In the present study, we provided a systematic behavioral analysis of SIB in minks for the first time. Meanwhile, we observed that minks with SIB exhibit serious nerve damage in brain tissues. Mechanistically, CBP was significantly increased and in turn activated CREB signaling in the brain tissues of the minks with SIB, indicating the significant roles of CBP-CREB axis in the elicitation of SIB. Furthermore, an important finding was that inhibitors of CBP improve behavioral and physiological disorders of minks with SIB in vivo, suggesting that CBP is a critical molecular for SIB and it is potentially an effective target for SIB therapy.
SIB occurs in a number of neurological and neuropsychiatric conditions. However, the neuropathology of SIB has not been systematically explored. Because of the ethical difficulties in carrying out study in human subjects, experimental animal models were used to investigate SIB. Several animal models of SIB have been described [13, 29]. For examples, Matthew et al investigated the relationship between SIB with stress in rhesus monkey model of self injury [13]. In a rat model, Yuan et al illuminated the role of anxiety in vulnerability for self-injurious behavior [43]. Here, we used for the first time mink as the animal model to investigate the genesis and development of SIB and made several main behavioral observations and suggest that they are mechanistically and diagnostically indicative of SIB. SIB in minks arises spontaneously and is always accompanied by wounds, indicating the advantage of mink as the models of SIB. First, we confirmed that the frequency of self-biting and repeating wheel is significantly increased in the minks that spontaneously develop SIB. Meanwhile, our data showed that the sleeping time, dietary amount, drinking frequency, defecation frequency and body weight markedly reduced in SIB group.
Furthermore, we investigated the pathological change of SIB in mink brain. Our data showed that the microglial cells diffused hyperplasia in the brain parenchyma in minks with SIB, but not found in healthy minks. Meanwhile, activated Iba-1 microglial cells were increased in the brain parenchyma in SIB group. In addition, we examined the levels of NfL and NfH, in the CSF and serum of mink with or without SIB. We observed increased levels of NfL and NfH in the CSF and serum of minks with SIB. Taken together, these findings suggest that minks with SIB exhibited strong neurological illness signs.
Illuminating the molecular mechanism of SIB is significant to develop new prevention and therapeutic strategies for SIB. However, most research has focused on environmental factors that reinforce SIB, and only a few studies have investigated the underlying biological mechanism of SIB. For examples, Subbiah et al found that SIB is associated with an induction of a MAPK signaling pathway and an activation of the transcription factor CREB in rats with L-DOPA-induced SIB, suggesting that the induction of CREB transcription may be associated with elicitation of SIB [29].
Cyclic-AMP response element (CRE) binding protein (CREB) belongs to a large family of basic leucine zipper (bZIP)-containing transcription factors [44–46], which has long been known to be important for the formation of memories [47, 48]. Recent study have shown that CREB signaling is dysfunctional in mouse and human with Alzheimer’s disease (AD), a disease characterized by cognitive decline and memory impairments[25, 49]. In our study, we observed that the phosphorylation levels of CREB were significantly increased in the brain tissues of minks with SIB, consistent with the precious study [29]. Furthermore, we found for the first time that the CREB signaling is indeed activated in the brain tissues of minks with SIB by detecting the mRNA levels of CREB target genes, including Bcl2, NOR1, FoxO4 and c-FOS.
It is well-known that the phosphorylated CREB (p-CREB) binds the CBP [30, 31, 44]. This binding event will further enhance the transcriptional activity of p-CREB and thereby activate the transcription of CREB target genes. Given that the significant roles of CREB in SIB development, we assumed that CBP is also associated with SIB development in minks. Indeed, CBP markedly up-regulated in the brain tissues of minks with SIB, indicating the significant roles in elicitation of SIB. Consistently, we also found that the expression is increased in the SIB mice and mink models induced by (±) Bay K 8644 agonist. And to our best knowledge, this is the first time to prove that CBP participates in SIB. However the molecular mechanism that CBP expression increases in the brain tissues of minks with SIB deserved to further investigate.
Small molecules that target protein–protein interactions are important research technologies for dissecting the biological functions of protein-protein interactions and potential therapeutics for many diseases [44]. To validate the effect of CBP and CREB signaling on SIB development, we used CBP-CREB interaction inhibitor to inhibit the interaction between CBP and CREB in vivo. Our results showed that sustained administration of CBP-CREB interaction inhibitor significantly reduced the expression of CREB target genes and relieved the nerve damage in brain tissues of minks with SIB, which in turn gradually relieved the self-injury behavior and promoted the wound healing. Consistently, we also achieved the same results in mice models. Taken together, our findings shed light on the critical role of CBP in the genesis and development of SIB.
In summary, the present study used a mink model of SIB to investigate underlying mechanism involved in the genesis of SIB. Our results illustrated an induction of CBP and an activation of CREB signaling, as a novel mechanism in the genesis of SIB. Importantly, CBP-CREB interaction inhibitor markedly relieved the SIB severity in vivo, supplying an effective strategy for SIB therapy. These findings are also important supplements for the full understanding of SIB.