Resolving the neural circuits of anxiety

Abstract

Although anxiety disorders represent a major societal problem demanding new therapeutic targets, these efforts have languished in the absence of a mechanistic understanding of this subjective emotional state. While it is impossible to know with certainty the subjective experience of a rodent, rodent models hold promise in dissecting well-conserved limbic circuits. The application of modern approaches in neuroscience has already begun to unmask the neural circuit intricacies underlying anxiety by allowing direct examination of hypotheses drawn from existing psychological concepts. This information points toward an updated conceptual model for what neural circuit perturbations could give rise to pathological anxiety and thereby provides a roadmap for future therapeutic development.

Figure 1

Few new pharmacotherapies for the treatment of anxiety have been developed since the 1940s. The cumulative FDA approvals of medications with an indication for anxiety (blue line) are compared to those for medications with an indication for hypertension (dark blue line), a more thoroughly understood condition. In addition to the comparatively slow rate of overall approvals of anxiolytics, a lesser number of mechanistically distinct targets have been identified for the treatment of anxiety than hypertension during the past 75 years (inset). The relative paucity of pharmacological strategies for the treatment of anxiety disorders and the imperfect efficacy of these drugs betrays a need for a more thorough understanding of the neural substrates of anxiety.

Figure 2

Validated tests to assay anxiety and related emotional states in mice. State anxiety in mice is measured behaviorally through a variety of tests, highlighted in orange. Exemplars of fear and physiological stress assays are highlighted in red and yellow, respectively.

Figure 3

Neural circuits implicated in anxiety-related behaviors in the rodent brain. Recent work using optogenetics, behavioral neuroscience and electrophysiology has begun to establish causal relationships between anxiety behaviors and activity in specific neural circuits. (a) A sagittal view of rodent brain including distal circuits implicated in anxiety-related behaviors. (b) Septohippocampal microcircuitry linked to anxiety. (c,d) Extended amygdala microcircuits involved in anxiety-related behaviors, including BLA projections to the BNST (c) and BLA projections to CeA (d). ad, anterodorsal nucleus of the BNST; AHA, anterior hypothalamic area; BLA, basolateral amygdala; BNST, bed nucleus of the stria terminalis; CeA, central amygdala; CeL, lateral subdivision of the central amygdala; CeM, centromedial subdivision of the amygdala; CRFR2α, type 2 corticotropin releasing factor receptor; DR, dorsal raphe nucleus; DVC, dorsal vagal complex; HPC, hippocampus; Hyp, hypothalamus; IL, infralimbic division of the mPFC; LC, locus coeruleus; LH, lateral hypothalamus; LS, lateral septum; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; ov, oval nucleus of the BNST; PAG, periaqueductal gray; PB, parabrachial nucleus; PL, prelimbic division of the mPFC; PVH, paraventricular nucleus of the hypothalamus; PVT, paraventricular thalamus; SI substantia innominata; Thal, thalamus; v, ventral nucleus of the BNST; vHPC, ventral hippocampus; VTA, ventral tegmental area.

Figure 4

Circuit organization in anxiety: a problem with interpretation. We propose a four-step model wherein external events are detected, interpreted, evaluated, and responded to by succeeding levels of highly interconnected neural circuits. Whether events are interpreted as threatening or nonthreatening depends on the balance between opposing circuits among the amygdala, vHPC, mPFC and BNST. In anxiety, balance is shifted toward projections interpreting events as threatening. Red, anxiogenic pathway; blue, anxiolytic pathway. ad, anterodorsal nucleus of the BNST; AHA, anterior hypothalamic area; BLA, basolateral amygdala; BNST, bed nucleus of the stria terminalis; CeA, central amygdala; CeL, lateral subdivision of the central amygdala; CeM, centromedial subdivision of the amygdala; DVC, dorsal vagal complex; IL, infralimbic division of the mPFC; LH, lateral hypothalamus; LS, lateral septum; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; ov, oval nucleus of the BNST; PAG, periaqueductal gray; PB, parabrachial nucleus; PL, prelimbic division of the mPFC; PVH, paraventricular nucleus of the hypothalamus; v, ventral BNST; vHPC, ventral hippocampus; vPallidum, ventral pallidum; VTA, ventral tegmental area.