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Major Depressive Disorder (MDD) is a debilitating neuropsychiatric illness affecting over 20% of the population worldwide. Despite its prevalence, our understanding of its pathophysiology is severely limited, thus hampering the development of novel therapeutic strategies. Recent advances have clearly established astrocytes as major players in the pathophysiology, and plausibly pathogenesis, of major depression. In particular, astrocyte density in the hippocampus is severely diminished in MDD patients and correlates strongly with the disease outcome. Moreover, astrocyte densities from different subfields of the hippocampus show varying trends in terms of their correlation to the disease outcome. Given the central role that hippocampus plays in the pathophysiology of depression and in the action of antidepressant drugs, changes in hippocampal astrocyte density and physiology may have a significant effect on behavioral symptoms of MDD. In this study, we used Chronic Mild Unpredictable Stress (CMUS) in mice, which induces a depressive-like state, and examined its effects on astrocytes from different subfields of the hippocampus. We used S100β immunostaining to estimate the number of astrocytes per mm2 from various hippocampal subfields. Furthermore, using confocal images of fluorescently labeled GFAP-immunopositive hippocampal astrocytes, we quantified various morphology-related parameters and performed Sholl analysis. We found that CMUS exerts differential effects on astrocyte cell density, ramification, cell radius, surface area, and process width of hippocampal astrocytes from different hippocampal subfields. Taken together, our study reveals that chronic stress doesn’t uniformly affect all hippocampal astrocytes; but exerts its effects differentially on different astrocytic subpopulations within the hippocampus.

In this paper, a new class of problem known as the generalized bilevel mixed equilibrium problem with perturbations (GBMEPP) has been introduced on a real Banach space. Based on the diameter and th...

Early-life stress (ELS), including chronic deprivation of maternal care, exerts persistent life-long effects on animal physiology and behavior, and is associated with several neurodevelopmental disorders. Long-lasting changes in neuronal plasticity and electrophysiology are documented extensively in the animal models of ELS. However, the role of astroglia in the lasting effects of ELS remains elusive. Astrocytes are intricately involved in the regulation of synaptic physiology and behavior. Moreover, astrocytes play a major role in the innate and adaptive immune responses in the central nervous system (CNS). The role of immune responses and neuroinflammation in the altered brain development and persistent adverse effects of ELS are beginning to be explored. Innate immune response in the CNS is characterized by a phenomenon called astrogliosis, a process in which astrocytes undergo hypertrophy, along with changes in gene expression and function. While the immune activation and neuroinflammatory changes concomitant with ELS, or in juveniles and young adults have been reported, it is unclear whether mice subjected to ELS exhibit astrogliosis-like alterations well into late-adulthood. Here, we subjected mice to maternal separation from postnatal day 2 to day 22 and performed comprehensive morphometric analysis of hippocampal astrocytes during late-adulthood. We found that the astrocytes in the stratum radiatum region of the CA1 hippocampal subfield from maternally separated mice exhibit significant hypertrophy as late as 8 months of age, revealing the crucial changes in astrocytes that manifest long after the cessation of ELS. This study highlights the persistence of neuroinflammatory changes in mice exposed to ELS.

Nervous system development and plasticity involve changes in cellular morphology, making morphological analysis a valuable exercise in the study of nervous system development, function and disease. Morphological analysis is a time-consuming exercise requiring meticulous manual tracing of cellular contours and extensions. We have developed a software tool, called SMorph, to rapidly analyze the morphology of cells of the nervous system. SMorph performs completely automated Sholl analysis. It extracts 23 morphometric features based on cell images and Sholl analysis parameters, followed by principal component analysis (PCA). SMorph was tested on neurons, astrocytes and microglia and reveals subtle changes in cell morphology. Using SMorph, we found that chronic 21-day treatment with the antidepressant desipramine results in a significant structural remodeling in hippocampal astrocytes in mice. Given the proposed involvement of astroglial structural changes and atrophy in major depression in humans, our results reveal a novel kind of structural plasticity induced by chronic antidepressant administration.

Nervous system development and plasticity involves changes in cellular morphology, making morphological analysis a valuable exercise in the study of nervous system development, function and disease. Morphological analysis is a time-consuming exercise requiring meticulous manual tracing of cellular contours and extensions. We have developed a software tool, called SMorph, to rapidly analyse the morphology of cells of the nervous system. SMorph performs completely automated Sholl analysis. It extracts 23 morphometric features based on cell images and Sholl analysis parameters, followed by Principal Component Analysis. SMorph is tested on neurons, astrocytes and microglia and reveals subtle changes in cell morphology. Using SMorph, we found that chronic 21-day treatment with antidepressant desipramine results in a significant structural remodeling in hippocampal astrocytes. Given the proposed involvement of astroglial structural changes and atrophy in major depression in humans, our results reveal a novel kind of structural plasticity induced by chronic antidepressant administration.

Forced swim test (FST) and tail suspension test (TST) are commonly used behavioral tests for screening antidepressant drugs with a high predictive validity. These tests have also proved useful to assess the non-motor symptoms in the animal models of movement disorders such as Parkinson's disease and Huntington's disease. Manual analysis of FST and TST is a time-consuming exercise, and has large observer-to-observer variability. Automation of behavioral analysis alleviates these concerns, but there are no easy-to-use open source tools for such analysis. Here, we describe the development of DBscorer, an open source program installable on Windows®, with an intuitive graphical user interface, that helps in accurate quantification of immobility behavior in FST and TST from video analysis. Several calibration options allow customization of various parameters to suit the experimental requirements. Apart from the readout of time spent immobile, DBscorer also provides additional data and graphics of immobility/mobility states across time revealing the evolution of behavioral despair over the duration of the test and allows the analysis of additional parameters. Such comprehensive analysis allows a more nuanced understanding of the expression of behavioral despair in FST and TST. We believe that DBscorer would make analysis of behavior in FST and TST unbiased, automated and rapid, and hence prove to be helpful to the wider neuroscience community.Significance StatementFST and TST are commonly used to rapidly screen novel antidepressant compounds. They are also used to assess the non-motor behaviors in models of Parkinson's and Huntinton's disease. However, the manual analysis of behavior is time-consuming and subject to observer-to-observer variability. The tools available for automation are either difficult to use, are expensive, require special apparatus, or not comprehensively validated. DBscorer, described here, is an open source software for Windows® with a user-friendly GUI, which we have extensively validated against the performance of highly trained human scorers. We believe that the ease of installation and use, as well as the high accuracy would lead to a widespread adoption of DBscorer by the neuroscience community.

Astrocytes play several critical roles in the normal functioning of the mammalian brain including ion homeostasis, synapse formation and synaptic plasticity. Following injury and infection or in the setting of neurodegeneration, astrocytes become hypertrophic and reactive, a process termed astrogliosis. Although acute reactive gliosis is beneficial in limiting further tissue damage, chronic gliosis becomes detrimental for neuronal recovery and regeneration. Several extracellular factors have been identified that generate reactive astrocytes; however, very little is known about the cell-autonomous transcriptional mechanisms that regulate the maintenance of astrocytes in the normal non-reactive state. Herein, we show that conditional deletion of the stimulus-dependent transcription factor, serum response factor (SRF) in astrocytes (SrfGFAP-CKO) results in astrogliosis marked by hypertrophic morphology and increased expression of GFAP, vimentin and nestin. These reactive astrocytes were not restricted to any specific brain region and were seen in both white and grey matter in the entire brain. This astrogliosis persisted throughout adulthood concomitant with microglial activation. Importantly, the Srf mutant mouse brain did not exhibit any cell death or blood brain barrier (BBB) deficits suggesting that apoptosis and leaky BBB are not the causes for the reactive phenotype. The mutant astrocytes expressed more A2 reactive astrocyte marker genes and the SrfGFAPCKO mice exhibited normal neuronal numbers indicating that SRF-deficient gliosis astrocytes are not neurotoxic. Together our findings suggest that SRF plays a critical role in astrocytes to maintain them in a non-reactive state. SIGNIFICANCE STATEMENT In response to CNS injury, infection and in neurodegeneration, astrocytes undergo complex structural and physiological changes termed as reactive gliosis. Currently, the molecular mechanisms that regulate the non-reactive state of the astrocytes are poorly understood. We report that the SRF transcription factor is required for the maintenance of astrocytes in the non-reactive state such that its conditional deletion in astrocytes results in widespread reactive astrogliosis. The SRF-deficient reactive astrocytes are persistent, non-proliferating and are not caused by cell death or impaired blood brain barrier integrity. In this regard, SRF regulates reactive astrocyte generation in the mammalian brain in a cell-autonomous manner.

In this article, we introduce and study different types of Levitin–Polyak well-posedness for a constrained inverse quasivariational inequality problem. Criteria and characterizations for these types of well-posedness for inverse quasivariational inequality problems are given. Sufficient conditions for the Levitin–Polyak well-posedness of inverse quasivariational inequality problems are also established.

In this paper, we consider an extension of well-posedness for a minimization problem to a class of perturbed variational-hemivariational inequalities with perturbations VHVI. We establish some metric characterizations for the Levitin–Polyak (LP) -well-posedness of VHVI and give some conditions under which the above problem is LP -well-posed in the generalized sense. Links are established between the LP well-posedness of VHVI and the corresponding inclusion problem.