抑郁症病理生理学,动物模型 z-bo 2020-11-05 358

　　Introduction: Ideally, an effective animal model should meet at least three criteria and have appearance, structure, and predictive validity. Later, an additional criterion was added, that is, the similarity in etiology, that is, effective models should have similar induction conditions. Briefly summarize these criteria: animal models must be similar to human conditions in several aspects, including (1) similarity between behavioral phenotypes and clinical symptom characteristics (apparent effectiveness), and (2) through clinically effective antidepressants The treatment is improved or reduced. On the contrary, the clinically ineffective treatment for human diseases does not change (predictive effectiveness), (3) triggers of events known to be important for inducing human diseases (etiological effectiveness), and (4) similar nerve Biological basis (structural validity). None of the currently available animal models can meet all of these criteria, but can only meet certain aspects. The most widely used model is based on genetic manipulation, drug therapy or various social or environmental pressures. Despite their limitations, these models have been widely used in drug development and academic research to understand the pathophysiology of diseases. Even in such an era when new and powerful methods are available, such as human induced pluripotent stem cell (iPSC) technology, they are all excellent model systems for studying the genetic and cellular mechanisms of MDD, and they continue to provide valuable information. Recent findings indicate that chronic stress models can not only replicate the behavioral and cellular aspects of depression, but they can also share common transcriptional characteristics with MDD. The traditional hypothesis of MDD pathophysiology is the "monoamine theory of depression", which believes that interference with serotonergic neurotransmission is the main neurobiological factor that constitutes clinical symptoms. For many years, this has been an outstanding working hypothesis, but since then, people have realized that this theory has some limitations, so new theories have been proposed, focusing on other neurotransmitter systems, endocrine or inflammatory disorders, gene-environment Interactions, changes in neuroplasticity, or the role of gut microbiota. Essentially, these theories are based on clinical observations, while animal studies are used to refine and validate new concepts.

　　The neuroplasticity theory of depression: This theory assumes that neuroplasticity is a core feature of a healthy brain and is essential for adapting to environmental challenges. Impaired neuroplasticity is the cellular basis of depressive mood and leads to cognitive bias and cognitive impairment that often occur in patients with depression. According to this concept, different types of antidepressants have a common mechanism of action, even if the neuroplasticity damage is normalized. These ideas are mainly based on clinical neuroimaging data, which indicates that the volume of different border structures in patients with depression is reduced, and the observation that antidepressant treatment can prevent or normalize this volume reduction. Although the exact cellular changes that cause these volume changes are still not fully understood, the concept is constantly being refined and can be used as a good assumption. Animal experiments have made important contributions to the development of this theory, mainly because of the morphological changes found in the chronic stress model that are comparable to those in patients with depression. A large number of experiments have shown that through antidepressant treatment, stress and reversal reactions can cause molecular and cellular changes. Most of these studies have focused on key limbic brain regions, such as the hippocampus, prefrontal cortex (PFC), and amygdala. Animal studies on the neurogenesis of the adult dentate gyrus have made an important contribution to the neuroplasticity theory of depression, because this cellular plasticity has been identified as a key player in the neurobiology of depression. It was later confirmed that neurogenesis was impaired in the hippocampus of patients with depression, and antidepressants had a normalizing effect. Although the importance of adult hippocampal neurogenesis in the pathophysiology of depression has been continuously questioned, this concept continues to stimulate the interest of the scientific community. Another form of cellular plasticity that played a key role in the establishment of the neuroplasticity theory is the dendritic reorganization of pyramidal neurons in the hippocampus, amygdala, and prefrontal cortex in response to stress or antidepressants. Many molecular pathways have been studied in animal experiments, and neurotrophic factors have been pointed out, the most important being BDNF (brain-derived neurotrophic factor), which is the main regulator of neuroplasticity.

　　Synaptic communication disorders and the role of glial cells: Synaptic connections are important functions and structural elements of the central nervous system (CNS), and accurate synaptic transmission is essential for neuronal communication in a healthy brain. The "synaptic hypothesis for depression" assumes that synaptic transmission disorders are an essential element of the pathophysiology of MDD. Since most of the synapses in the neocortex are glutamatergic, and the smaller ones are GABAergic, the theory of synapse generation mainly focuses on these two neurotransmitter systems. Clinical studies have shown that PFC and hippocampus dysfunction and the number of synapses in depression patients are reduced. Animal experiments produced similar data, and reported stress-induced disturbances in synaptic communication and a decrease in the number of synapses in the hippocampus and PFC of rodents. Glial cells play an active role in synaptic transmission, and they are considered to be the third element of tripartite synapses. Histopathological studies after death showed that the number of glial cells in the PFC, hippocampus and amygdala of depression patients decreased. Glial cell dysfunction contributes to changes in cortical glutamatergic and GABAergic signal transmission in depression. So far, all major glial cell types are involved in the pathophysiology of depression. Therefore, astrocytes, microglia and oligodendrocytes all seem to be involved in the pathogenesis of MDD. Consistent with clinical findings, animal studies provide experimental evidence that stress induces hippocampal and PFC astrocyte defects. Changes in the morphology and function of microglia have been reported in the chronic stress model of MDD. Oligodendrocytes are also involved in stress-induced pathophysiological changes. Compared with neurons, the study of glial cells is much more difficult, but animal studies can provide valuable information and reveal the glial cell-specific molecular mechanisms behind behavioral disorders. For example, a recent study reported that the expression of the astrocyte-specific protein menin in the brains of mice exposed to chronic stress is down-regulated, and this decrease contributes to depression.

　　Glutamate and GABA system as targets for the development of antidepressant drugs: In mature human brains, glutamate is the main excitatory neurotransmitter, because more than 90% of synaptic connections use glutamate (Glu) , And gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter.

　　MDD glutamate neurotransmitter disorder: Clinical studies have shown that glutamate levels in the serum, cerebrospinal fluid and brain of patients with depression have changed, and postmortem analysis revealed changes in the function or expression of NMDA receptor subunits. Glial cells (mainly astrocytes) play an important role in these changes because they remove glutamate from the synaptic cleft and release glial transmitters that act on NMDA receptors and express metabotropic glutamine. Acid receptors to actively regulate glutamate signaling. Animal studies have shown that stress can induce the release of hippocampus and PFC glutamate, and lead to down-regulation of NMDA receptors. At the same time, the activation of NMDA receptors contributes to the suppression of stress-induced adult hippocampal neurogenesis and promotes the reorganization of stress-induced pyramidal cell dendrites. These effects can be reversed by NMDA receptor antagonists. A study using a mouse model reported that ketamine and other NMDA receptor antagonists have a rapid (within 30 minutes) antidepressant effect in a forced swimming test, which is mediated by BDNF. In another animal experiment, a single administration of ketamine can restore (within 24 hours) chronic stress-induced abnormal behavior and molecular and cellular changes in stress-susceptible rats. In addition, in the chronic stress model, stress has been shown to reduce AMPA receptor-mediated excitation of temporal ammonia synapses in the distal dendrites of CA1 pyramidal cells, and chronic antidepressant treatment with fluoxetine can restore this Kind of change.

　　GABAergic neurotransmission in patients with MDD is blocked: It has been suggested that the abnormal cortical GABAergic network is causally related to the pathophysiology of MDD. This theory is based on in vivo studies. The study used MR spectroscopy to find changes in the GABA concentration in the prefrontal cortex of patients with depression, and post-mortem research results proved the loss of cortical GABAergic neurons and GABA synthesis defects . Animal studies have provided increasing evidence that stress exposure not only affects glutamatergic neurotransmission, but also affects the function of GABAergic networks. According to reports, the number of inhibitory neurons in the hippocampus of chronically stressed rats is reduced, especially parbumin, somatostatin, calcitonin and neurons expressing neuropeptide Y are affected. Chronic stress exposure resulted in dendritic atrophy of GABAergic neurons in the hippocampus and amygdala, and reduced GABA synthase expression was found in the limbic brain regions of stressed animals. Recently, a study that put restraint pressure on mice for 21 days found that somatostatin-positive (SST+) neurons had dendritic hypertrophy and decreased expression of GAD67 enzyme in PFC. As a supplement to this finding, another study reported that SST+ positive cells showed greater transcriptome dysregulation after chronic stress compared with neighboring pyramidal neurons. A study on gender differences in stress sensitivity found that only female mouse albumin (PV) expression increased, suggesting that the increased vulnerability of the female prefrontal PV system may be due to gender differences in the prevalence and symptoms of stress-related mood disorders basis. An electrophysiological study found that after 14 days of variable stress, the inhibitory activity of the inner PFC of rats increased, and the inhibitory synapses of glutamatergic cells increased. In a comparable experimental design, we found that the medial PFC inhibitory activity of rats subjected to mild stress for 9 weeks was reduced, indicating that the duration of long-term stress exposure may eventually change the effect of stress. Recently, a 21-day chronic unpredictable stress study also reported a decrease in the inhibitory activity of PFC in the inner side of rats.

　　The gut microbiota-brain axis of depression patients: The gut microbiota is essential for maintaining health. Through the two-way communication between the intestine and the central nervous system, it can promote various neuropsychiatric diseases including MDD development of. A landmark study reported that low mood is related to the decrease in the abundance and diversity of the gut microbiota. Transplanting the fecal microbiota of depression patients into rats lacking microbiota can induce similarities in the recipient animals. Depressive behavior and metabolism. Animal studies support clinical data, and a landmark study showed that in sterile rats, the lack of intestinal flora enhances anxiety-like behaviors and neuroendocrine responses to stress. Recent studies have shown that the gut microbiota is involved in depression-like behaviors and inflammatory processes in the ventral hippocampus of stress-susceptible rats. A longitudinal study monitored changes in fecal and plasma metabolomes, changes in fecal metabolite abundance, depression-like behaviors and changes in hippocampal neurotransmitter levels during the development of depression-like behaviors in rats with chronic unpredictable mild stress related. The results of the study show that changes in the amino acid metabolism of the intestinal flora contribute to the changes in circulating amino acids and are related to the behavioral symptoms of depression. Long-term treatment with prebiotics cultivates beneficial intestinal microbiota, which has antidepressant and anti-anxiety effects on mice. A recent study showed that psychobiological treatment of mice with Bifidobacterium breve CCFM1025 can reverse the depression-like behavior caused by chronic stress, reduce HPA axis hyperfunction and inflammation, and change the brain BDNF and c-FOS. expression.

　　Looking for candidate biomarkers: One of the main limitations of understanding disease pathology and drug development is that the diagnosis of MDD is still based on subjective criteria, and objective laboratory measures are not yet available. Biomarkers can help diagnose and predict the onset or recurrence of MDD and the response to medication or psychotherapy.

　　Neuroimaging: The evolving functional neuroimaging method represents the forefront of MDD biomarker development. For many years, the research of magnetic resonance imaging (MRI) has mainly focused on the volume changes of various edge structures of MDD. According to the results of these studies, hippocampal volume reduction has become a potential diagnostic indicator. However, hippocampal atrophy is not unique to MDD. However, imaging technology is rapidly developing, and new structural and functional imaging methods are constantly being invented, allowing us to analyze changes in metabolism and microstructure, or by evaluating the internal and inter-system changes. Dynamic, quantify brain function on a larger scale. Due to its non-invasiveness, most neuroimaging studies are performed directly on clinical samples. The neuroimaging research of rodent models is still at a relatively early stage. The main obstacles are: 1) Small animal MRI equipment is expensive; 2) Because of the limited spatial resolution of MRI, the rodent’s brain is too small to detect fine details. Despite these obstacles, more and more imaging studies have investigated structural and functional changes in rodent models. These studies usually use various chronic stress models. A few studies have used small animal positron emission tomography (PET) to study the stress response, stress sensitivity, dynamic changes of serotonergic neurotransmitters in different brain areas, or hippocampus in rodents under chronic stress. Nerve inflammation. Another PET study used a different rat model of MDD, namely FSL, and reported hypometabolism in both temporal lobes of FSL rats.

　　The utility of animal models in the development of antidepressants: Mental disorders are a huge unmet medical need. The history of antidepressant drug discovery is a mixture of time periods, with chances, great successes, and serious disappointments.

　　Ketamine: Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, traditionally used as an anesthetic and analgesic. Due to poor oral bioavailability, it is usually administered intravenously. The S-ketamine enantiomer has a higher affinity for the NMDA receptor, and has fewer adverse reactions such as sleepiness, lethargy or cognitive impairment than the R-ketamine enantiomer. Animal studies help us clarify the molecular and cellular functions of ketamine. A recent study showed that the specific NMDA receptor subunit (GluN2B) on gamma-aminobutyric acid interneurons is the initial cellular trigger for the rapid antidepressant effect of ketamine. Ketamine not only activates NMDA receptors, but also amino-hydroxy-methyl-isoxazole propionic acid (AMPA) receptors. Another study found that ketamine treatment can inhibit brain glycogen synthase kinase 3 (GSK3) in learning helpless mice, and GSK3 is necessary for the rapid antidepressant effect of ketamine.

　　Conclusion: Although animal models have many obvious shortcomings, these models have been widely used in academic research and drug development. No model can simulate all aspects of this complex disease, but they can provide opportunities to understand the specific genetic, molecular and cellular mechanisms that promote the development of MDD.