Glucocorticoid In The Rat Model Of Depression, Adrenocorticotropic Hormone-releasing Hormone Action

Although major depression is thought to be the outcome of gene-environmental interactions, the causative genes and environmental factors underlying depression remain to be identified. Decades of research have uncovered the limitations of the monoamine hypothesis of depression. The pathophysiological mechanisms beyond monoamines were highlighted and increasing attention was paid to the stress-associated neuroendocrine system. Glucocorticoid and corticotrophin releasing factor (CRF) are the most well-known stress hormones in this system. In present study we plan to investigate the potential role of these two hormones in the rat model of depression induced by chronic unpredictable mild stress.1. The validity and reliability of the rat model of depression induced by CUMSReferring to the diagnostic criteria and the biological features of depression, we observed body weight, adrenal weight, depression-associated behaviors (sucrose preference test and open field test), the number of CRF immunoreactive neurons in paraventricular nucleus (PVN) of hypothalamus and DST in the rat model induced by CUMS. Results: A decreased body weight was observed. Sucrose preference test showed that percentage of sucrose solution from the total liquid was decreased, which simulates anhedonia (i.e. a loss of responsiveness to pleasant events), a core symptom of depression and the defining feature of melancholia. Open field test showed a low level of locomotion, rearing and grooming, which indicate a disruption of engagement in both a social and nonsocial nature and decreased explorational ability. These findings all fit the behaviors of depression. The increased adrenal weight and increased total number of CRF immunoreactive neurons in PVN of hypothalamus indicated the hyperactivity in HPA axis. DST showed that the pretreatment with dexamethasone (DEX) can not repress the total number of CRF immunoreactive neurons in the rat model induced by CUMS, by contrast with a normal repression in the number of CRF neurons in rat induced by acute stress. In brief, the rat model induced by CUMS represented decreased body weight, obvious depression-like behavior, hyperactivity in HPA axis and nonsuppression on the DST, which fits the criteria and neurobiological feature of depression. These results indicated that the rat model induced by CUMS is a suitable model for depression. The results also indicated that it is a nice model for study the neurobiological sequence of the high level of glucocorticoid induced by chronic stress.2. Mifepristone repairs region-dependent alteration of synapsin I in hippocampus in rat model of depressionClinical investigations present much evidence that the glucocorticoid receptor (GR) antagonist mifepristone leads to a rapid amelioration of psychotic major depression (PMD). Only one week use of mifepristone is efficacious in the treatment of major depression. The investigation of the molecular mechanisms underlying the antidepressant effect of mifepristone may contribute to understanding the role of glucocorticoid in the pathogenesis of depression.The hippocampus, a structure that plays a vital role in learning and memory, contextual fear conditioning, and neuroendocrine regulation is a target for adrenal steroids that provides a model for studying neurobiological consequences of stress. Depression is associated with hippocampal plasticity, for which increased excitatory amino acid (EAAs) release in CA3 induced by chronic stress is responsible, and glucocorticoids have a permissive role and act synergistically with EAAs in producing neuronal damage. Moreover, glucocorticoids increase synapsin I, which has a key role in the release of neurotransmitter, including EAAs. Hereby, we hypothesize that major depression involves synapsin I alteration induced by chronic stress and that mifepristone blocks this alteration. In the present study, we observed both the expression of hippocampal synapsin I and depression-associated behavior in a rat model of depression induced by chronic unpredictable mild stress (CUMS). The result showed that a region-dependent synapsin I alteration occurs in the rat hippocampus after 21 days of CUMS, i.e., it increases in DG/CA3 and decreases in the CA1 region. Correlation analysis indicated that the decrease of synapsin I in CA1 is highly correlated with the increase in the DG/CA3 subfield. Simultaneously, the region-dependent alteration of synapsin I is correlated with depression-associated behaviors. Both the alteration of synapsin I and the depression-associated behavior were rapidly restored after treatment with mifepristone for one week. The result suggests that the alteration of synapsin I is involved in the pathogenesis of depression and that the role of glucocorticoid in depression is associated with the region-dependent synaptic alteration in hippocampus.3. CRF immunoreactive neurons increase in neopallium in the rat model of depression induced by CUMSCorticotrophin releasing factor (CRF) is generally acknowledged as the key activator of the hypothalamus-pituitary-adrenal (HPA) axis. In fact, CRF, independently from its neuroendocrine effects on the HPA system acts at diverse locations within brain as a neurotransmitter / neuromodulator to coordinate endocrine, immune, autonomic and behavioral responses to stress. There is no study about the role of cortical CRF neurons in chronic stress and depression. We find that there are two types of CRF immunoreactive neurons in the cerebral cortex. Type I cells were mainly distributed in layers II -III. Morphologically this type of cells is interneuron and is the true CRF neuron in general meaning (synthesizing and secreting CRF). The fibers of these neurons projected into the pia mater at the surface of cortex. This finding implied that Type I cells may be CSF-contacting neurons, which act as both sensor and secretor. Type II cells were mainly distributed in layer V of cortex. It appeared that these cells receive the CRF immunostaining fibers terminals afferent from other cells rather than synthesize CRF by themselves. It is probable that type II cells receive afferent fibers from both extracortex and type I cells within layers II -III cortex. Considered that Type I cells morphologically are inhibitory interneuron, we presumed that type I in layer II -III could inhibit activity of type II cells in layer V. The number of these two types of cells increased in the neopallium of rats induced by CUMS, accompanied by depression-like behaviors. The number of them decreased after treatment with the antidepressant imipramine, accompanied by the recovery of behaviors. These result implied that CRF immunoreactive cells in the neopallium may be involved in depression-like behaviors. The results also implied that the increased number of CRF neurons in the neopallium may be partly responsible for elevated CSF-CRF, which is commonly seen in patients with depression.