The prelimbic prefrontal cortex mediates the development of lasting social avoidance as a consequence of social threat conditioning
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Dopamine in the tail of the striatum facilitates avoidance in threat–reward conflicts
Responding appropriately to potential threats before they materialize is critical to avoiding disastrous outcomes. Here we examine how threat-coping behavior is regulated by the tail of the striatum (TS) and its dopamine input. Mice were presented with a potential threat (a moving object) while pursuing rewards. Initially, the mice failed to obtain rewards but gradually improved in later trials. We found that dopamine in TS promoted avoidance of the threat, even at the expense of reward acquisition. Furthermore, the activity of dopamine D1 receptor-expressing neurons promoted threat avoidance and prediction. In contrast, D2 neurons suppressed threat avoidance and facilitated overcoming the potential threat. Dopamine axon activation in TS not only potentiated the responses of dopamine D1 receptor-expressing neurons to novel sensory stimuli but also boosted them acutely. These results demonstrate that an opponent interaction of D1 and D2 neurons in the TS, modulated by dopamine, dynamically regulates avoidance and overcoming potential threats.
Intersect between brain mechanisms of conditioned threat, active avoidance, and reward
Active avoidance is a core behavior for human coping, and its excess is common across psychiatric diseases. The decision to actively avoid a threat is influenced by cost and reward. Yet, threat, avoidance, and reward have been studied in silos. We discuss behavioral and brain circuits of active avoidance and the interactions with fear and threat. In addition, we present a neural toggle switch model enabling fear-to-anxiety transition and approaching reward vs. avoiding harm decision. To fully comprehend how threat, active avoidance, and reward intersect, it is paramount to develop one shared experimental approach across phenomena and behaviors, which will ultimately allow us to better understand human behavior and pathology.
Person-centered analyses reveal that developmental adversity at moderate levels and neural threat/safety discrimination are associated with lower anxiety in early adulthood
Parsing heterogeneity in the nature of adversity exposure and neurobiological functioning may facilitate better understanding of how adversity shapes individual variation in risk for and resilience against anxiety. One putative mechanism linking adversity exposure with anxiety is disrupted threat and safety learning. Here, we applied a person-centered approach (latent profile analysis) to characterize patterns of adversity exposure at specific developmental stages and threat/safety discrimination in corticolimbic circuitry in 120 young adults. We then compared how the resultant profiles differed in anxiety symptoms. Three latent profiles emerged: (1) a group with lower lifetime adversity, higher neural activation to threat, and lower neural activation to safety; (2) a group with moderate adversity during middle childhood and adolescence, lower neural activation to threat, and higher neural activation to safety; and (3) a group with higher lifetime adversity exposure and minimal neural activation to both threat and safety. Individuals in the second profile had lower anxiety than the other profiles. These findings demonstrate how variability in within-person combinations of adversity exposure and neural threat/safety discrimination can differentially relate to anxiety, and suggest that for some individuals, moderate adversity exposure during middle childhood and adolescence could be associated with processes that foster resilience to future anxiety.
Astrocyte-to-neuron H2O2 signalling supports long-term memory formation in Drosophila and is impaired in an Alzheimer’s disease model
Astrocytes help protect neurons from potential damage caused by reactive oxygen species (ROS). While ROS can also exert beneficial effects, it remains unknown how neuronal ROS signalling is activated during memory formation, and whether astrocytes play a role in this process. Here we discover an astrocyte-to-neuron H2O2 signalling cascade in Drosophila that is essential for long-term memory formation. Stimulation of astrocytes by acetylcholine induces an increase in intracellular calcium ions, which triggers the generation of extracellular superoxide (O2•–) by astrocytic NADPH oxidase. Astrocyte-secreted superoxide dismutase 3 (Sod3) converts O2•– to hydrogen peroxide (H2O2), which is imported into neurons of the olfactory memory centre, the mushroom body, as revealed by in vivo H2O2 imaging. Notably, Sod3 activity requires copper ions, which are supplied by neuronal amyloid precursor protein. We also find that human amyloid-β peptide, implicated in Alzheimer’s disease, inhibits the nAChRα7 astrocytic cholinergic receptor and impairs memory formation by preventing H2O2 synthesis. These findings may have important implications for understanding the aetiology of Alzheimer’s disease.
Resting-state fMRI reveals altered functional connectivity associated with resilience and susceptibility to chronic social defeat stress in mouse brain
Chronic stress is a causal antecedent condition for major depressive disorder and associates with altered patterns of neural connectivity. There are nevertheless important individual differences in susceptibility to chronic stress. How functional connectivity (FC) amongst interconnected, depression-related brain regions associates with resilience and susceptibility to chronic stress is largely unknown. We used resting-state functional magnetic resonance imaging (rs-fMRI) to examine FC between established depression-related regions in susceptible (SUS) and resilient (RES) adult mice following chronic social defeat stress (CSDS). Seed-seed FC analysis revealed that the ventral dentate gyrus (vDG) exhibited the greatest number of FC group differences with other stress-related limbic brain regions. SUS mice showed greater FC between the vDG and subcortical regions compared to both control (CON) or RES groups. Whole brain vDG seed-voxel analysis supported seed-seed findings in SUS mice but also indicated significantly decreased FC between the vDG and anterior cingulate area compared to CON mice. Interestingly, RES mice exhibited enhanced FC between the vDG and anterior cingulate area compared to SUS mice. Moreover, RES mice showed greater FC between the infralimbic prefrontal cortex and the nucleus accumbens shell compared to CON mice. These findings indicate unique differences in FC patterns in phenotypically distinct SUS and RES mice that could represent a neurobiological basis for depression, anxiety, and negative-coping behaviors that are associated with exposure to chronic stress.
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