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

• Published in: Translational psychiatry Vol. 9; no. 1; p. 33
• Main Authors: Johnson, Philip L., Molosh, Andrei I., Federici, Lauren M., Bernabe, Cristian, Haggerty, David, Fitz, Stephanie D., Nalivaiko, Eugene, Truitt, William, Shekhar, Anantha
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22-01-2019; Nature Publishing Group
• Subjects: 13/51; 14/63; 38/61; 38/77; 631/378/1595/2167; 631/378/340; 631/443; 9/74; Amygdala - metabolism; Animals; Anxiety; Anxiety - metabolism; Anxiety Disorders - metabolism; Basolateral Nuclear Complex - metabolism; Behavior, Animal - physiology; Behavioral Sciences; Biological Psychology; Conditioning, Psychological - physiology; Extinction, Psychological - physiology; Fear & phobias; Fear - physiology; Gene expression; Male; Medicine; Medicine & Public Health; Neurosciences; Pharmacotherapy; Post traumatic stress disorder; Psychiatry; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/s41398-019-0368-y

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.