Dopamine and serotonin signaling during two sensitive developmental periods differentially impact adult aggressive and affective behaviors in mice

Abstract

Pharmacologic blockade of monoamine oxidase A (MAOA) or serotonin transporter (5-HTT) has antidepressant and anxiolytic efficacy in adulthood. Yet, genetically conferred MAOA or 5-HTT hypo-activity is associated with altered aggression and increased anxiety/depression. Here we test the hypothesis that increased monoamine signaling during development causes these paradoxical aggressive and affective phenotypes. We find that pharmacologic MAOA blockade during early postnatal development (P2-P21) but not during peri-adolescence (P22-41) increases anxiety- and depression-like behavior in adult (> P90) mice, mimicking the effect of P2-21 5-HTT inhibition. Moreover, MAOA blockade during peri-adolescence, but not P2-21 or P182-201, increases adult aggressive behavior, and 5-HTT blockade from P22-P41 reduced adult aggression. Blockade of the dopamine transporter, but not the norepinephrine transporter, during P22-41 also increases adult aggressive behavior. Thus, P2-21 is a sensitive period during which 5-HT modulates adult anxiety/depression-like behavior, and P22-41 is a sensitive period during which DA and 5-HT bi-directionally modulate adult aggression. Permanently altered DAergic function as a consequence of increased P22-P41 monoamine signaling might underlie altered aggression. In support of this hypothesis, we find altered aggression correlating positively with locomotor response to amphetamine challenge in adulthood. Proving that altered DA function and aggression are causally linked, we demonstrate that optogenetic activation of VTA DAergic neurons increases aggression. It therefore appears that genetic and pharmacologic factors impacting dopamine and serotonin signaling during sensitive developmental periods can modulate adult monoaminergic function and thereby alter risk for aggressive and emotional dysfunction.

Behavioral and Physiological Consequences of Adult Brain 5-HT Depletion in Mice

“…The extension of the active period in 5-HT-depleted mice described by Whitney et al (2016) confirms the role of 5-HT in maintaining the normal circadian rhythm (Ciarleglio et al, 2011). Interestingly, Whitney et al (2016) also found that 5-HT depletion suppressed breaks during nocturnal activity (siestas).…”

“…The hyperactive phenotype reported by Whitney et al (2016) in 5-HT-depleted mice was not accompanied by changes in anxiety-like behavior in the open field, elevated plus maze, and light/dark box tests. This finding is surprising, considering that genetic and pharmacological mouse models targeting the 5-HT transporter (Kalueff et al, 2007), specific 5-HT receptors (Ramboz et al, 1998), or 5-HT depletion (Näslund et al, 2013), have consistently shown alterations in anxiety-like behavior.…”

“…Indeed, patients carrying a polymorphism of the Tph2 gene show higher susceptibility to develop ADHD (Sheehan et al, 2005). Accordingly, mice lacking the 5-HT transporter show higher 5-HT extracellular levels (Kim et al, 2005) and lower locomotor activity than controls (Kalueff et al, 2007).…”

“…Investigating whether a similar mechanism is involved in the modulation of amygdala activity by 5-HT neurons would help explain the unaltered anxiety-like behavior of adult 5-HT-depleted mice. It is worth mentioning that, in the study by Whitney et al (2016), not all 5-HT nuclei were targeted. However, the near absence of forebrain 5-HT in these mice makes it unlikely that spared nuclei contributed to the observed behavior in anxiety tests.…”

Michel Henry: afetividade e alucinação

“…Supported by the affect that is experienced from the outburst of the innermost emotion (Henry, 1996), supported by that which the observation of an X-ray can tell us what from there results for a flesh (Henry, 2000, p. 317), supported by an affection that translates into a protein with implications to memory (Teixeira & Martins, 2006, p. 321-233), or in the creation of an enriched environment that favors a certain morphology of neurons with implications to the quality of life of an Alzheimer patient or in the determination of human development periods that are more or less conducive to the appearance of psychiatric disorders (Yu, Teixeira, Mahadevia, Huang, Balsam, Mann, Gingrich & Ansorge, 2014), supported by its essence, the phenomenality of life, as evidenced by itself, enables passing from the approach of objectivity to that of subjectivity so in it are found the laws that revolve it completely: with the phenomenological reversal life is reborn in its essence and the essence is reborn with it.…”