Assessment of fear and anxiety associated behaviors, physiology and neural circuits in rats with reduced serotonin transporter (SERT) levels

Philip Johnson, Andrei I. Molosh, Lauren M. Federici, Cristian Bernabe, David Haggerty, Stephanie D. Fitz, Eugene Nalivaiko, William Truitt, Anantha Shekhar

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Genetic variation in serotonin transporter (SERT) that reduces transcriptional efficiency is associated with higher anxiety and fear traits and a greater incidence of post traumatic stress disorder (PTSD). Although previous studies have shown that rats with no expression of SERT (SERT−/−) have increased baseline anxiety behaviors, SERT+/− rats with low SERT expression (and more relevant to the clinical condition with low SERT expression) do not. Yet, no systematic studies of fear acquisition/extinction or their underlying neural mechanisms have been conducted in this preclinical genetic SERT+/− model. Here we sought to determine if SERT+/− or SERT−/−, compared to wildtype, rats would show exacerbated panic responses and/or persistent conditioned fear responses that may be associated with PTSD or phobia vulnerability. Results: Only SERT−/− rats showed increased baseline anxiety-like behaviors with heightened panic respiratory responses. However SERT+/− (also SERT-/-) rats showed enhanced acquisition of fear and delayed extinction of fear that was associated with changes in serotonergic-related genes (e.g., reduced 5-HT1A receptor) and disrupted inhibition within the basolateral amygdala (BLA). Furthermore, the disrupted fear responses in SERT+/− rats were normalized with 5HT1A antagonist infusions into the BLA. Enhanced acquisition and failure to extinguish fear memories displayed by both SERT−/− and SERT+/− rats are cardinal symptoms of disabling anxiety disorders such as phobias and PTSD. The data here support the hypothesis that reduced SERT function is a genetic risk that disrupts select gene expression and network properties in the amygdala that could result in vulnerability to these syndromes.

Original languageEnglish (US)
Article number33
JournalTranslational Psychiatry
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

Serotonin Plasma Membrane Transport Proteins
Fear
Anxiety
Post-Traumatic Stress Disorders
Panic
Phobic Disorders
Receptor, Serotonin, 5-HT1A
Gene Regulatory Networks
Amygdala
Anxiety Disorders

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

Cite this

Assessment of fear and anxiety associated behaviors, physiology and neural circuits in rats with reduced serotonin transporter (SERT) levels. / Johnson, Philip; Molosh, Andrei I.; Federici, Lauren M.; Bernabe, Cristian; Haggerty, David; Fitz, Stephanie D.; Nalivaiko, Eugene; Truitt, William; Shekhar, Anantha.

In: Translational Psychiatry, Vol. 9, No. 1, 33, 01.12.2019.

Research output: Contribution to journalArticle

Johnson, Philip ; Molosh, Andrei I. ; Federici, Lauren M. ; Bernabe, Cristian ; Haggerty, David ; Fitz, Stephanie D. ; Nalivaiko, Eugene ; Truitt, William ; Shekhar, Anantha. / Assessment of fear and anxiety associated behaviors, physiology and neural circuits in rats with reduced serotonin transporter (SERT) levels. In: Translational Psychiatry. 2019 ; Vol. 9, No. 1.
@article{bd88e023a5cb4a1581f77159d0c87851,
title = "Assessment of fear and anxiety associated behaviors, physiology and neural circuits in rats with reduced serotonin transporter (SERT) levels",
abstract = "Genetic variation in serotonin transporter (SERT) that reduces transcriptional efficiency is associated with higher anxiety and fear traits and a greater incidence of post traumatic stress disorder (PTSD). Although previous studies have shown that rats with no expression of SERT (SERT−/−) have increased baseline anxiety behaviors, SERT+/− rats with low SERT expression (and more relevant to the clinical condition with low SERT expression) do not. Yet, no systematic studies of fear acquisition/extinction or their underlying neural mechanisms have been conducted in this preclinical genetic SERT+/− model. Here we sought to determine if SERT+/− or SERT−/−, compared to wildtype, rats would show exacerbated panic responses and/or persistent conditioned fear responses that may be associated with PTSD or phobia vulnerability. Results: Only SERT−/− rats showed increased baseline anxiety-like behaviors with heightened panic respiratory responses. However SERT+/− (also SERT-/-) rats showed enhanced acquisition of fear and delayed extinction of fear that was associated with changes in serotonergic-related genes (e.g., reduced 5-HT1A receptor) and disrupted inhibition within the basolateral amygdala (BLA). Furthermore, the disrupted fear responses in SERT+/− rats were normalized with 5HT1A antagonist infusions into the BLA. Enhanced acquisition and failure to extinguish fear memories displayed by both SERT−/− and SERT+/− rats are cardinal symptoms of disabling anxiety disorders such as phobias and PTSD. The data here support the hypothesis that reduced SERT function is a genetic risk that disrupts select gene expression and network properties in the amygdala that could result in vulnerability to these syndromes.",
author = "Philip Johnson and Molosh, {Andrei I.} and Federici, {Lauren M.} and Cristian Bernabe and David Haggerty and Fitz, {Stephanie D.} and Eugene Nalivaiko and William Truitt and Anantha Shekhar",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41398-019-0368-y",
language = "English (US)",
volume = "9",
journal = "Translational Psychiatry",
issn = "2158-3188",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Assessment of fear and anxiety associated behaviors, physiology and neural circuits in rats with reduced serotonin transporter (SERT) levels

AU - Johnson, Philip

AU - Molosh, Andrei I.

AU - Federici, Lauren M.

AU - Bernabe, Cristian

AU - Haggerty, David

AU - Fitz, Stephanie D.

AU - Nalivaiko, Eugene

AU - Truitt, William

AU - Shekhar, Anantha

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Genetic variation in serotonin transporter (SERT) that reduces transcriptional efficiency is associated with higher anxiety and fear traits and a greater incidence of post traumatic stress disorder (PTSD). Although previous studies have shown that rats with no expression of SERT (SERT−/−) have increased baseline anxiety behaviors, SERT+/− rats with low SERT expression (and more relevant to the clinical condition with low SERT expression) do not. Yet, no systematic studies of fear acquisition/extinction or their underlying neural mechanisms have been conducted in this preclinical genetic SERT+/− model. Here we sought to determine if SERT+/− or SERT−/−, compared to wildtype, rats would show exacerbated panic responses and/or persistent conditioned fear responses that may be associated with PTSD or phobia vulnerability. Results: Only SERT−/− rats showed increased baseline anxiety-like behaviors with heightened panic respiratory responses. However SERT+/− (also SERT-/-) rats showed enhanced acquisition of fear and delayed extinction of fear that was associated with changes in serotonergic-related genes (e.g., reduced 5-HT1A receptor) and disrupted inhibition within the basolateral amygdala (BLA). Furthermore, the disrupted fear responses in SERT+/− rats were normalized with 5HT1A antagonist infusions into the BLA. Enhanced acquisition and failure to extinguish fear memories displayed by both SERT−/− and SERT+/− rats are cardinal symptoms of disabling anxiety disorders such as phobias and PTSD. The data here support the hypothesis that reduced SERT function is a genetic risk that disrupts select gene expression and network properties in the amygdala that could result in vulnerability to these syndromes.

AB - Genetic variation in serotonin transporter (SERT) that reduces transcriptional efficiency is associated with higher anxiety and fear traits and a greater incidence of post traumatic stress disorder (PTSD). Although previous studies have shown that rats with no expression of SERT (SERT−/−) have increased baseline anxiety behaviors, SERT+/− rats with low SERT expression (and more relevant to the clinical condition with low SERT expression) do not. Yet, no systematic studies of fear acquisition/extinction or their underlying neural mechanisms have been conducted in this preclinical genetic SERT+/− model. Here we sought to determine if SERT+/− or SERT−/−, compared to wildtype, rats would show exacerbated panic responses and/or persistent conditioned fear responses that may be associated with PTSD or phobia vulnerability. Results: Only SERT−/− rats showed increased baseline anxiety-like behaviors with heightened panic respiratory responses. However SERT+/− (also SERT-/-) rats showed enhanced acquisition of fear and delayed extinction of fear that was associated with changes in serotonergic-related genes (e.g., reduced 5-HT1A receptor) and disrupted inhibition within the basolateral amygdala (BLA). Furthermore, the disrupted fear responses in SERT+/− rats were normalized with 5HT1A antagonist infusions into the BLA. Enhanced acquisition and failure to extinguish fear memories displayed by both SERT−/− and SERT+/− rats are cardinal symptoms of disabling anxiety disorders such as phobias and PTSD. The data here support the hypothesis that reduced SERT function is a genetic risk that disrupts select gene expression and network properties in the amygdala that could result in vulnerability to these syndromes.

UR - http://www.scopus.com/inward/record.url?scp=85060376574&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060376574&partnerID=8YFLogxK

U2 - 10.1038/s41398-019-0368-y

DO - 10.1038/s41398-019-0368-y

M3 - Article

VL - 9

JO - Translational Psychiatry

JF - Translational Psychiatry

SN - 2158-3188

IS - 1

M1 - 33

ER -