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The hippocampus is not a homogeneous brain area, and the complex organization of this structure underlies its relevance and functional pleiotropism. The new data related to the involvement of the ventral hippocampus in the cognitive function, behavior, stress response and its association with brain pathology, in particular, depression, are analyzed with a focus on neuroplasticity, specializations of the intrinsic neuronal network, corticosteroid signaling through mineralocorticoid and glucocorticoid receptors and neuroinflammation in the hippocampus. The data on the septo-temporal hippicampal gradient are analyzed with particular emphasis on the ventral hippocampus, a region where most important alteration underlying depressive disorders occur. According to the recent data, the existing simple paradigm “learning (dorsal hippocampus) versus emotions (ventral hippocampus)” should be substantially revised and specified. A new hypothesis is suggested on the principal involvement of stress response mechanisms (including interaction of released glucocorticoids with hippocampal receptors and subsequent inflammatory events) in the remote hippocampal damage underlying delayed dementia and depression induced by focal brain damage (e.g. post-stroke and post-traumatic). The translational validity of this hypothesis comprising new approaches in preventing post-stroke and post-trauma depression and dementia can be confirmed in experimental and clinical studies.

The review analyzes modern concepts about the control of various mechanisms of the hippocampal neuroplasticity in adult mammals and humans by glucocorticoids. Glucocorticoid hormones ensure the coordinated functioning of key components and mechanisms of hippocampal plasticity: neurogenesis, glutamatergic neurotransmission, microglia and astrocytes, systems of neurotrophic factors, neuroinflammation, proteases, metabolic hormones, neurosteroids. Regulatory mechanisms are diverse; along with the direct action of glucocorticoids through their receptors, there are conciliated glucocorticoid-dependent effects, as well as numerous interactions between various systems and components. Despite the fact that many connections in this complex regulatory scheme have not yet been established, the study of the factors and mechanisms considered in the work forms growth points in the field of glucocorticoid-regulated processes in the brain and primarily in the hippocampus. These studies are fundamentally important for the translation into the clinic and the potential treatment/prevention of common diseases of the emotional and cognitive spheres and respective comorbid conditions.

The review discusses molecular and cellular mechanisms common to the temporal lobe epileptogenesis/epilepsy and depressive disorders. Comorbid temporal lobe epilepsy and depression are associated with dysfunction of the hypothalamic-pituitary-adrenocortical axis. Excessive glucocorticoids disrupt the function and impair the structure of the hippocampus, a brain region key to learning, memory, and emotions. Selective vulnerability of the hippocampus to stress, mediated by the reception of glucocorticoid hormones secreted during stress, is the price of the high functional plasticity and pleiotropy of this limbic structure. Common molecular and cellular mechanisms include the dysfunction of glucocorticoid receptors, neurotransmitters, and neurotrophic factors, development of neuroinflammation, leading to neurodegeneration and loss of hippocampal neurons, as well as disturbances in neurogenesis in the subgranular neurogenic niche and formation of aberrant neural networks. These glucocorticoid-dependent processes underlie altered stress response and the development of chronic stress-induced comorbid pathologies, in particular, temporal lobe epilepsy and depressive disorders.

Chronic alcohol consumption is characterized by disturbances of neuroplasticity. Brain-derived neurotrophic factor (BDNF) is believed to be critically involved in this process. Here we aimed to review actual experimental and clinical data related to BDNF participation in neuroplasticity in the context of alcohol dependence. As has been shown in experiments with rodents, alcohol consumption is accompanied by the brain region-specific changes of BDNF expression and by structural and behavioral impairments. BDNF reverses aberrant neuroplasticity observed during alcohol intoxication. According to the clinical data parameters associated with BDNF demonstrate close correlation with neuroplastic changes accompanying alcohol dependence. In particular, the rs6265 polymorphism within the BDNF gene is associated with macrostructural changes in the brain, while peripheral BDNF concentration may be associated with anxiety, depression, and cognitive impairment. Thus, BDNF is involved in the mechanisms of alcohol-induced changes of neuroplasticity, and polymorphisms within the BDNF gene and peripheral BDNF concentration may serve as biomarkers, diagnostic or prognostic factors in treatment of alcohol abuse.

Background: The hypothalamic-pituitary-adrenal (HPA) axis, inflammatory processes and neurotrophic factor systems are involved in pathogenesis of both epilepsy and depressive disorders. The study aimed to explore these systems in patients with focal epilepsy (PWE, n = 76), epilepsy and comorbid depression (PWCED n = 48), and major depressive disorder (PWMDD, n = 62) compared with healthy controls (HC, n = 78). Methods: Parameters of the HPA axis, neurotrophic factors, and TNF-α were measured in blood serum along with the hemogram. Results: Serum cortisol level was augmented in PWE, PWCED, and PWMDD compared with HC and was higher in PWMDD than in PWE. Serum cortisol negatively correlated with Mini–Mental State Examination (MMSE) score in PWE, and positively with depression inventory–II (BDI-II) score in PWMDD. Only PWMDD demonstrated elevated plasma ACTH. Serum TNF-α, lymphocytes, and eosinophils were augmented in PWMDD; monocytes elevated in PWE and PWCED, while neutrophils were reduced in PWE and PWMDD. Serum BDNF was decreased in PWE and PWCED, CNTF was elevated in all groups of patients. In PWE, none of above indices depended on epilepsy etiology. Conclusions: The results confirm the involvement of HPA axis and inflammatory processes in pathogenesis of epilepsy and depression and provide new insights in mechanisms of epilepsy and depression comorbidity.

Progress in treating ischemic stroke (IS) and its delayed consequences has been frustratingly slow due to the insufficient knowledge on the mechanism. One important factor, the hypothalamic-pituitary-adrenocortical (HPA) axis is mostly neglected despite the fact that both clinical data and the results from rodent models of IS show that glucocorticoids, the hormones of this stress axis, are involved in IS-induced brain dysfunction. Though increased cortisol in IS is regarded as a biomarker of higher mortality and worse recovery prognosis, the detailed mechanisms of HPA axis dysfunction involvement in delayed post-stroke cognitive and emotional disorders remain obscure. In this review, we analyze IS-induced HPA axis alterations and supposed association of corticoid-dependent distant hippocampal damage to post-stroke brain disorders. A translationally important growing point in bridging the gap between IS pathogenesis and clinic is to investigate the involvement of the HPA axis disturbances and related hippocampal dysfunction at different stages of SI. Valid models that reproduce the state of the HPA axis in clinical cases of IS are needed, and this should be considered when planning pre-clinical research. In clinical studies of IS, it is useful to reinforce diagnostic and prognostic potential of cortisol and other HPA axis hormones. Finally, it is important to reveal IS patients with permanently disturbed HPA axis. Patients-at-risk with high cortisol prone to delayed remote hippocampal damage should be monitored since hippocampal dysfunction may be the basis for development of post-stroke cognitive and emotional disturbances, as well as epilepsy.

Substance use disorders are associated with structural and functional changes in the neuroendocrine, neuromediator, and neuromodulator systems in brain areas involved in the reward and stress response circuits. Chronic intoxication provokes emergence of somatic diseases and aggravates existing pathologies. Substance use disorders and somatic diseases often exacerbate the clinical courses of each other. Elucidation of biochemical pathways common for comorbidities may serve as a basis for the development of new effective pharmacotherapy agents, as well as drug repurposing. Here, we discussed molecular mechanisms underlying integration of visceral systems into the central mechanisms of drug dependence.

Data from clinical trials and animal experiments demonstrate relationship between chronic hypertension and development of cognitive impairments. Here, we review structural and biochemical alterations in the hippocampus of SHR rats with genetic hypertension, which are used as a model of essential hypertension and vascular dementia. In addition to hypertension, dysfunction of the hypothalamic-pituitary-adrenal system observed in SHR rats already at an early age may be a key factor of changes in the hippocampus at the structural and molecular levels. Global changes at the body level, such as hypertension and neurohumoral dysfunction, are associated with the development of vascular pathology and impairment of the blood-brain barrier. Changes in multiple biochemical glucocorticoid-dependent processes in the hippocampus, including dysfunction of steroid hormones receptors, impairments of neurotransmitter systems, BDNF deficiency, oxidative stress, and neuroinflammation are accompanied by the structural alterations, such as cellular signs of neuroinflammation micro- and astrogliosis, impairments of neurogenesis in the subgranular neurogenic zone, and neurodegenerative processes at the level of synapses, axons, and dendrites up to the death of neurons. The consequence of this is dysfunction of hippocampus, a key structure of the limbic system necessary for cognitive functions. Taking into account the available results at various levels starting from the body and brain structure (hippocampus) levels to molecular one, we can confirm translational validity of SHR rats for modeling mechanisms of vascular dementia.

Dependence on psychoactive substances is a phenomenon that is based on the alterations of common molecular and cellular mechanisms, structures and neuronal networks underlying normal brain functioning and realizing stress response, reinforcement and aversion, learning and memory. As a result, aberrant neuroplasticity states associated with somatic changes are formed, which determine the pathogenesis and symptoms of dependence and at the same time can be considered as targets for the development of therapies for such addictions. An integrative scheme of stress and neuroplastic changes participation in the formation of the vicious circle of substance use disorders based on a holistic approach is presented. This special issue of the journal focuses on the molecular mechanisms of psychoactive substance use disorders.

Glucocorticoid-dependent mechanisms of inflammation-mediated distant hippocampal damage are discussed with a focus on the consequences of traumatic brain injury. The effects of glucocorticoids on specific neuronal populations in the hippocampus depend on their concentration, duration of exposure and cell type. Previous stress and elevated level of glucocorticoids prior to pro-inflammatory impact, as well as long-term though moderate elevation of glucocorticoids, may inflate pro-inflammatory effects. Glucocorticoid-mediated long-lasting neuronal circuit changes in the hippocampus after brain trauma are involved in late post-traumatic pathology development, such as epilepsy, depression and cognitive impairment. Complex and diverse actions of the hypothalamic–pituitary–adrenal axis on neuroinflammation may be essential for late post-traumatic pathology. These mechanisms are applicable to remote hippocampal damage occurring after other types of focal brain damage (stroke, epilepsy) or central nervous system diseases without obvious focal injury. Thus, the liaisons of excessive glucocorticoids/dysfunctional hypothalamic–pituitary–adrenal axis with neuroinflammation, dangerous to the hippocampus, may be crucial to distant hippocampal damage in many brain diseases. Taking into account that the hippocampus controls both the cognitive functions and the emotional state, further research on potential links between glucocorticoid signaling and inflammatory processes in the brain and respective mechanisms is vital.