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Mice were divided into two groups to assess the effects of chronic stress on depressive and anxiety related behaviors. The non-stressed group was housed with littermates, while individuals assigned to the stressed group were housed individually to determine the effects of social isolation. Mice assigned to the stressed group were exposed to one mild stress stimuli in a randomized fashion for a duration of 7 weeks to allow ample time for the development of depressive and anxious behaviors.
Behavioral testing was conducted during the last week of the 7 week procedure, and mice were not exposed to stressors before behavioral testing. After the behavioral testing, mice were and euthanized for biochemical and neurochemical measurements. Biochemical analyses reveal that both subunits of the alphavbeta3 receptor are downregulated during chronic stress.
As a compensatory mechanism, the downstream adaptor proteins talin and FAK are upregulated. These modifications correlate with latency to immobility and immobility time in the forced swim test, respectively. We then examined the behavioral and neurochemical responses in mice with reduced integrin beta3 expression Itgb3. Neurochemical analysis of brain tissue samples was conducted to provide an indirect measure of monoamine neurotransmission.
Discussion: Here we identify a novel signaling pathway involved in the modulation of emotional reactivity in mice. Our studies demonstrate that integrin alphavbeta3 represents a novel mechanism by which the response to chronic stress is modulated. Both alphav and talin expression levels are correlated with immobility in the forced swim test, suggesting that reduced alphavbeta3 levels may influence the depressive response to chronic stress.
Neurochemical results indicate that integrin alphavbeta3 influences serotonergic metabolism and neurotransmission, which may underlie observed differences in the behavioral responses. Given the roles of integrin alphavbeta3 in the modulation of the serotonin and glutamate systems, our further investigation of this novel network promises insights into the pathophysiology of depression and post-traumatic stress disorder.
The Daily Journal from Franklin, Indiana · Page 21
Varney: None. Gaskill: None. Jessen: None. Carneiro: None. Background: Clinical evidence suggests that pro-inflammatory cytokines play an important role in the pathology of Major Depressive Disorder MDD. Elevated circulating pro-inflammatory cytokines can be found in depressed patients. Stimulation of the primary host defense system and immunotherapy such as is used in the treatment of multiple sclerosis has been shown to precipitate depressive symptoms.
In addition, acute treatment with pro-inflammatory cytokines has been shown to increase glutamate function in the CNS. The studies described herein begin to elucidate the neuroadaptive mechanisms in the hippocampus associated with elevated circulating pro-inflammatory cytokines, induction of indoleamine-2,3-dioxygenase IDO and associated behavioral changes. We have treated CD-1 mice with BacilleCalmetteGuerin BCG to stimulate the innate immune response and examined hippocampal tissue from these animals for changes in protein expression and phosphorylation state of markers for a glutamatergic synapse.
Food and water were available ad libitum. Mice were handled daily for at least 1 week before the onset of the experiment to minimize stress reactions to manipulation.
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All mice were weighed for 5 days before treatment and for 7 consecutive days after. Plasma cytokines were measured using the Luminex XMap technology. Hippocampal tissue was processed in homogenization buffer and changes in total protein expression and phosphorylation state for GLUR1, NR1, and CREB and total protein expression of synaptophysin and PSD95 were assessed using polyacrylamide gel electrophoresis, transfer of proteins to nitrocellulose, hybridization with primary antibodies and the use of LiCor Infrared imaging.
Beta-actin total protein was used to normalize the quantitative measure of the changes in protein expression and phosphorylation state. Results: Transient body weight loss shortly after BCG inoculation together with an enlargement of the spleen, a significant increase in lung cytokine and IDO mRNA expression and elevation in plasma cytokines served as positive controls for BCG treatment efficiency in stimulating the innate immune response. Data from these studies confirm the development of an acute sickness behavior and are in agreement with data published by Moreau and colleagues.
Hippocampal tissue from the above mentioned experiments was examined for changes in expression and phosphorylation state of synaptic markers as a measure of neuroadaptive changes at 9days post BCG treatment, a time point where a depressive phenotype has been reported previously.
Discussion: We have shown that stimulation of the innate immune response with BCG corresponds with changes in the expression and phosphorylation state of both presynaptic and postsynaptic markers in the glutamatergic synapse in the hippocampus. Our data suggest that neuroadaptive changes in the glutamatergic system are stimulated by BCG treatment. Future studies will focus on determining the physiological relevance of these synaptic changes by looking at hippocampal dependent cognitive tasks in BCG-treated animals. Nizami: None. Recent preclinical and clinical studies demonstrate that altered synaptic and structural plasticity play a critical role in the pathogenic mechanisms of depression; however, the precise molecular and cellular nature of events that lead to such altered plasticity remains unclear.
In the present study we tested the hypothesis whether calcium sensing proteins play a role in depression. Methods: To examine the status of calcium sensing proteins, mRNA levels of various eural calcium sensing proteins were determined in dorsolateral prefrontal cortex of age-, gender, and postmortem interval-matched normal controls and major depressed subjects. To examine whether the changes in expression of calcium sensing proteins are specific to depression, we examined their expression levels in dorsolateral prefrontal cortex of bipolar and schizophrenia subjects.
A total of 20 subjects in each group were included. Further correlation analysis showed that mRNA levels of these eural calcium sensing proteins were not affected by age, postmortem interval, or brain pH p values ranged between. Discussion: Our study demonstrates that various calcium sensing proteins are decreased in prefrontal cortex of depressed subjects. These decreases were specific to depression as schizophrenia and bipolar subjects either showed no change or showed differential regulation.
Our study suggests the possibility that altered expression of calcium sensing proteins could be associated with altered neural plasticity in depressed subjects. Sailor, Guo-li Ming, Hongjun Song. Background: Major depression is one of the most common mental disorders affecting millions of people worldwide.
Emerging evidence has shown that the all classes of antidepressants exhibit a significant stimulatory role on adult hippocampal neurogenesis, the process of generating mature neurons from neural progenitors.
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In addition, adult neurogenesisis required for some of the behavioral effects of antidepressants in rodents, suggesting that neurogenesis plays a crucial role in the mechanism of antidepressant actions. The molecular and cellular mechanisms underlying the modulation of different stages of adult neurogenesis by antidepressants are not fully understood.
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Here we identified secreted frizzled related protein 3 sFRP3 , a Wnt inhibitor highly expressed in the adult dentate gyrus, as a key regulator of activity-dependent modulation of neurogenesis by antidepressants in the adult brain. These findings indicate that sFRP3 serves as a key regulator that controls adult neurogenesis and antidepressant actions. Methods: In order to evaluate the specific role of sFRP3 in adult neurogenesis and antidepressant action, we utilized multiple histological techniques, retroviral-based single cell genetic manipulations, confocal imaging, animal behaviors and animal genetic model systems.
Results: We demonstrated that deletion of the gene encoding sfrp3 enhances several essential steps of adult hippocampal neurogenesis in vivo , including proliferation of neural progenitors, maturation, migration and dendritic growth of newborn dentate granule cells in the adult brain. Interestingly, stimulation of the adult hippocampal neuronal circuitry leads to a rapid decrease of sfrp3 expression in the dentate gyrus, resulting in accelerated development of newborn granule cells in vivo.
In addition, chronic, but not subchronic treatment with an antidepressant suppresses sfrp3 expression in the dentate gyrus and sFRP3 null mice exhibit behavioral phenotypes mimicking wild-type mice receiving antidepressants. Discussion: Our study identifies sFRP3 as a key regulator of not only adult neurogenesis but also antidepressant actions, and suggests a potential therapeutic target for the treatment of depression.
These discoveries provide a strong body of evidence in support of the essential role of adult neurogenesis in mediating the benefits of antidepressant treatment and thus will be a foundation for further clinical studies and developing new therapeutic interventions. Jang: None. Kitabatake: None. Guo: None. Kim: None. Sailor: None. Ming: None. Song: None. Background: Mood disorders are emotionally and cognitively debilitating illnesses afflicting millions of people in the USA and potent, specific pharmacotherapies are needed.
In bipolar mood disorders the increased activity of glycogen synthase kinase 3 GSK3 correlates with neuronal hyperexcitability. This evidence suggests that mood stabilizers might converge on a common molecular target. Discovering this target will potentially provide insights into the complexity of the disease and offer an unprecedented opportunity for medication development. Previous discoveries demonstrate that the fibroblast growth factor 14 FGF14 is a relevant component of the Nav channelosome that controls channel targeting and neuronal excitability through a direct interaction with the Nav channel intracellular C-tail.
Plasmids were transiently co-expressed in HEK cells and interaction was detected upon d-luciferin addition as luminescence. LCA was employed to screen a library of kinase inhibitors seeking compounds that could robustly and specifically regulate the FGFNav channel complex formation. Kinase inhibitors were delivered to cells 2 hours prior luminescence readings. Co-immunoprecipitation studies were conducted in HEK cells stably expressing full length Nav1. Additional studies aiming at validating the effect of selective kinase inhibitors on the FGF Nav channel complex were conducted using quantitative immunolabeling of native FGF14 and Nav channels and single cell patch-clamp electrophysiology in primary hippocampal neurons.
Disclosure: F. Laezza: None. Shavkunov: None.