Long term effects of stress on hippocampal function: Emphasis on early life stress paradigms and potential involvement of neuropeptide Y

The brain is both central in orchestrating the response to stress, and, a very sensitive target when such response is not controlled. In fact, stress has long been associated with the onset and/or exacerbation of several neuropsychiatric disorders such as anxiety, depression, and drug addiction. The hippocampus is a key brain region involved in the response to stress, not only due to its anatomical connections with the hypothalamic-pituitary-adrenal axis but also as a major target of stress mediators. The hippocampal dentate gyrus (DG)-CA3 circuit, composed of DG granule cells axons (mossy fibers) synapsing onto CA3 pyramidal cells, plays an essential role in memory encoding and retrieval, functions that are vulnerable to stress. Although naturally excitatory, this circuit is under the inhibitory control of GABAergic interneurons that maintain the excitation/inhibition balance. One subgroup of such interneurons produces neuropeptide Y (NPY), which has emerged as a promising endogenous stress "resilience molecule" due to its anxiolytic and anti-epileptic properties. Here we examine existing evidence that reveals a potential role for hilar NPY+ interneurons in mediating stress-induced changes in hippocampal function. We will focus specifically on rodent models of early life stress (ELS), defined as adverse conditions during the early postnatal period that can have profound consequences for neurodevelopment. Collectively, these findings suggest that the long-lasting effects of ELS might stem from the loss of GABAergic NPY+ cells, which then can lead to reduced inhibition in the DG-CA3 pathway. Such change might then lead to hyperexcitability and concomitant hippocampal-dependent behavioral deficits.