Impaired fear extinction in serotonin transporter knockout rats is associated with increased 5‐hydroxymethylcytosine in the amygdala

Abstract

SummaryAimsOne potential risk factor for posttraumatic stress disorder (PTSD) involves the low activity (short; s) allelic variant of the serotonin transporter‐linked polymorphic region (5‐HTTLPR), possibly due to reduced prefrontal control over the amygdala. Evidence shows that DNA methylation/demethylation is crucial for fear extinction in these brain areas and is associated with neuronal activation marker c‐Fos expression. We hypothesized that impaired fear extinction in serotonin transporter knockout (5‐HTT −/−) rats is related to changes in DNA (de) methylation and c‐Fos expression in the prefrontal cortex (PFC) and/or amygdala.Methods5‐HTT −/− and 5‐HTT +/+ rats were subjected to fear extinction. 2 hours after the extinction session, the overall levels of DNA methylation (5‐mC), demethylation (5‐hmC), and c‐Fos in fear extinction and nonfear extinction rats were measured by immunohistochemistry.Results5‐HTT −/− rats displayed decreased fear extinction. This was associated with reduced c‐Fos activity in the infralimbic PFC. In the central nucleus of the amygdala, c‐Fos immunoreactivity was increased in the fear extinction group compared to the no‐fear extinction group, regardless of genotype. 5‐hmC levels were unaltered in the PFC, but reduced in the amygdala of nonextinction 5‐HTT −/− rats compared to nonextinction wild‐type rats, which caught up to wild‐type levels during fear extinction. 5‐mC levels were stable in central amygdala in both wild‐type and 5‐HTT −/− extinction rats. Finally, c‐Fos and 5‐mC levels were correlated with the prelimbic PFC, but not amygdala.ConclusionsIn the amygdala, DNA demethylation, independent from c‐Fos activation, may contribute to individual differences in risk for PTSD, as conferred by the 5‐HTTLPR s‐allele.

Impaired Fear Extinction Recall in Serotonin Transporter Knockout Rats Is Transiently Alleviated during Adolescence

“…Here, we confirm that fear extinction recall is impaired in 5-HTT −/− rats, an established and often replicated phenomenon [44,45,55,56], as is extinction learning in rats of this genotype [46]. Strikingly, an effect of age on fear extinction recall was seen only in 5-HTT −/− rats, which enjoyed a transient normalization (i.e.…”

“…Time spent freezing during the conditioning session was not assessed, as previous work as indicated no differences between genotypes in the acquisition of fear memory [46]. For assessing the time spent freezing during extinction learning and both extinction recall sessions, we used the Ethovision 9.0 behavioral software package (Noldus Information Technology B.V., Wageningen, the Netherlands).…”

“…Serotonin transporter knockout (5-HTT −/− ) rats are used as a model organism for the 5-HTTLPR s-allele in humans and show many phenotypical similarities, both adaptive and maladaptive, to s-allele carriers [39]. Similar to humans and rodents during adolescence, as well as adult 5-HTTLPR s-allele carriers, 5-HTT −/− rodents display impaired fear extinction (recall) [40,41,42,43,44,45,46]. Since 5-HTT −/− rats display decreased inhibitory GABAergic control over excitatory neurons in the cortex during preadolescence [47], reduced expression of BDNF and GABA system components across development [48], altered NMDA receptor subunit expression in the PFC at adulthood [49], and an association with impaired fear extinction-reduced c-Fos expression in the IL [46], it is possible that the 5-HTT genotype affects the development of the PFC–amygdala circuitry and thereby fear extinction recall across developmental stages.…”

Histamine-4 receptor antagonist JNJ7777120 inhibits pro-inflammatory microglia and prevents the progression of Parkinson-like pathology and behaviour in a rat model

“…To get the same amount of light, the intensity of light was adjusted for unstained control areas in the same section. The collected α-synuclein staining images were transformed into optical density (OD) images by use of a standard transformation curve, as described in a previous own publication in detail (Shan et al, 2018). The ratio of positive cells between ipsilateral side against the contralateral side was used to evaluate the treatment effects.…”

Correlation between Serotonin Transporter Promoter Gene Polymorphism and PTSD in Children

“…Abnormal 5-HT activity may mediate emotional abnormalities. Susceptibility to PTSD [15]. Therefore, regulation of the 5-HT system gene may play a role in the depression response of various stressors in the susceptibility or life process of PTSD.…”