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The negative societal impacts associated with the increasing prevalence of violence and aggression is increasing, and, with this rise, is the need to understand the molecular and cellular changes that underpin ultrasound-induced aggressive behavior. In mice, stress-induced aggression is known to alter AMPA receptor subunit expression, plasticity markers, and oxidative stress within the brain. Here, we induced aggression in BALB/c mice using chronic ultrasound exposure and examined the impact of the psychoactive anti-oxidant compounds thiamine (vitamin B1), and its derivative benfotiamine, on AMPA receptor subunit expression, established plasticity markers, and oxidative stress. The administration of thiamine or benfotiamine (200 mg/kg/day) in drinking water decreased aggressive behavior following 3-weeks of ultrasound exposure and benfotiamine, reduced floating behavior in the swim test. The vehicle-treated ultrasound-exposed mice exhibited increases in protein carbonyl and total glutathione, altered AMPA receptor subunits expression, and decreased expression of plasticity markers. These ultrasound-induced effects were ameliorated by thiamine and benfotiamine treatment; in particular both antioxidants were able to reverse ultrasound-induced changes in GluA1 and GluA2 subunit expression, and, within the prefrontal cortex, significantly reversed the changes in protein carbonyl and polysialylated form of neural cell adhesion molecule (PSA-NCAM) expression levels. Benfotiamine was usually more efficacious than thiamine. Thus, the thiamine compounds were able to counteract ultrasound-induced aggression, which was accompanied by the normalization of markers that have been showed to be associated with ultrasound-induced aggression. These commonly used, orally-active compounds may have considerable potential for use in the control of aggression within the community.
This article is part of the Special Issue entitled ‘Current status of the neurobiology of aggression and impulsivity’.
Plastic changes in synaptic properties are considered as fundamental for adaptive behaviors. Extracellular-signal-regulated kinase (ERK)-mediated signaling has been implicated in regulation of synaptic plasticity. Ribosomal S6 kinase 2 (RSK2) acts as a regulator and downstream effector of ERK. In the brain, RSK2 is predominantly expressed in regions required for learning and memory. Loss-of-function mutations in human RSK2 cause Coffin-Lowry syndrome, which is characterized by severe mental retardation and low IQ scores in affected males. Knockout of RSK2 in mice or the RSK ortholog in Drosophila results in a variety of learning and memory defects. However, overall brain structure in these animals is not affected, leaving open the question of the pathophysiological consequences. Using the fly neuromuscular system as a model for excitatory glutamatergic synapses, we show that removal of RSK function causes distinct defects in motoneurons and at the neuromuscular junction. Based on histochemical and electrophysiological analyses, we conclude that RSK is required for normal synaptic morphology and function. Furthermore, loss of RSK function interferes with ERK signaling at different levels. Elevated ERK activity was evident in the somata of motoneurons, whereas decreased ERK activity was observed in axons and the presynapse. In addition, we uncovered a novel function of RSK in anterograde axonal transport. Our results emphasize the importance of fine-tuning ERK activity in neuronal processes underlying higher brain functions. In this context, RSK acts as a modulator of ERK signaling.
The most prominent brain region evaluating the significance of external stimuli immediately after their onset is the amygdala. Stimuli evaluated as being stressful actuate a number of physiological processes as an immediate stress response. Variation in the serotonin transporter gene has been associated with increased anxiety- and depression-like behavior, altered stress reactivity and adaptation, and pathophysiology of stress-related disorders. In this study the instant reactions to an acute stressor were measured in a serotonin transporter knockout mouse model. Mice lacking the serotonin transporter were verified to be more anxious than their wild-type conspecifics. Genome-wide gene expression changes in the amygdala were measured after the mice were subjected to control condition or to an acute stressor of one minute exposure to water. The dissection of amygdalae and stabilization of RNA was conducted within nine minutes after the onset of the stressor. This extremely short protocol allowed for analysis of first wave primary response genes, typically induced within five to ten minutes of stimulation, and was performed using Affymetrix GeneChip Mouse Gene 1.0 ST Arrays. RNA profiling revealed a largely new set of differentially expressed primary response genes between the conditions acute stress and control that differed distinctly between wild-type and knockout mice. Consequently, functional categorization and pathway analysis indicated genes related to neuroplasticity and adaptation in wild-types whereas knockouts were characterized by impaired plasticity and genes more related to chronic stress and pathophysiology. Our study therefore disclosed different coping styles dependent on serotonin transporter genotype even directly after the onset of stress and accentuates the role of the serotonergic system in processing stressors and threat in the amygdala. Moreover, several of the first wave primary response genes that we found might provide promising targets for future therapeutic interventions of stress-related disorders also in humans.