ABSTRACT
Malfunction of the ventral subiculum (vSub), the main subregion controlling the output connections from the hippocampus, is associated with major depressive disorder (MDD). Although the vSub receives cholinergic innervation from the medial septum and diagonal band of Broca (MSDB), whether and how the MSDB-to-vSub cholinergic circuit is involved in MDD is elusive. Here, we found that chronic unpredictable mild stress (CUMS) induced depression-like behaviors with hyperactivation of vSub neurons, measured by c-fos staining and whole-cell patch-clamp recording. By retrograde and anterograde tracing, we confirmed the dense MSDB cholinergic innervation of the vSub. In addition, transient restraint stress in CUMS increased the level of ACh in the vSub. Furthermore, chemogenetic stimulation of this MSDB-vSub innervation in ChAT-Cre mice induced hyperactivation of vSub pyramidal neurons along with depression-like behaviors; and local infusion of atropine, a muscarinic receptor antagonist, into the vSub attenuated the depression-like behaviors induced by chemogenetic stimulation of this pathway and CUMS. Together, these findings suggest that activating the MSDB-vSub cholinergic pathway induces hyperactivation of vSub pyramidal neurons and depression-like behaviors, revealing a novel circuit underlying vSub pyramidal neuronal hyperactivation and its associated depression.
Subject(s)
Rats , Mice , Animals , Rats, Sprague-Dawley , Depressive Disorder, Major/metabolism , Basal Forebrain , Depression , Hippocampus/metabolism , Cholinergic AgentsABSTRACT
Abstract Introduction: Major depressive disorder (MDD) is a prevalent medical illness that is associated with chronic stress. Patients with MDD can show an imbalance in cortisol levels, which can be restored with the remission of symptoms. Physical exercise training has been used as a tool to promote changes in cortisol levels in healthy individuals. However, it is unknown if exercise can produce the same results in individuals with MDD. Objective: To review evidence of cortisol changes after exercise training in individuals with MDD. Methods: We conducted a search on PubMed, SciELO, LILACS, ISI Web of Knowledge, Scopus, and PsycInfo databases. Random effects meta-analysis was performed and standardized mean difference (SMD) effect size was calculated. Analyses of forest and funnel plots was conducted using Stata v.11.0 software. Results: At first, 463 studies were obtained in the search. After completion of the selection procedure, five articles with seven analyses were included. Type of exercise, frequency of training, cortisol measurement, and type of control group were analyzed. There was a reduction of cortisol levels in the exercise group (SMD = −0.65, 95%CI 1.30-0.01). Moreover, sensitivity analysis and subgroup analyses revealed an effect of type (aerobic exercise) and frequency (five times per week) of exercise on reduction of cortisol levels. However, these results should be interpreted cautiously due to the small number of studies and a substantial heterogeneity among them. Conclusion: Physical exercise promotes a reduction in cortisol levels in individuals with MDD. However, this finding can be influenced by type of exercise, weekly frequency, and type of cortisol measurement.
Resumo Introdução: A depressão maior (DM) é uma doença associada ao estresse crônico que pode apresentar um desequilíbrio nos níveis de cortisol, podendo ser recuperado com a remissão dos sintomas. O exercício tem sido utilizado como uma ferramenta para promover mudanças nos níveis de cortisol em indivíduos saudáveis. No entanto, não se sabe se o exercício produz os mesmos resultados em indivíduos com DM. Objetivo: Revisar evidências de alterações dos níveis de cortisol após o exercício em indivíduos com DM. Métodos: Foi realizada busca nas bases de dados PubMed, SciELO, LILACS, ISI Web of Knowledge, Scopus e PsycInfo. Procedeu-se a metanálise com o cálculo do tamanho do efeito da diferença de média padronizada. Foi utilizado o software Stata v.11.0. Resultados: Foram obtidos na busca 463 estudos. Após o procedimento de seleção, cinco artigos com sete análises foram incluídos. O tipo de exercício, frequência de treinamento, tipo de medida do cortisol e tipo de grupo controle foram analisados como subgrupos. Houve uma redução dos níveis de cortisol no grupo de exercício. Além disso, a análise de sensibilidade e análises de subgrupos revelaram um efeito do tipo (exercício aeróbico) e da frequência (cinco vezes por semana) de exercício na redução dos níveis de cortisol. No entanto, esses resultados devem ser interpretados com cautela, devido ao pequeno número de estudos e uma heterogeneidade substancial entre eles. Conclusão: O exercício promove redução dos níveis de cortisol em indivíduos com DM. No entanto, esse achado pode ser influenciado pelo tipo de exercício, medida do cortisol e frequência semanal.