Vortioxetine improves context discrimination in mice through a neurogenesis independent mechanism

Daniela Felice, Jean Philippe Guilloux, Alan Pehrson, Yan Li, Indira Mendez-David, Alain M. Gardier, Connie Sanchez, Denis J. David

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Major Depressive Disorders (MDD) patients may exhibit cognitive deficits and it is currently unclear to which degree treatment with antidepressants may affect cognitive function. Preclinical and clinical observations showed that vortioxetine (VORT, an antidepressant with multimodal activity), presents beneficial effects on aspects of cognitive function. In addition, VORT treatment increases adult hippocampal neurogenesis (AHN) in rodents, a candidate mechanism for antidepressant activity. Pattern separation (PS) is the ability to discriminate between two similar contexts/events generating two distinct and non-overlapping representations. Impaired PS may lead to overgeneralization and anxiety disorders. If PS impairments were described in depressed patients, the consequences of antidepressant treatment on context discrimination (CD) are still in its infancy. We hypothesized that VORT-increased AHN may improve CD. Thus, in an attempt to elucidate the molecular mechanism underpinning VORT treatment effects on CD, a rodent model of PS, the role of AHN and stress-induced c-Fos activation was evaluated in the adult mouse hippocampus. Chronic treatment with VORT (1.8 g/kg of food weight; corresponding to a daily dose of 10 mg/kg, 3 weeks) improved CD in mice. Interestingly, chronic treatment with VORT reversed ablation of AHN-induced delay in CD and freezing behavior. VORT treatment decreased stress-induced c-Fos activation in the dorsal but not ventral dentate gyrus. VORT treatment did not affect c-Fos activity in the hippocampus of mice with ablated neurogenesis. This study highlights a role of VORT in CD, which may be independent from AHN and hippocampal c-Fos activation. Further studies elucidating the mechanisms underlying VORT's effects in CD could contribute to future strategies for alleviating the disease burden for individuals suffering from depression and/or anxiety disorders.

Original languageEnglish
Article number204
JournalFrontiers in Pharmacology
Volume9
Issue numberMAR
DOIs
StatePublished - 12 Mar 2018

Fingerprint

Neurogenesis
Antidepressive Agents
Therapeutics
Anxiety Disorders
Cognition
Rodentia
Hippocampus
Aptitude
vortioxetine
Discrimination (Psychology)
Dentate Gyrus
Major Depressive Disorder
Freezing
Depression
Weights and Measures
Food

Keywords

  • C-Fos
  • Context discrimination
  • Mice
  • Neurogenesis
  • Vortioxetine

Cite this

Felice, Daniela ; Guilloux, Jean Philippe ; Pehrson, Alan ; Li, Yan ; Mendez-David, Indira ; Gardier, Alain M. ; Sanchez, Connie ; David, Denis J. / Vortioxetine improves context discrimination in mice through a neurogenesis independent mechanism. In: Frontiers in Pharmacology. 2018 ; Vol. 9, No. MAR.
@article{48f331b4e62146549534ee911d92ad00,
title = "Vortioxetine improves context discrimination in mice through a neurogenesis independent mechanism",
abstract = "Major Depressive Disorders (MDD) patients may exhibit cognitive deficits and it is currently unclear to which degree treatment with antidepressants may affect cognitive function. Preclinical and clinical observations showed that vortioxetine (VORT, an antidepressant with multimodal activity), presents beneficial effects on aspects of cognitive function. In addition, VORT treatment increases adult hippocampal neurogenesis (AHN) in rodents, a candidate mechanism for antidepressant activity. Pattern separation (PS) is the ability to discriminate between two similar contexts/events generating two distinct and non-overlapping representations. Impaired PS may lead to overgeneralization and anxiety disorders. If PS impairments were described in depressed patients, the consequences of antidepressant treatment on context discrimination (CD) are still in its infancy. We hypothesized that VORT-increased AHN may improve CD. Thus, in an attempt to elucidate the molecular mechanism underpinning VORT treatment effects on CD, a rodent model of PS, the role of AHN and stress-induced c-Fos activation was evaluated in the adult mouse hippocampus. Chronic treatment with VORT (1.8 g/kg of food weight; corresponding to a daily dose of 10 mg/kg, 3 weeks) improved CD in mice. Interestingly, chronic treatment with VORT reversed ablation of AHN-induced delay in CD and freezing behavior. VORT treatment decreased stress-induced c-Fos activation in the dorsal but not ventral dentate gyrus. VORT treatment did not affect c-Fos activity in the hippocampus of mice with ablated neurogenesis. This study highlights a role of VORT in CD, which may be independent from AHN and hippocampal c-Fos activation. Further studies elucidating the mechanisms underlying VORT's effects in CD could contribute to future strategies for alleviating the disease burden for individuals suffering from depression and/or anxiety disorders.",
keywords = "C-Fos, Context discrimination, Mice, Neurogenesis, Vortioxetine",
author = "Daniela Felice and Guilloux, {Jean Philippe} and Alan Pehrson and Yan Li and Indira Mendez-David and Gardier, {Alain M.} and Connie Sanchez and David, {Denis J.}",
year = "2018",
month = "3",
day = "12",
doi = "10.3389/fphar.2018.00204",
language = "English",
volume = "9",
journal = "Frontiers in Pharmacology",
issn = "1663-9812",
publisher = "Frontiers Media S.A.",
number = "MAR",

}

Felice, D, Guilloux, JP, Pehrson, A, Li, Y, Mendez-David, I, Gardier, AM, Sanchez, C & David, DJ 2018, 'Vortioxetine improves context discrimination in mice through a neurogenesis independent mechanism', Frontiers in Pharmacology, vol. 9, no. MAR, 204. https://doi.org/10.3389/fphar.2018.00204

Vortioxetine improves context discrimination in mice through a neurogenesis independent mechanism. / Felice, Daniela; Guilloux, Jean Philippe; Pehrson, Alan; Li, Yan; Mendez-David, Indira; Gardier, Alain M.; Sanchez, Connie; David, Denis J.

In: Frontiers in Pharmacology, Vol. 9, No. MAR, 204, 12.03.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Vortioxetine improves context discrimination in mice through a neurogenesis independent mechanism

AU - Felice, Daniela

AU - Guilloux, Jean Philippe

AU - Pehrson, Alan

AU - Li, Yan

AU - Mendez-David, Indira

AU - Gardier, Alain M.

AU - Sanchez, Connie

AU - David, Denis J.

PY - 2018/3/12

Y1 - 2018/3/12

N2 - Major Depressive Disorders (MDD) patients may exhibit cognitive deficits and it is currently unclear to which degree treatment with antidepressants may affect cognitive function. Preclinical and clinical observations showed that vortioxetine (VORT, an antidepressant with multimodal activity), presents beneficial effects on aspects of cognitive function. In addition, VORT treatment increases adult hippocampal neurogenesis (AHN) in rodents, a candidate mechanism for antidepressant activity. Pattern separation (PS) is the ability to discriminate between two similar contexts/events generating two distinct and non-overlapping representations. Impaired PS may lead to overgeneralization and anxiety disorders. If PS impairments were described in depressed patients, the consequences of antidepressant treatment on context discrimination (CD) are still in its infancy. We hypothesized that VORT-increased AHN may improve CD. Thus, in an attempt to elucidate the molecular mechanism underpinning VORT treatment effects on CD, a rodent model of PS, the role of AHN and stress-induced c-Fos activation was evaluated in the adult mouse hippocampus. Chronic treatment with VORT (1.8 g/kg of food weight; corresponding to a daily dose of 10 mg/kg, 3 weeks) improved CD in mice. Interestingly, chronic treatment with VORT reversed ablation of AHN-induced delay in CD and freezing behavior. VORT treatment decreased stress-induced c-Fos activation in the dorsal but not ventral dentate gyrus. VORT treatment did not affect c-Fos activity in the hippocampus of mice with ablated neurogenesis. This study highlights a role of VORT in CD, which may be independent from AHN and hippocampal c-Fos activation. Further studies elucidating the mechanisms underlying VORT's effects in CD could contribute to future strategies for alleviating the disease burden for individuals suffering from depression and/or anxiety disorders.

AB - Major Depressive Disorders (MDD) patients may exhibit cognitive deficits and it is currently unclear to which degree treatment with antidepressants may affect cognitive function. Preclinical and clinical observations showed that vortioxetine (VORT, an antidepressant with multimodal activity), presents beneficial effects on aspects of cognitive function. In addition, VORT treatment increases adult hippocampal neurogenesis (AHN) in rodents, a candidate mechanism for antidepressant activity. Pattern separation (PS) is the ability to discriminate between two similar contexts/events generating two distinct and non-overlapping representations. Impaired PS may lead to overgeneralization and anxiety disorders. If PS impairments were described in depressed patients, the consequences of antidepressant treatment on context discrimination (CD) are still in its infancy. We hypothesized that VORT-increased AHN may improve CD. Thus, in an attempt to elucidate the molecular mechanism underpinning VORT treatment effects on CD, a rodent model of PS, the role of AHN and stress-induced c-Fos activation was evaluated in the adult mouse hippocampus. Chronic treatment with VORT (1.8 g/kg of food weight; corresponding to a daily dose of 10 mg/kg, 3 weeks) improved CD in mice. Interestingly, chronic treatment with VORT reversed ablation of AHN-induced delay in CD and freezing behavior. VORT treatment decreased stress-induced c-Fos activation in the dorsal but not ventral dentate gyrus. VORT treatment did not affect c-Fos activity in the hippocampus of mice with ablated neurogenesis. This study highlights a role of VORT in CD, which may be independent from AHN and hippocampal c-Fos activation. Further studies elucidating the mechanisms underlying VORT's effects in CD could contribute to future strategies for alleviating the disease burden for individuals suffering from depression and/or anxiety disorders.

KW - C-Fos

KW - Context discrimination

KW - Mice

KW - Neurogenesis

KW - Vortioxetine

UR - http://www.scopus.com/inward/record.url?scp=85043475007&partnerID=8YFLogxK

U2 - 10.3389/fphar.2018.00204

DO - 10.3389/fphar.2018.00204

M3 - Article

AN - SCOPUS:85043475007

VL - 9

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

SN - 1663-9812

IS - MAR

M1 - 204

ER -