Tryptophan Hydroxylase 2 Knockout Male Rats Exhibit a Strengthened Oxytocin System, Are Aggressive, and Are Less Anxious

Abstract

The central serotoninergic system is critical for stress responsivity and social behavior, and its dysregulations have been centrally implicated in virtually all neuropsychiatric disorders. Genetic serotonin depletion animal models could provide a tool to elucidate the causes and mechanisms of diseases and to develop new treatment approaches. Previously, mice lacking tryptophan hydroxylase 2 (Tph2) have been developed, showing altered behaviors and neurotransmission. However, the effect of congenital serotonin deficiency on emotional and social behavior in rats is still largely unknown, as are the underlying mechanisms. In this study, we used a Tph2 knockout (Tph2–/–) male rat model to study how the lack of serotonin in the rat brain affects anxiety-like and social behaviors. Since oxytocin is centrally implicated in these behaviors, we furthermore explored whether the effects of Tph2 knockout on behavior would relate to changes in the oxytocin system. We show that Tph2–/– rats display reduced anxiety-like behavior and a high level of aggression in social interactions. In addition, oxytocin receptor expression was increased in the infralimbic and prelimbic cortices, paraventricular nucleus, dorsal raphe nucleus, and some subregions of the hippocampus, which was paralleled by increased levels of oxytocin in the medial frontal cortex and paraventricular nucleus but not the dorsal raphe nucleus, central amygdala, and hippocampus. In conclusion, our study demonstrated reduced anxiety but exaggerated aggression in Tph2–/– male rats and reveals for the first time a potential involvement of altered oxytocin system function. Meanwhile, the research of oxytocin could be distinguished in almost any psychiatric disorder including anxiety and mental disorders. This research potentially proposes a new target for the treatment of such disorders, from a genetic serotonin deficiency aspect.

miR-669g-mediated Tryptophan hydroxylase 2 inhibition induces behavioral abnormalities via modulating the central 5-HT activity in mice

“…Additionally, studies have demonstrated that TPH2 depletion led to more impulsivity and high aggressiveness [15]. Consistent with these reports, Tph2 -/male rats also displayed low levels of anxiety-like behavior and high levels of aggression during social interaction [17]. Consequently, the regulation of the 5-HT rate-limiting enzyme TPH2 and its impact on behavior is crucial for the development of effective treatments for these disorders.…”

Tryptophan Metabolism in Developmental Origins of Health and Disease (DOHaD)

“…In this context, it is known that mice without TPH2 are less anxious and show more social interaction, but social interaction shows elevated levels of aggression [99]. The first study to evaluate oxytocin levels in TPH -/-mice found increased oxytocin levels in the hypothalamus's prefrontal cortex and paraventricular nucleus [100]. Oxytocin in the prefrontal cortex reduces anxiety-like behaviour [101] and promotes social behaviour [102].…”

“…Oxytocin in the prefrontal cortex reduces anxiety-like behaviour [101] and promotes social behaviour [102]. Given the range of polymorphisms or deletions of serotonin synthesis enzymes or serotonin itself, other pathways with phenotypic plasticity may arise to keep appropriate serotonin levels, such as reduction of serotonin catabolism [103], as well as modification of other systems such as oxytocin [100].…”

Neurobiology of Aggression—Review of Recent Findings and Relationship with Alcohol and Trauma

“…Despite such a modest effect, modern neuroscientific tools keep pointing towards a serotonergic role in aggression. Since the discovery that the central nervous system has its own enzyme to synthesize serotonin (Tryptophan hydroxylase-2 (Tph-2); [ 106 ]), it was shown that a partial or complete knockdown led to more aggressive behavior in rodents [ 107 , 108 , 109 , 110 ] and could be linked to a diminished 5-HT 1A receptor sensitivity [ 111 ]. On the other hand, highly aggressive wild-derived mice had higher mRNA levels of Tph-2 than other laboratory animals [ 112 ].…”