Abstract
Both the development and relief of stress-related psychiatric conditions such as major depression (MD) and post-traumatic stress disorder (PTSD) have been linked to neuroplastic changes in the brain. One such change involves the birth of new neurons (neurogenesis), which occurs throughout adulthood within discrete areas of the mammalian brain, including the dorsal hippocampus (HIP). Stress can trigger MD and PTSD in humans, and there is considerable evidence that it can decrease HIP neurogenesis in laboratory animals. In contrast, antidepressant treatments increase HIP neurogenesis, and their efficacy is eliminated by ablation of this process. These findings have led to the working hypothesis that HIP neurogenesis serves as a biomarker of neuroplasticity and stress resistance. Here we report that local alterations in the expression of Sprouty2 (SPRY2), an intracellular inhibitor of growth factor function, produces profound effects on both HIP neurogenesis and behaviors that reflect sensitivity to stressors. Viral vector-mediated disruption of endogenous Sprouty2 function (via a dominant negative construct) within the dorsal HIP of adult rats stimulates neurogenesis and produces signs of stress resilience including enhanced extinction of conditioned fear. Conversely, viral vector-mediated elevation of SPRY2 expression intensifies the behavioral consequences of stress. Studies of these manipulations in HIP primary cultures indicate that SPRY2 negatively regulates fibroblast growth factor-2 (FGF2), which has been previously shown to produce antidepressant- and anxiolytic-like effects via actions in the HIP. Our findings strengthen the relationship between HIP plasticity and stress responsiveness, and identify a specific intracellular pathway that could be targeted to study and treat stress-related disorders.
Highlights
Accumulating evidence suggests that the rate of neurogenesis in the hippocampus (HIP) plays an important role in the development, manifestation, and relief of depressive and anxiety disorders [1,2,3]
Immunohistochemical analysis of brain sections from rats treated with the Electroconvulsive seizure (ECS) regimen that affects gliosis and SPRY2 expression within the prefrontal cortex (PFC) [20] revealed that, as in the PFC, the number of BrdU-labeled cells increased as the number of SPRY2-labeled cells decreased within the DG of the dorsal HIP (Fig 1a–1c)
We show that a prominent consequence of the ability of ECS to downregulate SPRY2 function—as modeled by expression of a dominant negative form of SPRY2—is elevated neurogenesis in the dorsal HIP and behavioral effects that may reflect resistance to stress
Summary
Accumulating evidence suggests that the rate of neurogenesis in the hippocampus (HIP) plays an important role in the development, manifestation, and relief of depressive and anxiety disorders [1,2,3]. It is well established that stress, which can trigger psychiatric illnesses including major depression (MD) and post traumatic stress disorder (PTSD) in humans [4], decreases HIP neurogenesis in laboratory animals [5,6]. Various treatments with antidepressant effects (including selective serotonin reuptake inhibitors [SSRIs], norepinephrine reuptake inhibitors [NRIs], and electroconvulsive seizure [ECS]) can increase neurogenesis in the HIP of laboratory animals [2,3,5]. The efficacy of antidepressants is eliminated by ablation of HIP neurogenesis, suggesting that this process is critical for the relief of depressive signs [7,8]. While the available evidence suggests that neurogenesis can serve as a biomarker of neuroplasticity and stress resistance, additional research is needed to test this hypothesis in a way that provides deeper insight on the conditions under which it is—and is not—supported
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