Abstract
Emotions, such as fear and anxiety, can be modulated by both environmental and genetic factors. One genetic factor is for example the genetically encoded variation of the serotonin transporter (5-HTT) expression. In this context, the 5-HTT plays a key role in the regulation of central 5-HT neurotransmission, which is critically involved in the physiological regulation of emotions including fear and anxiety. However, a systematic study which examines the combined influence of environmental and genetic factors on fear-related behavior and the underlying neurophysiological basis is missing. Therefore, in this study we used the 5-HTT-deficient mouse model for studying emotional dysregulation to evaluate consequences of genotype specific disruption of 5-HTT function and repeated social defeat for fear-related behaviors and corresponding neurophysiological activities in the lateral amygdala (LA) and infralimbic region of the medial prefrontal cortex (mPFC) in male 5-HTT wild-type (+/+), homo- (−/−) and heterozygous (+/−) mice. Naive males and experienced losers (generated in a resident-intruder paradigm) of all three genotypes, unilaterally equipped with recording electrodes in LA and mPFC, underwent a Pavlovian fear conditioning. Fear memory and extinction of conditioned fear was examined while recording neuronal activity simultaneously with fear-related behavior. Compared to naive 5-HTT+/+ and +/− mice, 5-HTT−/− mice showed impaired recall of extinction. In addition, 5-HTT−/− and +/− experienced losers showed delayed extinction learning and impaired recall of extinction. Impaired behavioral responses were accompanied by increased theta synchronization between the LA and mPFC during extinction learning in 5-HTT-/− and +/− losers. Furthermore, impaired extinction recall was accompanied with increased theta synchronization in 5-HTT−/− naive and in 5-HTT−/− and +/− loser mice. In conclusion, extinction learning and memory of conditioned fear can be modulated by both the 5-HTT gene activity and social experiences in adulthood, accompanied by corresponding alterations of the theta activity in the amygdala-prefrontal cortex network.
Highlights
The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) plays, besides vegetative and neuroendocrine functions, a key role in the physiological regulation of behavior, such as aggression, and emotions, such as mood and fear [1,2]
The 5-HTT is a cell membrane protein that regulates the serotonin signaling via reuptake of 5-HT from the extracellular space [6] to be recycled into presynaptic vesicles where it becomes anew available for serotonergic transmitter release [7,8,9], and plays a major role in regulating extracellular serotonin volume transmission [10]
Freezing behavior was assessed during the retrieval/extinction sessions (R1-R6), with repetitive presentations of conditioned (CS+) and neutral (CS2) stimuli, and during recall of extinction (E) twenty-four hours later
Summary
The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) plays, besides vegetative and neuroendocrine functions, a key role in the physiological regulation of behavior, such as aggression, and emotions, such as mood and fear [1,2]. 5-HT is implicated in the pathophysiology of psychiatric disorders such as impulse control disorders, depression and anxiety disorders [3,4]. In this context, the serotonin transporter (SERT, 5-HTT) is a key regulator of central serotonergic activity [5]. Concerning genetic factors, the genetically encoded variation of 5-HTT expression is a mediator for the susceptibility to anxiety disorders [12]. Due to the major role as a key regulator during serotonergic neurotransmission, 5-HTT represents an important molecular target which is involved in the treatment of neuropsychiatric disorders (e.g. depression, anxiety and posttraumatic stress disorders (PTSD)) [13,14,15,16,17,18,19,20,21,22]. A polymorphism in the 5-HTT gene regulatory region [23] was identified, resulting in an allelic variation of the 5-HTT expression, and associated traits of negative emotionality including depression and anxiety [23,24,25,26] and risk for PTSD [27]
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