Abstract
Rodent models are an indispensable tool for studying etiology and progress of depression. Since interrelated systems of neurotrophic factors and cytokines comprise major regulatory mechanisms controlling normal brain plasticity, impairments of these systems form the basis for development of cerebral pathologies, including mental diseases. The present review focuses on the numerous experimental rodent models of depression induced by different stress factors (exteroceptive and interoceptive) during early life (including prenatal period) or adulthood, giving emphasis to the data on the changes of neurotrophic factors and neuroinflammatory indices in the brain. These parameters are closely related to behavioral depression-like symptoms and impairments of neuronal plasticity and are both gender- and genotype-dependent. Stress-related changes in expression of neurotrophins and cytokines in rodent brain are region-specific. Some contradictory data reported by different groups may be a consequence of differences of stress paradigms or their realization in different laboratories. Like all experimental models, stress-induced depression-like conditions are experimental simplification of clinical depression states; however, they are suitable for understanding the involvement of neurotrophic factors and cytokines in the pathogenesis of the disease—a goal unachievable in the clinical reality. These major regulatory systems may be important targets for therapeutic measures as well as for development of drugs for treatment of depression states.
Highlights
Depression, one of the most prevalent and life-threatening forms of mental illness affecting about 21% of the world’s population, is believed to be related to individual alterations of a complex signaling network including the hypothalamicpituitary-adrenal axis; the production of neurotrophins and proinflammatory cytokines and these alterations may be intimately involved in major mood changes
Prenatal Stress (PNS) resulted in a significant decrease in the activity and expression of tissue plasminogen activator, a key serine protease involved in the extracellular conversion of pro-Brain-derived neurotrophic factor (BDNF) to mBDNF. These results suggest that PNS downregulates tPA level in the hippocampus by inhibiting the conversion of proBDNF to mature form of BDNF (m-BDNF). van den Hove et al [30] showed that in newborn Fischer 344 rats PNS resulted in an approximately 50% decrease in brain cell proliferation just after birth in both genders with a concomitant increase in caspase-3-like activity accompanied by a decrease of BDNF protein content in the hippocampus
Goshen et al [89] showed that mice subjected to chronic mild stress (CMS) for 5 weeks exhibited depressive-like symptoms, including decreased sucrose preference, reduced social exploration and adrenocortical activation, and increased IL-1β level in the hippocampus
Summary
Depression, one of the most prevalent and life-threatening forms of mental illness affecting about 21% of the world’s population, is believed to be related to individual alterations of a complex signaling network including the hypothalamicpituitary-adrenal axis; the production of neurotrophins and proinflammatory cytokines and these alterations may be intimately involved in major mood changes. Responding to this knotty question, Frazer and Morilak [9] stressed that rather than trying to recreate or mimic the entire spectrum of symptoms comprising the syndrome of depression, it may be more informative to develop animal models for specific behavioral dimensions This gives a hope to understand the neurobiological changes underlying respective symptoms and the molecular and cellular regulatory mechanisms by which antidepressants can alleviate those symptoms. There are major regulatory mechanisms controlling normal brain plasticity and, to a significant extent, forming a determinative background for specific pathological events accompanying mental diseases These mechanisms include, in particular, the complex system of NTFs and their receptors as well as multifaceted neuroinflammatory processes. Most of these data are correlative; data from transgenic models and studies on direct effects of NTFs and cytokines will be present when appropriate
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