Ongoing neurogenesis in the adult dentate gyrus mediates behavioral responses to ambiguous threat cues

Abstract

Fear learning is highly adaptive if utilized in appropriate situations but can lead to generalized anxiety if applied too widely. A role of predictive cues in inhibiting fear generalization has been suggested by stress and fear learning studies, but the effects of partially predictive cues (ambiguous cues) and the neuronal populations responsible for linking the predictive ability of cues and generalization of fear responses are unknown. Here, we show that inhibition of adult neurogenesis in the mouse dentate gyrus decreases hippocampal network activation and reduces defensive behavior to ambiguous threat cues but has neither of these effects if the same negative experience is reliably predicted. Additionally, we find that this ambiguity related to negative events determines their effect on fear generalization, that is, how the events affect future behavior under novel conditions. Both new neurons and glucocorticoid hormones are required for the enhancement of fear generalization following an unpredictably cued threat. Thus, adult neurogenesis plays a central role in the adaptive changes resulting from experience involving unpredictable or ambiguous threat cues, optimizing behavior in novel and uncertain situations.

Stress and Loss of Adult Neurogenesis Differentially Reduce Hippocampal Volume

“…Adult neurogenesis can be specifically inhibited, but this manipulation has few behavioral effects under baseline testing conditions. Complete inhibition of adult neurogenesis had no effect on NSF in this study, consistent with previous findings that new neurons only affect behavior in this test under stressful conditions (42; 43; 89). Adult neurogenesis also had no effect on sucrose preference, possibly because ablation of new neurons did not affect weight, as stress did.…”

“…These patterns do not demonstrate any causative relationship, they are consistent with current thinking on the effects of new neurons on hippocampal circuits and the causes of pyramidal cell dendritic atrophy. Young neurons appear to enhance excitability in the hippocampus (74–78), and inhibiting neurogenesis can decrease overall hippocampal activity during unpredictable stress (42). Work on dendritic remodeling following stress suggests that CA3 pyramidal neuron atrophy results from glutamate excitotoxicity associated with DG hyperexcitability (26; 79), which could potentially be exacerbated by the presence of excitable new neurons.…”

“…In humans, progressive hippocampal volume shrinkage and decreases in perceived stress levels are associated with increasing numbers of prior depressive episodes (4; 92), suggesting that structural changes may eventually diminish stress perception in the context of depressive illness. Similarly, continued neurogenesis may function to bias perception of, or response to, the potentially threatening experiences (42), suggesting that ongoing plasticity may enable more resilient and flexible behavior (93; 94). Future studies will be needed to understand exactly how the interacting microcircuits within the hippocampus function to affect behavior in the face of chronic stressors.…”

“…Generation of new dentate gyrus (DG) granule neurons can also be inhibited by stress and corticosterone, though the effects of chronic stress on adult neurogenesis are complex and not fully understood (36–41). The impact of stress on adult neurogenesis is of particular interest because inhibition of adult neurogenesis impacts stress-induced anxiodepressive-like behavior in rodents (42; 43) and is suggested to play a role in depression in humans as well (44). …”

New neurons restore structural and behavioral abnormalities in a rat model of PTSD

“…Mice without neurogenesis show increased anxiety‐like behavior for several days after acute or chronic stress (Anacker et al, ; Glover, Schoenfeld, Karlsson, Bannerman, & Cameron, ; Seo, Carillo, Chih‐Hsiung Lim, Tanaka, & Drew, ; Snyder et al, ). The current study found increased anxiety‐like behavior for at least 10 days after SPS regardless of the presence or absence of new neurons.…”