence to date in humans that the hippocampus is active during trace eyeblink conditioning or is differentially responsive to delay and trace paradigms. The present work provides a direct comparison of the neural correlates of human delay and trace eyeblink conditioning by using functional MRI. Behavioral results showed that humans can learn both delay and trace conditioning in parallel. Comparable delay and trace activation was measured in the cerebellum, whereas greater hippocampal activity was detected during trace compared with delay conditioning. These findings further support the position that the cerebellum is involved in both delay and trace eyeblink conditioning whereas the hippocampus is critical for trace eyeblink conditioning. These results also suggest that the neural circuitry supporting delay and trace eyeblink classical conditioning in humans and laboratory animals may be functionally similar. • cerebellum • functional MRI • hippocampus
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The ability to form associations between predictive environmental events and rewarding outcomes is a fundamental aspect of learned behavior. This apparently simple ability likely requires complex neural processing evolved to identify, seek, and use natural rewards and redirect these activities based on updated sensory information. Emerging evidence from both animal and human research suggests that this type of processing is mediated in part by the nucleus accumbens (NAc) and a closely associated network of brain structures. The NAc is required for a number of reward-related behaviors and processes specific information about reward availability, value, and context. In addition, this structure is critical for the acquisition and expression of most Pavlovian stimulus-reward relationships, and cues that predict rewards produce robust changes in neural activity in the NAc. Although processing within the NAc may enable or promote Pavlovian reward learning in natural situations, it has also been implicated in aspects of human drug addiction, including the ability of drug-paired cues to control behavior. This article provides a critical review of the existing animal and human literature concerning the role of the NAc in Pavlovian learning with nondrug rewards and considers some clinical ture concerning the role of the NAc in Pavlovian learning with nondrug implications of these findings.
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Money is a secondary reinforcer commonly used across a range of disciplines in experimental paradigms investigating reward learning and decision-making. The effectiveness of monetary reinforcers during aversive learning and associated neural basis, however, remains a topic of debate. Specifically, it is unclear if the initial acquisition of aversive representations of monetary losses depends on similar neural systems as more traditional aversive conditioning that involves primary reinforcers. This study contrasts the efficacy of a biologically defined primary reinforcer (shock) and a socially defined secondary reinforcer (money) during aversive learning and its associated neural circuitry. During a two-part experiment, participants first played a gambling game where wins and losses were based on performance to gain an experimental bank. Participants were then exposed to two separate aversive conditioning sessions. In one session, a primary reinforcer (mild shock) served as an unconditioned stimulus (US) and was paired with one of two colored squares, the conditioned stimuli (CS+ and CS-, respectively). In another session, a secondary reinforcer (loss of money) served as the US and was paired with one of two different CS. Skin conductance responses were greater for CS+ compared to CS- trials irrespective of type of reinforcer. Neuroimaging results revealed that the striatum, a region typically linked with reward-related processing, was found to be involved in the acquisition of aversive conditioned response irrespective of reinforcer type. In contrast, the amygdala was involved during aversive conditioning with primary reinforcers, as suggested by both an exploratory fMRI analysis and a follow-up case study with a patient with bilateral amygdala damage. Taken together, these results suggest that learning about potential monetary losses may depend on reinforcement learning related systems, rather than on typical structures involved in more biologically based fears.
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The acquisition of reward and the avoidance of punishment could logically be contingent on either emitting or withholding particular actions. However, the separate pathways in the striatum for go and no-go appear to violate this independence, instead coupling affect and effect. Respect for this interdependence has biased many studies of reward and punishment, so potential action-outcome valence interactions during anticipatory phases remain unexplored. In a functional magnetic resonance imaging study with healthy human volunteers, we manipulated subjects' requirement to emit or withhold an action independent from subsequent receipt of reward or avoidance of punishment. During anticipation, in the striatum and a lateral region within the substantia nigra/ventral tegmental area (SN/VTA), action representations dominated over valence representations. Moreover, we did not observe any representation associated with different state values through accumulation of outcomes, challenging a conventional and dominant association between these areas and state value representations. In contrast, a more medial sector of the SN/VTA responded preferentially to valence, with opposite signs depending on whether action was anticipated to be emitted or withheld. This dominant influence of action requires an enriched notion of opponency between reward and punishment.
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Attentional capture and behavioral control by conditioned stimuli have been dissociated in animals. The current study assessed this dissociation in humans. Participants were trained on a Pavlovian schedule in which 3 visual stimuli, A, B, and C, predicted the occurrence of an aversive noise with 90%, 50%, or 10% probability, respectively. Participants then went on to separate instrumental training in which a key-press response canceled the aversive noise with a .5 probability on a variable interval schedule. Finally, in the transfer phase, the 3 Pavlovian stimuli were presented in this instrumental schedule and were no longer differentially predictive of the outcome. Observing times and gaze dwell time indexed attention to these stimuli in both training and transfer. Aware participants acquired veridical outcome expectancies in training--that is, A > B > C, and these expectancies persisted into transfer. Most important, the transfer effect accorded with these expectancies, A > B > C. By contrast, observing times accorded with uncertainty--that is, they showed B > A = C during training, and B < A = C in the transfer phase. Dwell time bias supported this association between attention and uncertainty, although these data showed a slightly more complicated pattern. Overall, the study suggests that transfer is linked to outcome prediction and is dissociated from attention to conditioned stimuli, which is linked to outcome uncertainty.
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The tripartite model of anxiety includes three response domains: cognitive (most often identified by self report), behavioral, and physiological. Each is suggested to bring a separate element of response characteristics and, in some cases, potentially independent underlying mechanisms to the construct of anxiety. In this chapter, commonly used behavioral correlates of anxiety in human research, including startle reflex, attentional bias, and avoidance tasks, as well as future tasks using virtual reality technology will be discussed. The focus will be in evaluating their translational utility supported by (1) convergent validity with other measures of anxiety traits or anxiety disorders, (2) their use in identifying neural and genetic mechanisms of anxiety, and (3) ability to predict treatment efficacy.
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The basal ganglia were once believed to function as part of an “extrapyramidal” motor system, operating separately from the pyramidal tract [1,2]. However, this concept has been discarded for two fundamental reasons. First, the basal ganglia have been shown to be an intrinsic part of well-defined anatomical circuits that not only receive cortical input but also send projections, via the thalamus, back to those cortical areas that control motor output. Second, a wealth of experimental work has shown that the striatum, the main input structure for the basal ganglia, can no longer be regarded purely as a “motor” structure. The observation that striatal damage could induce deficits in cognitive function led researchers such as H. Enger Rosvold and Ivan Divac to state that the striatum may reflect the function of those areas of neocortex that project to it [3]. These pioneers investigating striatal function laid the foundation for the “functional loop” concept that proposes multiple, topographically arranged basal ganglia circuits that serve as substrates for motor, oculomotor, prefrontal, and limbic functions [4]. The theory that the striatum may mediate a wide variety of functions reflecting its diverse cortical innervation has become evident in studies of patients with basal ganglia disorders. Thus, impairments in cognitive function are now well documented in patients with neurodegenerative diseases such as Huntington’s disease (HD) or Parkinson’s disease (PD), disorders which were once regarded as entirely “movement” related. Attempts to examine disease states such as HD in experimental animals can provide both insight into normal brain function and a means by which to assess potential therapeutic strategies. In either scenario, an operant analysis of behavior can prove particularly powerful. The detailed functional analyses that are permitted by operant paradigms not only allow more specific questions to be asked of normal brain function, but can also provide experimental paradigms that are extremely sensitive to brain insults and subsequent recovery.
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Many forms of psychopathology and substance abuse problems are characterized by chronic ritualized forms of avoidance and escape behavior that are designed to control or modify external or internal (i.e., thoughts, emotions, bodily sensations) threats. In this functional magnetic resonance imaging investigation, we examined amygdala reactivity to threatening cues when avoidance responding consistently prevented contact with an upcoming aversive event (money loss). In addition, we examined escape responding that terminated immediate escalating money loss and approach responding that produced a future money gain. Results showed cues prompting avoidance, escape and approach behavior recruited a similar fronto-striatal-parietal network. Within the amygdala, bilateral activation was observed to threatening avoidance and escape cues, even though money loss was consistently avoided, as well as to the reward cue. The magnitude of amygdala responses within subjects was relatively similar to avoidance, escape and approach cues, but considerable between-subject differences were found. The heightened amygdala response to avoidance and escape cues observed within a subset of subjects suggests threat-related responses can be maintained even when aversive events are consistently avoided, which may account for the persistence of avoidance-coping in various clinical disorders. Further assessment of the relation between amygdala reactivity and avoidance-escape behavior may prove useful in identifying individuals with or at risk for neuropsychiatric disorders.
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A study is reported with represents, to the authors' knowledge, the first laboratory demonstration of extreme human avoidance responding in extinction following a fear conditioning procedure. Responding in extinction was also found to be enhanced by a serial CS procedure, and support was obtained for the conservation of anxiety hypothesis upon which the serial CS hypothesis is based. Skin conductance, dynomometer, and self-report data supported the contention that fear is the motivating source for avoidance maintenance. The procedure used should provide a valuable paradigm for investigating the underlying principle responsible for maintaining persistent avoidance responding.
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