As a step toward addressing limitations in the current psychiatric diagnostic
As a step toward addressing limitations in the current psychiatric diagnostic system, the NIMH recently developed the Research Domain Criteria (RDoC) to stimulate integrative researchspanning self-report, behavior, neural circuitry, and molecular/genetic mechanismson core psychological processes implicated in mental illness. that document negative effects of acute threats and chronic stress on reward responses in humans. The mechanisms underlying such effects are unclear, but new optogenetic data in rodents indicate that GABAergic inhibition of midbrain dopamine neurons, driven by activation of the habenula, may play a fundamental role in stress-induced anhedonia. In addition to its basic scientific value, a better understanding of interactions between the neural systems that mediate threat and reward responses may offer relief from the burdensome condition of anxious depression. short allele carriers showed bilateral amygdala hyperactivation to fearful and angry faces.[43C45] Furthermore, decreased functional coupling between the amygdala and perigenual cingulate, Rabbit Polyclonal to SF3B3. as well as decreased gray matter volume in both regions, has been observed in short allele carriers. These findings support hypotheses linking emotional stability to serotonergic functioning,[47,48] and suggest a genetic contribution to amygdala hypersensitivity in anxiety. However, caution must be exercised when extrapolating from these studies to conclusions about excessive anxiety. First, the initial demonstrations of amygdala hyperactivation in short allele carriers involved healthy samples displaying normative anxiety,[43,44] suggesting that neither possession of the short allele nor amygdala hyperactivity is sufficient to yield an anxious phenotype. Second, whether stress can explain links between the short allele and anxietyor psychopathology more broadlyis unclear. Enthusiasm stems from a well-known report that the relationship between genotype and depressive illness depends on life stress. However, two meta-analyses did not find support for this x interaction,[50,51] and another concluded that most candidate x interactions, including the x stress interaction, are unreliable, largely because most studies are underpowered. Neuroimaging may help circumvent this limitation, as neural data lie closer to the genetic effects of interest than self-report data.[but see 53] Along these lines, one study found a positive correlation between life stress and resting activation of the amygdala and hippocampus, but only in short allele carriers. Finally, it is important not to overlook the environment in x interactions. short allele carriers appear to be exquisitely sensitive to environmental cues, which engenders anxiety when stressors abound. However, when conditions are VX-765 more salubrious, short allele carriers may be especially able to take advantage. For instance, one study used a gambling task to show that, compared to long allele carriers, short allele were more sensitive to changes in their chances of winning, altering their behavioral adaptively to maximize VX-765 their gains. Thus, increased responsivity to negative cues in short allele carriers may only be one side of the storythey may be more sensitive to positive cues as well. Summary Heightened vigilance for potential threats is a prominent feature of anxiety that is supported by the BNST, basolateral amygdala, and vACC/VMPFC; other regions, such as the PAG, central amygdala, dACC, and insula, respond more robustly when threats are imminent. Specific anxiety disorders have been associated with hyperactivity in some of these structures (amygdala, insula) and hypoactivity in others (e.g., hypoactivation of dACC, VX-765 vACC, VMPFC in PTSD). Individual differences in amygdalar responses to potential threat vary with genotype, but this may be counterbalanced by greater sensitivity to positive features of the environment. Overall, the evident connections among genetic, neural, and behavioral systems that support threat vigilance make an excellent fit for the RDoC initiative. II. Anhedonia and Reward Processing While heightened negative affect characterizes both anxiety and depression, anhedonia plays a more central role in depressive illness.[57,58] Anhedonia VX-765 research has flourished with the development of a basic literature that describes partially dissociable neural systems for reward anticipation versus consummation,[59,60] for.