PMID- 33896623
OWN - NLM
STAT- MEDLINE
DCOM- 20220104
LR  - 20230102
IS  - 1873-2402 (Electronic)
IS  - 0006-3223 (Print)
IS  - 0006-3223 (Linking)
VI  - 91
IP  - 1
DP  - 2022 Jan 1
TI  - Sex-Specific Role for SLIT1 in Regulating Stress Susceptibility.
PG  - 81-91
LID - S0006-3223(21)01096-9 [pii]
LID - 10.1016/j.biopsych.2021.01.019 [doi]
AB  - BACKGROUND: Major depressive disorder is a pervasive and debilitating syndrome 
      characterized by mood disturbances, anhedonia, and alterations in cognition. 
      While the prevalence of major depressive disorder is twice as high for women as 
      men, little is known about the molecular mechanisms that drive sex differences in 
      depression susceptibility. METHODS: We discovered that SLIT1, a secreted protein 
      essential for axonal navigation and molecular guidance during development, is 
      downregulated in the adult ventromedial prefrontal cortex (vmPFC) of women with 
      depression compared with healthy control subjects, but not in men with 
      depression. This sex-specific downregulation of Slit1 was also observed in the 
      vmPFC of mice exposed to chronic variable stress. To identify a causal, 
      sex-specific role for SLIT1 in depression-related behavioral abnormalities, we 
      performed knockdown (KD) of Slit1 expression in the vmPFC of male and female 
      mice. RESULTS: When combined with stress exposure, vmPFC Slit1 KD reflected the 
      human condition by inducing a sex-specific increase in anxiety- and 
      depression-related behaviors. Furthermore, we found that vmPFC Slit1 KD decreased 
      the dendritic arborization of vmPFC pyramidal neurons and decreased the 
      excitability of the neurons in female mice, effects not observed in males. RNA 
      sequencing analysis of the vmPFC after Slit1 KD in female mice revealed an 
      augmented transcriptional stress signature. CONCLUSIONS: Together, our findings 
      establish a crucial role for SLIT1 in regulating neurophysiological and 
      transcriptional responses to stress within the female vmPFC and provide 
      mechanistic insight into novel signaling pathways and molecular factors 
      influencing sex differences in depression susceptibility.
CI  - Copyright (c) 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All 
      rights reserved.
FAU - van der Zee, Yentl Y
AU  - van der Zee YY
AD  - Department of Psychiatry and Neuropsychology, School for Mental Health and 
      Neuroscience, Maastricht University, Maastricht, the Netherlands; Nash Family 
      Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine 
      at Mount Sinai, New York, New York.
FAU - Lardner, Casey K
AU  - Lardner CK
AD  - Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School 
      of Medicine at Mount Sinai, New York, New York.
FAU - Parise, Eric M
AU  - Parise EM
AD  - Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School 
      of Medicine at Mount Sinai, New York, New York.
FAU - Mews, Philipp
AU  - Mews P
AD  - Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School 
      of Medicine at Mount Sinai, New York, New York.
FAU - Ramakrishnan, Aarthi
AU  - Ramakrishnan A
AD  - Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School 
      of Medicine at Mount Sinai, New York, New York.
FAU - Patel, Vishwendra
AU  - Patel V
AD  - Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School 
      of Medicine at Mount Sinai, New York, New York.
FAU - Teague, Collin D
AU  - Teague CD
AD  - Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School 
      of Medicine at Mount Sinai, New York, New York.
FAU - Salery, Marine
AU  - Salery M
AD  - Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School 
      of Medicine at Mount Sinai, New York, New York.
FAU - Walker, Deena M
AU  - Walker DM
AD  - Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School 
      of Medicine at Mount Sinai, New York, New York.
FAU - Browne, Caleb J
AU  - Browne CJ
AD  - Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School 
      of Medicine at Mount Sinai, New York, New York.
FAU - Labonte, Benoit
AU  - Labonte B
AD  - Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School 
      of Medicine at Mount Sinai, New York, New York.
FAU - Parise, Lyonna F
AU  - Parise LF
AD  - Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School 
      of Medicine at Mount Sinai, New York, New York.
FAU - Kronman, Hope
AU  - Kronman H
AD  - Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School 
      of Medicine at Mount Sinai, New York, New York.
FAU - Pena, Catherine J
AU  - Pena CJ
AD  - Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School 
      of Medicine at Mount Sinai, New York, New York.
FAU - Torres-Berrio, Angelica
AU  - Torres-Berrio A
AD  - Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School 
      of Medicine at Mount Sinai, New York, New York.
FAU - Duffy, Julia E
AU  - Duffy JE
AD  - Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School 
      of Medicine at Mount Sinai, New York, New York.
FAU - de Nijs, Laurence
AU  - de Nijs L
AD  - Department of Psychiatry and Neuropsychology, School for Mental Health and 
      Neuroscience, Maastricht University, Maastricht, the Netherlands.
FAU - Eijssen, Lars M T
AU  - Eijssen LMT
AD  - Department of Psychiatry and Neuropsychology, School for Mental Health and 
      Neuroscience, Maastricht University, Maastricht, the Netherlands.
FAU - Shen, Li
AU  - Shen L
AD  - Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School 
      of Medicine at Mount Sinai, New York, New York.
FAU - Rutten, Bart
AU  - Rutten B
AD  - Department of Psychiatry and Neuropsychology, School for Mental Health and 
      Neuroscience, Maastricht University, Maastricht, the Netherlands.
FAU - Issler, Orna
AU  - Issler O
AD  - Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School 
      of Medicine at Mount Sinai, New York, New York. Electronic address: 
      orna.issler@mssm.edu.
FAU - Nestler, Eric J
AU  - Nestler EJ
AD  - Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School 
      of Medicine at Mount Sinai, New York, New York. Electronic address: 
      eric.nestler@mssm.edu.
LA  - eng
GR  - K99 AA027839/AA/NIAAA NIH HHS/United States
GR  - K99 DA042100/DA/NIDA NIH HHS/United States
GR  - P50 MH096890/MH/NIMH NIH HHS/United States
GR  - R01 MH051399/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210227
PL  - United States
TA  - Biol Psychiatry
JT  - Biological psychiatry
JID - 0213264
SB  - IM
MH  - Anhedonia
MH  - Animals
MH  - Anxiety
MH  - *Depressive Disorder, Major
MH  - Female
MH  - Male
MH  - Mice
MH  - Prefrontal Cortex
MH  - Sex Characteristics
PMC - PMC8390577
MID - NIHMS1678391
OTO - NOTNLM
OT  - Chronic variable stress
OT  - Major depressive disorder
OT  - Prefrontal cortex
OT  - RNA sequencing
OT  - SLIT1
COIS- Disclosures The authors report no biomedical financial interests or potential 
      conflicts of interest.
EDAT- 2021/04/27 06:00
MHDA- 2022/01/05 06:00
PMCR- 2023/01/01
CRDT- 2021/04/26 05:35
PHST- 2020/09/04 00:00 [received]
PHST- 2020/12/22 00:00 [revised]
PHST- 2021/01/06 00:00 [accepted]
PHST- 2021/04/27 06:00 [pubmed]
PHST- 2022/01/05 06:00 [medline]
PHST- 2021/04/26 05:35 [entrez]
PHST- 2023/01/01 00:00 [pmc-release]
AID - S0006-3223(21)01096-9 [pii]
AID - 10.1016/j.biopsych.2021.01.019 [doi]
PST - ppublish
SO  - Biol Psychiatry. 2022 Jan 1;91(1):81-91. doi: 10.1016/j.biopsych.2021.01.019. 
      Epub 2021 Feb 27.