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Title: The Duration of Stress Determines Sex Specificities in the Vulnerability to Depression and in the Morphologic Remodeling of Neurons and Microglia
Authors: Gaspar, Rita 
Soares-Cunha, Carina
Domingues, Ana Verónica
Coimbra, Bárbara
Baptista, Filipa 
Pinto, Luísa 
Ambrósio, António 
Rodrigues, Ana-João 
Gomes, Catarina A. 
Keywords: chronic stress; microglia morphology; sex differences; dorsal hippocampus; nucleus accumbens; neurons morphology
Issue Date: 2022
Project: info:eu-repo/grantAgreement/FCT/POR_CENTRO/PD/BD/114116/2015/PT/Microglia morphology and susceptibiity to depression - impact of gender differences 
info:eu-repo/grantAgreement/FCT/CEEC IND 2017/CEECIND/03887/2017/CP1458/CT0027/PT/Not available 
info:eu-repo/grantAgreement/FCT/CEEC IND 2018/CEECIND/00922/2018/CP1581/CT0012/PT/Not available 
info:eu-repo/grantAgreement/FCT/POR_NORTE/SFRH/BD/147066/2019/PT/Neuronal substrates of effort-based decision-making: integrating signals of the anterior cingulate cortex, nucleus accumbens and ventral tegmental area 
POCI-01-0145-FEDER-016428 (MEDPERSYST) 
info:eu-repo/grantAgreement/FCT/9471 - RIDTI/PTDC/MED-NEU/29071/2017/PT/Impact of prenatal stress in the reward system: from depression to addiction and back 
info:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC/MED-NEU/4804/2020/PT/Neuronal circuits of reward and aversion: where do endogenous opioids stand? 
info:eu-repo/grantAgreement/EC/H2020/101003187/EU/Challenging current models of valence encoding in the mammalian brain 
info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID/NEU/04539/2019/PT 
info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP/50026/2020/PT/ICVS/3B's - Associate Laboratory 
info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB/50026/2020/PT/ICVS/3B's - Associate Laboratory 
info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB/04539/2020/PT 
info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP/04539/2020/PT 
BrainHealth2020 (CENTRO-01-0145-FEDER-000008) 
Serial title, monograph or event: Frontiers in Behavioral Neuroscience
Volume: 16
Abstract: Stress exposure has been shown to induce a variety of molecular and functional alterations associated with anxiety and depression. Some studies suggest that microglia, the immune cells of the brain, play a significant role in determining neuronal and behavioral responses to chronic stress and also contribute to the development of stress-related psychopathologies. However, little is known about the impact of the duration of stress exposure upon microglia and neurons morphology, particularly considering sex differences. This issue deserves particular investigation, considering that the process of morphologic remodeling of neurons and microglia is usually accompanied by functional changes with behavioral expression. Here, we examine the effects of short and long unpredictable chronic mild stress (uCMS) protocols on behavior, evaluating in parallel microglia and neurons morphology in the dorsal hippocampus (dHIP) and in the nucleus accumbens (NAc), two brain regions involved in the etiology of depression. We report that long-term uCMS induced more behavioral alterations in males, which present anxiety and depression-like phenotypes (anhedonia and helplessness behavior), while females only display anxiety-like behavior. After short-term uCMS, both sexes presented anxiety-like behavior. Microglia cells undergo a process of morphologic adaptation to short-term uCMS, dependent on sex, in the NAc: we observed a hypertrophy in males and an atrophy in females, transient effects that do not persist after long-term uCMS. In the dHIP, the morphologic adaptation of microglia is only observed in females (hypertrophy) and after the protocol of long uCMS. Interestingly, males are more vulnerable to neuronal morphological alterations in a region-specific manner: dendritic atrophy in granule neurons of the dHIP and hypertrophy in the medium spiny neurons of the NAc, both after short- or long-term uCMS. The morphology of neurons in these brain regions were not affected in females. These findings raise the possibility that, by differentially affecting neurons and microglia in dHIP and NAc, chronic stress may contribute for differences in the clinical presentation of stress-related disorders under the control of sex-specific mechanisms.
ISSN: 1662-5153
DOI: 10.3389/fnbeh.2022.834821
Rights: openAccess
Appears in Collections:I&D ICBR - Artigos em Revistas Internacionais
I&D CIBB - Artigos em Revistas Internacionais
FMUC Medicina - Artigos em Revistas Internacionais

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