Neurobiological links between stress and anxiety

Abstract

Stress and anxiety have intertwined behavioral and neural underpinnings. These commonalities are critical for understanding each state, as well as their mutual interactions. Grasping the mechanisms underlying this bidirectional relationship will have major clinical implications for managing a wide range of psychopathologies. After briefly defining key concepts for the study of stress and anxiety in pre-clinical models, we present circuit, as well as cellular and molecular mechanisms involved in either or both stress and anxiety. First, we review studies on divergent circuits of the basolateral amygdala (BLA) underlying emotional valence processing and anxiety-like behaviors, and how norepinephrine inputs from the locus coeruleus (LC) to the BLA are responsible for acute-stress induced anxiety. We then describe recent studies revealing a new role for mitochondrial function within the nucleus accumbens (NAc), defining individual trait anxiety in rodents, and participating in the link between stress and anxiety. Next, we report findings on the impact of anxiety on reward encoding through alteration of circuit dynamic synchronicity. Finally, we present work unravelling a new role for hypothalamic corticotropin-releasing hormone (CRH) neurons in controlling anxiety-like and stress-induce behaviors. Altogether, the research reviewed here reveals circuits sharing subcortical nodes and underlying the processing of both stress and anxiety. Understanding the neural overlap between these two psychobiological states, might provide alternative strategies to manage disorders such as post-traumatic stress disorder (PTSD).

Keywords: Corticotrophin releasing hormone; Emotional valence; Mitochondria; Neural circuits; Optogenetics.

Fig. 1

Valence coding in the basolateral amygdala (BLA) projector populations. A. Projector valence coding (adapted from Beyeler et al. 2016). a. Schematic of Pavlovian conditioning paradigm. Head-fixed mice were trained to discriminate between one cue paired with sucrose (CS–S) and a different cue paired with quinine (CS-Q). b. Peri-stimulus time histogram (PSTH) of the firing rates of representative units excited (top) or inhibited (bottom) during a CS-S presentation followed by a sucrose delivery. c. Fraction of BLA neurons excited or inhibited by CS-S, CS-Q or both. d. PSTH of action potentials of a BLA single-unit photoidentified as a BLA-NAc projector. e. Within-cell difference of response to CS-S and CS-Q depending on the neurons projection targets. f. Percentage of positive and negative valence units in the BLA. B. Behavioral impact of optogenetic activation of different BLA pathways (BLA-NAc and BLA-CeA projectors and BLA-vHPC terminals). C. Synaptic plasticity mechanism observed in BLA-NAc and BLA-CeA projection neurons after learning of valence associations. D. Topographic maps of three projectors populations in the BLA. CS: conditioned stimuli, S: sucorse, Q: quinine, NAc: nucleus accumbens, CeA: central amygdala, vHPC: ventral hippocampus.

Fig. 2

Circuit and molecular mechanisms of stress and anxiety. A.LC-NE projections to BLA increases anxiety-like behaviors acting on β-adrenergic receptors (βARs) and through projections to downstream structures such as the CeA. B.NAc mitochondrial function and anxiety, and its influence on social dominance. C.Circuit synchronicity between the PFC and VTA under different punishment probabilities. LC: locus coeruleus, BLA: basolateral amygdala, CeA: central amygdala, NAc: nucleus accumbens, PFC: prefrontal cortex, VTA: ventral tegmental area, NE: norepinephrine; ATP: adenosine triphosphate CRH: corticotropin-releasing hormone TH: tyrosine hydroxylase DBH: dopamine beta-hydroxylase Gal: galanin.

Fig. 3

PVN-CRH neurons coordinate behavioral patterns after stress(adapted fromFüzesi et al., 2016). A. Behavioral quantification of mice in their home-cage, before (naïve) and immediately after a footshock (stress). Eight distinct behaviors are prominent. Each row represents one mouse. B. Histogram of grooming behavior at each time-point for naïve and stress mice. C. Schematic of in vivo photostimulation of PVN-CRH to LH projections (20 Hz, 5 min) increases grooming time and stimulated CORT release. PVN: paraventricular nucleus of the hypothalamus CRH: corticotropin-releasing hormone LH: lateral hypothalamus ME: median eminence CORT: corticosterone.