Depression is one of the most frequently encountered forms of mental illness and more than 350 million people battle with it every day (Smith, 2014). Post-stroke depression (PSD) as a subtype of depression is a frequent complication after stroke, it is related to a variety of adverse health outcome including increased disability, difficult to recover and risk of suicide (Paolucci et al., 2001; Pompili et al., 2012). According to a meta-analysis, the prevalence of depression was 33% among stroke survivors by pooled estimate (Hackett et al., 2005).

Despite the high morbidity of PSD and major depressive disorder (MDD), there is yet little insight into the underlying neurobiological mechanisms. Preclinical and clinical studies suggest that many mechanisms are involved in this disorder including neurotrophic signaling, cellular plasticity and activation of the hypothalamic-pituitary-adrenal (HPA) axis (Spalletta et al., 2006; Loubinoux et al., 2012). In the aspect of the neurotrophic and neurochemical factors, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor and vascular endothelial growth factor were proved to play an important role in the pathophysiology of depression and antidepressant action of therapeutic interventions (Sharma et al., 2016). In addition, Neuropeptide Y (NPY), a 36-amino acid peptide, is widely distributed in the central and peripheral nervous systems such as most cortical areas, hippocampus, amygdala, olfactory bulb and spinal cord of the rat and human brain (Dumont et al., 1992). These brain regions are closely related to stress responses and mood disorders. With this in mind, researchers suggested that it as neuromodulators associated with MDD (Morales-Medina et al., 2010). NPY plays a regulatory role in feeding, body weight, sleep, cognition and emotion (Gehlert, 2004). In addition, NPY was found to regulate neurogenesis in the hippocampus. Significantly decreased NPY in the dorsal hippocampus was found in the maternally separated rats and Flinders sensitive line (FSL) rats (a genetic-based model of depression-like behavior; Caberlotto et al., 1999; Jiménez-Vasquez et al., 2001). Moreover, human and postmortem studies found decreased NPY levels in cerebrospinal fluid (CSF), plasma the frontal cortex and the caudate nucleus of depressive or attempted suicide patients, especially in repeatedly attempted suicides (Widerlöv et al., 1988; Widdowson et al., 1992; Westrin et al., 1999; Heilig, 2004). However, the NPY mRNA which was region specific in depressive-like animal models, significantly decreased in the nucleus accumbens, medial amygdala, hippocampal dentate gyrus, CA regions and prefrontal cortex, but increased in the arcuate nucleus and anterior cingulate cortex in the FSL and chronic mild stressed rats (Caberlotto et al., 1998; Sergeyev et al., 2005; Bjørnebekk et al., 2006; Zambello et al., 2008; Melas et al., 2012).

Withal NPY mediates neuroprotection against focal ischemia and regulates cerebral blood flow (Lundberg et al., 1982; Tuor et al., 1990; Cheung and Cechetto, 2000). Previous studies showed that NPY protein levels were increased in cortical and subcortical tissues around the lesions in the ischemic and hemorrhagic animal models (Kharlamov et al., 2007; Montaner et al., 2012). In plasma, NPY levels were significantly lower compared to the control group in the acute phase of female stroke patients (Baranowska et al., 2013).

Clinical and experimental investigations support that NPY is involved in the pathophysiology of depression and stroke. What is more, PSD as a disease integrated above two reciprocally relational factors, so we speculate NPY could be a molecular joint in this disease. Therefore, the first aim of this study was to explore the changes of NPY protein content and mRNA expression in PSD, stroke without depression (Non-PSD) and MDD patients. Then we further analyze the difference of NPY between the subtypes of depression including PSD and MDD patients.

The present study provides evidence that the protein and transcriptional changes of NPY occur in PSD and different depressions. The protein content shows a consistent decline in PSD, Non-PSD and MDD group, but only PSD and Non-PSD groups reach statistical significance when compared with NC group. While the transcriptional levels display significant differences between PSD, Non-PSD and MDD group. Moreover, the NPY mRNA expression can identify the different types of depression to some extent. It’s important to note that this is an exploratory study with small sample size, so replication of these findings in larger cohorts will be necessary for validation.

The reduced protein and mRNA of NPY in MDD group were obtained in genetic rat models of depression and other clinical research, suggesting that these changes most likely are triggered by stress (Lachman et al., 1992; Westrin et al., 1999; Melas et al., 2013). Previous studies demonstrated that enhancing NPY function boosts resilience (Christiansen et al., 2011; Southwick and Charney, 2012; Cohen et al., 2015). NPY can be served as a potential anti-depressive factor and used to monitor treatment of depression by recent findings (Bigio et al., 2016; Nakhate et al., 2016; Ozsoy et al., 2016; Wagner et al., 2016). NPY is one of the most abundant peptides in the central nervous system and mediates mood disorder, stress response and antidepressant effect mainly through the Y1 and Y2 receptors, which are densely expressed in the cortex, hippocampus and amygdala (Dumont et al., 1998; Price and Drevets, 2012). So it may be speculated that NPY participates in MDD through modulating the internal and mutual function of these brain regions. Furthermore, Mickey et al. (2011) found that individuals with low-expression NPY genotypes were inclined to negative affective experience under stress. Taken together, the evidence suggested that low NPY increased the risk for depression through adding sensitivity to negative stimuli and declining brain reserve capacity at the cellular levels and also possibly at the neural circuit levels (Freret et al., 2015).

Compared with the NC group, the change of protein had a significant difference in PSD and Non-PSD patients. The possible explanation could be that stress was the cause for stroke and depression (Sergeyev et al., 2005). Another mechanism could be HPA axis activation, then subsequent suppression of NPY levels by elevating glucocorticoid (Holsboer, 2000; Makino et al., 2000). Indeed, the neuroprotection role of NPY suggests that the reduced level counteracts the positive influence on the central and peripheral systems in PSD diseases. Other mechanisms including serotonin receptors and exaggerated inflammatory cytokines initiated by brain injury and persistent neuronal death might contribute to PSD (Popa-Wagner et al., 2014; Buga et al., 2016).

However, the result of mRNA level has a significant difference between PSD and MDD groups. It was consistent with the results of ROC and logistic regression analyses, which showed that NPY mRNA could be conducive to distinguish different subtypes of depression (PSD and MDD; AUC = 0.766). These suggest that PSD process the discrepantly pathological mechanisms though a subtype of depression encompasses many overlapping syndromes similar to MDD (Alexopoulos, 2003). The possible explanation was that the gene-expression changes were effected by the stress property (acute or chronic) as well as the time accumulation (Conrad and McEwen, 2000; Yang et al., 2013). MDD patients had decreased NPY protein and mRNA caused by chronic stress, while PSD patients mixed acute stress of stroke which leads to a transitory rise of mRNA, but the protein had no time to be affected for simultaneously collected blood samples. Moreover, the selected analyte of NPY mRNA expression, potentially provide new insights into exploring the molecular mechanism of different subtypes of depression.

Several issues should be considered in this exploring study. First, the present study yielded a relatively small sample size, so the findings cannot be considered categorical. Second, this was a cross-sectional study and the serum levels and mRNA of NPY measured at the acute stage of stroke patients, hence, the long-term dynamic evolution process of these biological characters is not known. Third, the NPY might be influenced by other neurochemical or genetic material, so it is important to enroll a set of subjects with high homogeneity. Given these limitations, the results should be considered preliminary and future studies should be well designed with several time points of large number of participants.

In conclusion, the present study demonstrates that NPY is abnormal in stroke, PSD and MDD patients and it has a significant distinguished function in the different subtypes of depression. These findings, together with previously published results, suggest that NPY system provides a novel version for the mechanism of depression pathology.

YYuan designed the study. YYue, HJ, YYin, YZ, JLiang, SL, JW, JLu and DG collected the participants. YYue experimented and analyzed the data, then wrote the article. AW, YYuan, YYue and all authors reviewed and approved for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.