RESUMEN
Gamma oscillations have attracted much attention in the field of mood disorders, but their role in depression remains poorly understood. This study aimed to investigate whether gamma oscillations in the medial prefrontal cortex (mPFC) could serve as a predictive biomarker of depression. Chronic restraint stress (CRS) or lipopolysaccharide (LPS) were used to induce depression-like behaviors in mice; local field potentials (LFPs) in the mPFC were recorded by electrophysiological techniques; We found that both CRS and LPS induced significant depression-like behaviors in mice, including increasing immobility durations in the forced swimming test (FST) and tail suspension test (TST) and increasing the latency to feed in the novelty-suppressed feeding test (NSFT). Electrophysiological results suggested that CRS and LPS significantly reduced low and high gamma oscillations in the mPFC. Furthermore, a single injection of ketamine or scopolamine for 24 h significantly increased gamma oscillations and elicited rapid-acting antidepressant-like effects. In addition, fluoxetine treatment for 21 days significantly increased gamma oscillations and elicited antidepressant-like effects. Taken together, our findings suggest that gamma oscillations are strongly associated with depression, yielding new insights into investigating the predictive biomarkers of depression and the time course of antidepressant effects.
Asunto(s)
Depresión , Lipopolisacáridos , Ratones , Animales , Depresión/tratamiento farmacológico , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Fluoxetina/farmacología , Fluoxetina/uso terapéutico , BiomarcadoresRESUMEN
Although clinical antidepressants have varied mechanisms of action, it remains unclear whether they may have a common mechanism underlying their antidepressant effects. We investigated the behavioral effects of five different antidepressants (differing in target, chemical structure, and rate of onset) and their effects on the firing activities of glutamatergic pyramidal neurons in the medial prefrontal cortex (mPFC) using the forced swimming test (FST) and electrophysiological techniques (in vivo). We employed fiber photometry recordings to validate the effects of antidepressants on the firing activity of pyramidal neurons. Additionally, multichannel electrophysiological recordings were conducted in mice exhibiting depressive-like behaviors induced by chronic restraint stress (CRS) to investigate whether antidepressants exert similar effects on pyramidal neurons in depressed mice. Behavioral tests were utilized for evaluating the depression model. We found that fluoxetine, duloxetine, vilazodone, YL-0919, and ketamine all increase the firing activities of glutamatergic pyramidal neurons (at least 57%) while exerting their initial onset of antidepressant effects. Fiber photometry revealed an increase in the calcium activity of pyramidal neurons in the mPFC at the onset of antidepressant effects. Furthermore, a significant reduction was observed in the firing activity of pyramidal neurons in the mPFC of CRS-exposed mice, which was reversed by antidepressants. Taken together, our findings suggested that five pharmacologically distinct classes of antidepressants share the common ability to increase the firing activity of pyramidal neurons, just different time, which might be a rate-limiting step in antidepressants onset. The study contributes to the body of knowledge of the mechanisms underlying antidepressant effects and paves the way for developing rapid-acting antidepressants.
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Antidepresivos , Roedores , Ratones , Animales , Antidepresivos/farmacología , Células Piramidales , Fluoxetina/farmacología , Corteza PrefrontalRESUMEN
Neuroinflammation contributes to the pathogenesis of depression. Inulin-type oligosaccharides of Morinda officinalis (IOMO) exert antidepressant-like effects in rodents and patients with depression, while the underlying mechanisms remain unclear. This study used chronic restraint stress (CRS) and lipopolysaccharide (LPS) to induce depression-like behaviors in mice. Western blotting and ELISA analysis were used to investigate the effects of IOMO on inflammatory cytokine levels. Immunofluorescence analysis was used to investigate the effects of IOMO on hippocampal NLRP3 inflammasome and microglial cells. The results suggested that 6 weeks of CRS induced significant depression-like behaviors based on the sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST), which were accompanied by increases in the expression of IL-6 and the activation of hippocampal microglial cells. Chronic treatment with IOMO (25 mg/kg, i.g.) for 28 days significantly reversed these depression-like behaviors and inhibited the activation of microglial cells. Furthermore, LPS (0.5 mg/kg, i.p.) also significantly induced depression-like behaviors in the TST, FST, and novelty-suppressed feeding test (NSFT), as well as increased the expression of IL-1ß and caspase-1, and activated the microglial cells and the NLRP3 inflammasome in the hippocampus. Treatment with IOMO for 9 days significantly reversed these depression-like behaviors and normalized the LPS-induced activation of the microglial cells and NLRP3 inflammasome. Taken together, these results suggested that IOMO exerted antidepressant-like effects via hippocampal microglial NLRP3 inflammasome mediation followed by caspase-1 inhibition and the production of IL-1ß. These findings provide a basis for developing new antidepressants targeting the microglial NLRP3 inflammasome.
Asunto(s)
Inflamasomas , Morinda , Ratones , Animales , Inflamasomas/metabolismo , Inulina/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Morinda/metabolismo , Lipopolisacáridos/farmacología , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Microglía/metabolismo , Hipocampo/metabolismo , Oligosacáridos/farmacología , Inflamación/metabolismo , Caspasas/metabolismo , Depresión/inducido químicamente , Estrés Psicológico/complicacionesRESUMEN
Social hierarchy greatly impacts physical and mental health, but the relationship between social hierarchy and depression/anxiety and the underlying neural mechanism remain unclear. The present study used the tube test to determine the social hierarchy status of mice and then performed several behavioral tests to evaluate depression-like and anxiety-like behaviors. Electrophysiological techniques were used to record the firing activities of glutamatergic pyramidal neurons and local field potentials in the medial prefrontal cortex (mPFC). The results suggested that the mice in each cage (4 per cage) established a stable social hierarchy after 2 weeks. Subordinate mice displayed significantly fewer pushing and advancing behaviors, and more retreat behaviors compared with dominant mice. Furthermore, subordinate mice had significantly more immobility durations in the TST, but significantly fewer distances, entries, and time into the center in the OFT, as well as significantly less percent of distances, entries, and time into the open arms in the EPMT, compared with dominant mice, which indicated that subordinate mice displayed depression- and anxiety-like behaviors. In addition, chronic restraint stress (CRS) significantly induced depression- and anxiety-like behaviors in mice and altered social dominance behaviors in the tube test. CRS mice displayed significantly fewer pushing and advancing behaviors, and more retreat behaviors compared with control mice. Furthermore, low social rank and CRS significantly decreased the firing of pyramidal neurons and γ-oscillation activity in the mPFC. Taken together, the present study revealed an inverse relationship between social hierarchy and depression/anxiety, and the neural basis underlying this association might be the excitability of pyramidal neurons and γ oscillation in the mPFC. These findings established an important foundation for a depression/anxiety model based on social hierarchy and provided a new avenue for the development of therapies for stress-related mood disorders.
RESUMEN
Objective:Comprehensively review national and provincial policies related to centralized procurement of Chinese Patent Medicines(CPM)and to compare the grouping rules and methods of centralized procurement in different regions,with the goal of providing guidance for enhancing the grouping rules for CPM.Methods:Through literature analysis and comparative analysis,the 22 policies included in the study were analyzed in depth,and the progress of centralized volume-based procurement of CPM in national and inter-provincial alliances was compared and summarized.Results:National and inter-provincial alliances'centralized volume-based procurement of CPM divides procurement groups according to functional indications,route of administration,and market conditions.The grouping rules are not closely related to drug dosage forms and quality.Dividing bidding groups based on the market competition pattern ignores the innovative value of some CPM,and does not take into account the unique brand value of the company and its drugs.The completeness of the grouping rules needs to be improved.Conclusions:There are many dosage forms of CPM and complex quality control indicators.The existing grouping rules follow the idea of grouping chemical drugs and lack a top-level design oriented to the value of CPM.It is recommended to adopt a diversified grouping method and advance the technical evaluation link in the existing shortlisting rules.This means that factors such as drug dosage form,quality and innovation value should be considered when formulating grouping rules.At the same time,it is necessary to improve and refine the current grouping rules.