Repeated, extreme, or traumatic stressors can elicit pathological effects leading to many negative physical and psychological outcomes. Stressors can precipitate the onset of psychiatric diseases, or exacerbate pre-existing disorders including various anxiety and mood disorders. As stressors can negatively impact human psychiatric health, it is essential to identify neurochemicals that may confer protection from the negative sequelae of repeated or extreme stress exposure. Elucidating the neurobiological underpinnings of stress resilience will enhance our ability to promote resilience to, or recovery from, stress-related psychiatric disease. Herein, we will review the evidence for neuropeptide Y as an endogenous mediator of resilience and its potential relevance for the treatment of stress-related psychiatric diseases.

The neuropeptide Y (NPY) system is emerging as a promising therapeutic target for neuropsychiatric disorders by intranasal delivery to the brain. However, the vast majority of underlying research has been performed with males despite females being twice as susceptible to many stress-triggered disorders such as posttraumatic stress disorder, depression, anorexia nervosa, and anxiety disorders. Here, we review sex differences in the NPY system in basal and stressed conditions and how it relates to varied susceptibility to stress-related disorders. The majority of studies demonstrate that NPY expression in many brain areas under basal, unstressed conditions is lower in females than in males. This could put them at a disadvantage in dealing with stress. Knock out animals and Flinders genetic models show that NPY is important for attenuating depression in both sexes, while its effects on anxiety appear more pronounced in males. In females, NPY expression after exposure to stress may depend on age, timing, and nature and duration of the stressors and may be especially pronounced in the catecholaminergic systems. Furthermore, alterations in NPY receptor expression and affinity may contribute to the sex differences in the NPY system. Overall, the review highlights the important role of NPY and sex differences in manifestation of neuropsychiatric disorders.

The locus coeruleus (LC) is a critical stress‐responsive location that mediates many of the responses to stress. We used immunoblotting and immunohistochemistry to investigate changes in induction and phosphorylation of several transcription factors and kinases in the LC that may mediate the stress‐triggered induction of tyrosine hydroxylase (TH) transcription. Rats were exposed to single or repeated immobilization stress (IMO) for brief (5 min), intermediate (30 min) or sustained (2 h) duration. Single IMO elicited rapid induction of c‐Fos and phosphorylation of cyclic AMP response element‐binding protein (CREB) without changing the expression of early growth response (Egr)1, Fos‐related antigen (Fra)‐2 or phosphorylated activating transcription factor‐2. Repeated IMO triggered increased phosphorylation and levels of CREB along with transient induction of c‐Fos and increased Fra‐2 expression. Several mitogen‐activated protein kinases were activated by repeated IMO, shown by increased phosphorylation of p38, c‐Jun N‐terminal kinase (JNK)1/2/3 and extracellular signal‐regulated kinase (ERK1/2). ERK1 was the major isoform expressed, and ERK2 the predominant isoform phosphorylated. Repeated IMO elicited hyperphosphorylation of ERK1/2 selectively in TH immunoreactive neurons, with substantial nuclear localization. These distinct alterations in transcriptional pathways following repeated compared with single stress may be involved in mediating long‐lasting neuronal remodeling and are implicated in the mechanisms by which acute beneficial responses to stress are converted into prolonged adaptive or maladaptive responses.