BDNF Alterations in Brain Areas and the Neurocircuitry Involved in the Antidepressant Effects of Ketamine in Animal Models, Suggest the Existence of a Primary Circuit of Depression

Abstract

Major depressive disorder is one of the primary causes of disability and disease worldwide. The therapy of depression is prevalently based on monoamine reuptake blockers; consequently, investigations aimed to clarify the aetiology of depression have mostly looked at brain areas innervated by monamines and brain circuitry involved in inputs and outputs of these areas. The recent approval of esketamine as a rapid-acting antidepressant drug in treatment-resistant depression, has definitively projected glutamatergic transmission as a key constituent in the use of new drugs in antidepressant therapy. In this review we have examined the role of several brain areas: namely, the hippocampus, the medial Prefrontal Cortex (mPFC), the nucleus accumbens (NAc), the Lateral Habenula (LHb), the amygdala and the Bed Nucleus of Stria Terminalis (BNST). The reason for undertaking an in-depth review is due to their significant role in animal models of depression, which highlight their inter-connections as well as their inputs and outputs. In particular, we examined the modification of the expression and release of the brain derived neurotrophic factor (BDNF) and associated changes in dendritic density induced by chronic stress in the above areas of animal models of depression (AnMD). We also examined the effectiveness of ketamine and standard antidepressants in reversing these alterations, with the aim of identifying a brain circuit where pathological alteration might trigger the appearance of depression symptoms. Based on the role that these brain areas play in the generation of the symptoms of depression, we assumed that the mPFC, the NAc/Ventral Tegmental Area (VTA) and the hippocampus form a primary circuit of depression, where regular performance can endure resilience to stress. We have also examined how this circuit is affected by environmental challenges and how the activation of one or more areas, including amygdala, LHb or BNST can produce local detrimental effects that spread over specific circuits and generate depression symptoms. Furthermore, we also examined how, through their outputs, these three areas can negatively influence the NAc/VTA-PFC circuit directly or through the BNST, to generate anhedonia, one of the most devastating symptoms of depression.

Engeletin alleviates depression‐like phenotype by increasing synaptic plasticity via the BDNF‐TrkB‐mTORC1 signalling pathway

“…BDNF is broadly expressed in the central nervous system and regulates synapsis, memory, learning and neuroprotection. BDNF and its receptor TrkB are crucially involved in depression aetiology and antidepressant's therapeutic mechanisms 22,34–36 . Various stress procedures reduce BDNF, whereas chronic treatment with antidepressants almost always increases BDNF in the hippocampus and frontal cortex.…”

“…BDNF and its receptor TrkB are crucially involved in depression aetiology and antidepressant's therapeutic mechanisms. 22,[34][35][36] The alterations in mTOR activity were also elucidated as BDNF is its upstream regulator, and mTOR phosphorylation is an intracellular signalling mechanism that modulates antidepressant efficiency in depressed animal models and humans. 24,37,38 As evaluated by the p-mTOR-specific antibody, the mTOR activity was notably increased in engeletin-treated mice than in CRS mice.…”

“…BDNF and its receptor TrkB are crucially involved in depression aetiology and antidepressant's therapeutic mechanisms. 22 , 34 , 35 , 36 Various stress procedures reduce BDNF, whereas chronic treatment with antidepressants almost always increases BDNF in the hippocampus and frontal cortex. Since bipolar and major depressive disorders indicate reduced PFCs' BDNF expression and other neurotrophic factors, antidepressant mechanism might involve elevating BDNF expression.…”