ReviewStriatum on the anxiety map: Small detours into adolescence
Introduction
This review focuses on the contribution of the striatum to the emergence of anxiety disorders in adolescence and to the expression of anxiety symptoms. The link of the striatum to anxiety may seem surprising given the canonical role of this structure in reward processes, which are not usually viewed as part of the root problems of anxiety. However, we will present arguments supporting this anxiety-striatum link, which has clear implications for the prevention and treatment of anxiety disorders. As we develop these arguments, it will become evident that much more research needs to be done. Indeed, this is the reason why we feel it is time to draw attention to the potentially critical role of the striatum in the pathogenesis of anxiety.
Up to now, the study of anxiety has primarily focused on the amygdala, bed nucleus of the stria terminalis (BNST), hippocampus (HPC), and prefrontal cortex (PFC) (Calhoon and Tye, 2015, Davis et al., 2010). While associated both anatomically and functionally with these structures (Avery et al., 2014, Calhoon and Tye, 2015, Torrisi et al., 2015), the striatum has not been considered central to the mechanisms underlying anxiety. The amygdala projects to the striatum and BNST (Fudge et al., 2002, Fudge et al., 2004, Novotny, 1977, Roy et al., 2009), and the striatum and BNST are densely interconnected (Avery et al., 2014, Dong and Swanson, 2006, Haber et al., 1990, Torrisi et al., 2015, Wood and Swann, 2005). The cortex also sends efferents directly to the striatum (Calhoon and Tye, 2015, Cisler and Koster, 2010, Liljeholm and O'Doherty, 2012). Finally, the HPC is strongly interconnected with the striatum, especially during context retrieval (Ross et al., 2011). Taken together, these data place the striatum in an ideal position to be part of the anxiety circuit. The goal of this review is to call attention to an area of research that has not been systematically explored to gain a more comprehensive understanding of the neurobiology of anxiety.
Fig. 1A illustrates the classical neural network of anxiety (for review Calhoon and Tye (2015)). Upon exposure to threat, the amygdala receives information directly from the sensory cortex and codes threat valence. Information about the detected threat is then sent to the BNST, ventral HPC (vHPC), and medial PFC (mPFC) to process threat responses. The mPFC and vHPC in turn relay the processed threat information back to the amygdala and BNST as part of a circular loop.
In Fig. 1B, the striatum is included in the anxiety network. In this model, the striatum receives information from the amygdala (BLA) and cortex (mPFC, entorhinal, insular) during threat exposure (for reviews Calhoon and Tye, 2015, Liljeholm and O'Doherty, 2012). Resting state fMRI and DTI studies have documented functional connectivity of the striatum with the HPC and BNST (Avery et al., 2014, Torrisi et al., 2015). However, the role of the BNST-striatum connection in the response to threat remains to be clarified.
Whereas the present work is not directly anchored in the developmental changes associated with adolescence, we hope to highlight the relationship between the high vulnerability of adolescents to anxiety disorders and concurrent striatal developmental plasticity. The striatum is a complex, multi-component structure, which contributes to many fundamental behavioral processes. Several of these processes are critically implicated in anxiety, including (1) attention, (2) conditioning/prediction error, and (3) motivation. As we address these processes, we will make detours into the adolescence period to revisit the role of the adolescent striatal plasticity in the emergence of clinical anxiety. Prior to this, however, we will briefly review general aspects of the adolescent period and striatal function.
Section snippets
Adolescence
Adolescence is the transition period linking childhood to adulthood. Behaviorally, typical adolescence is marked by an increase in the search for novelty, sensation and reward. These changes are thought to be adaptive and meant to facilitate the normative adolescent shift away from the familial nest and towards peer groups. However, they also contribute to the adolescent rise in morbidity and mortality, mainly secondary to deleterious consequences of risky goal-directed behaviors (for review
Striatum and its networks
The striatum is classically described as the key node of the reward/approach system (for review see Ernst and Spear (2009)). It receives dopaminergic projections from midbrain dopamine nuclei (substantia nigra and ventral tegmental area). Top-down cortical projections relay information to the striatum, which is then dispatched back to the cortex via the thalamus (reviews Ernst and Fudge, 2009, Liljeholm and O'Doherty, 2012).
These cortico-striatal-thalamic-cortical circuits are organized into
Effects of sex hormones
Fig. 1C incorporates the effects of sex hormones within the proposed model. Sex steroid hormones influence striatal function, mostly through their modulation of dopamine activity (Bazzett and Becker, 1994, Lewis and Dluzen, 2008). However, this literature is complex for three main reasons. First, reports on the direction of these effects diverge, a fact attributed to a number of factors, including within-studies differences in hormone levels (Becker, 1990, Clopton and Gordon, 1985), selected
Striatum and attention
“Attention” refers to a multi-faceted process that filters information. Attention permits individuals to orient towards task-relevant stimuli or rules in order to guide optimal behavior (review Shechner et al. (2012)). In anxiety, threat stimuli, real or imaginary, are imbued with heightened salience, which, in turn, determines a “threat attention bias” (Eldar et al., 2010). This “threat attention bias” is defined by a propensity to orient toward, and a difficulty to switch attention away from,
Conditioning
Fear conditioning is an associative learning process that consists of the tagging of threat onto otherwise neutral stimuli, environments, situations or actions, through repeated exposures to the pairing of the neutral event with threat. Two forms of conditioning, classical and instrumental, are identified. Classical (Pavlovian) fear conditioning refers to the pairing of threat with a stimulus (e.g., electrical shock with light), while instrumental conditioning refers to the pairing of threat
Striatum and motivation
Motivation can be defined as the intensity of drive, or the willingness to spend resources or exert efforts to reach a goal (review Ernst and Spear (2009)). Standard ways to study motivation involve either decision-making tasks, requiring individuals to execute a decision (e.g., button press), or reward tasks, like the monetary incentive delay task which requires individuals to press a button quickly enough to receive a reward (Knutson et al., 2000).
The study of motivation has most often been
Conclusion
This review focused solely on the role of the striatum in anxiety, and surveyed a large amount of research. Behavioral links between anxiety and striatal function were used as evidence of this link. Three key behavioral domains were addressed, (1) attention, (2) fear conditioning/prediction error, and (3) motivation, because they are both altered in anxiety and dependent on striatal function. Beyond these links, we also noted strong parallels in the developmental trajectories characterizing the
Disclosure/conflict of interest
The authors report no conflicts of interest. Financial support of this study was provided by the Intramural Research Program of the National Institute of Mental Health, ZIAMH002798 (ClinicalTrial.gov Identifier: NCT00026559: Protocol ID 01−M-0185).
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