Suppression of Serotonin Neuron Firing Increases Aggression in Mice

Abstract

Numerous studies link decreased serotonin metabolites with increased impulsive and aggressive traits. However, although pharmacological depletion of serotonin is associated with increased aggression, interventions aimed at directly decreasing serotonin neuron activity have supported the opposite association. Furthermore, it is not clear if altered serotonin activity during development may contribute to some of the observed associations. Here, we used two pharmacogenetic approaches in transgenic mice to selectively and reversibly reduce the firing of serotonin neurons in behaving animals. Conditional overexpression of the serotonin 1A receptor (Htr1a) in serotonin neurons showed that a chronic reduction in serotonin neuron firing was associated with heightened aggression. Overexpression of Htr1a in adulthood, but not during development, was sufficient to increase aggression. Rapid suppression of serotonin neuron firing by agonist treatment of mice expressing Htr1a exclusively in serotonin neurons also led to increased aggression. These data confirm a role of serotonin activity in setting thresholds for aggressive behavior and support a direct association between low levels of serotonin homeostasis and increased aggression.

Short Review on the Aggressive Behaviour: Genetical, Biological Aspects and Oxytocin Relevance

“…In this way, a 2013 study on transgenic mice showed that a chronic reduction in the levels of serotonin is associated with increased aggresivity. Moreover, pharmacological intervention on serotonergic neurons, aimed to suppress the neurotransmitter discharge, resulted in increased levels of aggression [25]. These data confirmed the fact that low serotonin activity is decreasing the threshold for aggressive behaviour and supports the idea of a direct association between low serotonin levels and increased aggressiveness.…”

Monoamine-Sensitive Developmental Periods Impacting Adult Emotional and Cognitive Behaviors

“…Supporting the model in which 5-HT 1B receptor signaling exerts inhibitory control over aggressive behavior, male mice that lack 5-HT 1B receptors exhibit increased aggressive behavior (Brunner and Hen, 1997;Saudou et al, 1994;Zhuang et al, 1999). Finally, decreasing 5-HTergic activity during adulthood using a pharmacogenetic approach increases territorial isolationinduced aggression using the resident-intruder assay (Audero et al, 2013).…”

Loss of neuronal 3D chromatin organization causes transcriptional and behavioural deficits related to serotonergic dysfunction

“…4i-k), were not altered in H2BGFP mice. The distinct actions of auto-and heteroreceptors 46 , and differential impact of impaired 5-HT signalling in immature and mature mood-related circuitry 47,48 together with the spatial and temporal pattern of transgenic expression, which restricts H2BGFP to areas of high heteroreceptor expression and late developmental stages, may explain the selective impact. Although it is unlikely that the disorganization of higher-order chromatin structure is a widespread feature of neuropsychiatric disorders, the overlap between the transcriptional deficits found in H2BGFP mice and some gene associations in neuropsychiatric disorders is striking.…”