Low cholesterol is not always good: low cholesterol levels are associated with decreased serotonin and increased aggression in fish

Abstract

The inverse relationship between serum cholesterol and levels of aggression led to the cholesterol-serotonin hypothesis. According to this hypothesis, low dietary cholesterol intake leads to depressed central serotonergic activity, which is associated with increased aggression. Here we present the hypothesis about the evolutionary origins of low cholesterol and aggressive behavior, investigating the relationship between low levels of plasma cholesterol and aggressive behavior in fish. We used Nile tilapia (Oreochromis niloticus), a species of aggressive fish with a clear dominant subordinate relation, as an experimental model. The fish were treated with statin, a cholesterol-lowering drug. Aggressive behavior, brain serotonin (5-HT) concentrations, 5-hydroxyindoleacetic acid (5-HIAA, the major 5-HT metabolite) and plasma cholesterol were analyzed after chronic administration of statin. Our results show that fish treated with statin exhibited reduced plasma cholesterol, reduced telencephalic indexes of 5-HIAA/5-HT and increased aggressive behavior compared to control fish. These results indicate that changes in plasma cholesterol may affect neurochemical processes underlying aggressive behavior in fish, suggesting an evolutionary mechanism conserved among vertebrates. Such mechanisms may be important for the control of aggression in many vertebrate species, not just mammals, as has been demonstrated so far.

Pleiotropic effects of statins on brain cells

“…In an interesting study designed to evaluate the neurobiological basis of aggressive behavior, it was demonstrated that in Nile tilapia, a fish with a belligerent behavior, atorvastatin treatment reduces plasma cholesterol and the telencephalic ratio between the main serotonin metabolite, 5-HIAA, and serotonin, and increases aggressive behavior compared to control fish [63]. These observations suggest that modification of plasma cholesterol may impact on the neurochemical mechanisms responsible for the belligerent tilapia behavior, pointing to the possibility that this mechanism is conserved in the phylogeny of vertebrates.…”

Serotonin Signaling through Lipid Membranes

“…Kaplan et al introduced the cholesterol-5-HT hypothesis, stating that lowered cholesterol levels from poor diet or inhibited synthesis might result in reduced central 5-HT activity. This theory provides some insight into cholesterol’s role in depressive behavior, suicidal tendencies, and aggressiveness. − It has been suggested that low cholesterol and 5-HT levels make men more prone to violent behavior and risk-taking compared to women …”

“…265 Statins, medications that hinder cholesterol synthesis and lower plasma levels, reduce the telencephalic 5-HIAA/5-HT ratio in Nile tilapia fish and decrease the 5-HT brain levels in rodents. 261,266 Meanwhile, treatment with antidepressants like paroxetine, clomipramine, sertraline, duloxetine, and fluoxetine, which have strong SERT affinity, leads to higher LDLcholesterol levels. 266 While there is a definitive link between cholesterol and 5-HT function, the exact process remains unknown.…”

Neurobiology of Impulsivity and Aggression As Substrates of Suicidal Behavior: A Narrative Focus on the Involvement of Serum Lipids

“…Psychological correlates of aggression including emotion, motivation, cognitive functions, and behavior are driven and nourished by extensive neural pathways and neuroendocrine mechanisms (74).…”

“…Similar to impulsivity, serotonergic neurotransmission is the most-studied neural function in the physiology of aggression (74). In recent decades, it has been shown that there is an inverse relationship between serotonin concentrations in the synaptic cleft in the brain and the expression of aggressive behavior (75).…”