Title: Developmental Monoamine Signaling Impacts Adult Affective and Aggressive Behaviors
Description: Most neuropsychiatric disorders have developmental origins and an emerging model postulates that such developmental vulnerability is often restricted to sensitive periods. The concept of sensitive developmental periods for the indelible modulation of complex behaviors is similar to that described for sensory systems (e.g. visual cortex, ocular dominance plasticity), but effected behaviors, modulating factors, and underlying mechanisms are much less well understood. Furthering our knowledge of sensitive periods that determine the developmental trajectory of complex behaviors is a necessary step towards improving diagnosis, prevention and treatment approaches for neuropsychiatric disorders. To fulfill this mission, I here investigate how genetic and environmental risk factors act during sensitive periods of brain development to alter adult behavior and thereby confer vulnerability to neuropsychiatric disorders. My thesis is divided into four chapters. Chapter I provides general background and significance information relevant to chapters II-IV.

Chapter II focuses on elucidating and comparing the consequences of developmental serotonin (5-HT) transporter (5-HTT) and monoamine oxidase A (MAOA) blockade. Pharmacologic MAOA or 5-HTT blockade in adulthood has antidepressant and anxiolytic efficacy. Yet, genetically conferred MAOA or 5-HTT hypo-activity is associated with altered aggression and increased anxiety/depression. Here I test the hypothesis that increased monoamine signaling during development causes these paradoxical aggressive and affective phenotypes. I find that pharmacologic MAOA blockade during early postnatal development (P2-P21) increases anxiety- and depression-like behavior in mice, mimicking the effect of P2-21 5-HTT inhibition. Moreover, MAOA or dopamine transporter (but not norepinephrine transporter) blockade during peri-adolescence (P22-P41) increases adult aggressive behavior. 5-HTT blockade from P2-P21 or P22-P41 reduces adult aggressive behavior. Altered aggression correlates positively with locomotor response to amphetamine challenge in adulthood and striatal dopamine and DOPAC content is increased while brainstem 5-HIAA content is decreased in high aggression.

Taken together, these data suggest that genetic and pharmacologic factors impacting dopamine and serotonin signaling during sensitive developmental periods confer risk for aggressive and emotional dysfunction in humans. Chapter III focuses on refining the 5-HT sensitive period affecting anxiety and depression-like behavior. Specifically, I hypothesized that the identified P2-21 period, which encompasses many developmental processes, contains a narrower critical period, affecting fewer developmental processes but having the same impact on adult behavior. This experiment serves two purposes: First, I seek to gain insight into the neural substrates and possible developmental processes underlying developmental programing of anxiety- and depression-like behaviors through 5-HT signaling. Second, I aim at providing translationally relevant data, informing clinical and epidemiological studies as to which developmental window might be sensitive to 5-HT altering factors in humans. This thesis research shows that postnatal fluoxetine (PN-FLX) treatment from P2-11 leads to increased adult anxiety- and depressive-like behavior in mice, while PN-FLX treatment from P12-21 or P22-41 has no effect in adult anxiety- and depressive-like behavior.

In addition, adult chronic FLX treatment could not rescue the behavioral phenotype produced by P2-11 5-HTT blockade. Chapter IV focuses on the role of 5-HT2A receptor signaling in mediating the effect of P2-11 5-HTT blockade on adult behavior. Htr2a-/- mice display reduced conflict anxiety. Because 5-HT2A receptor antagonists do not reduce conflict anxiety in adulthood, I hypothesized that the behavioral htr2a-/- phenotype is at least partially of developmental origin, which would further indicate that increased 5-HT2A receptor signaling during development could increase conflict anxiety. To investigate this hypothesis, I analyzed the effect of P2-11 5-HTT blockade on anxiety and depression-like behaviors in htr2a+/+, +/-, and -/- mice. Supporting my hypothesis, I find that absence of htr2a improved performance of PN-FLX treated mice in the novelty suppressed feeding task, by decreasing the latency to feed to control levels. Absence of htr2a, however, did not have ameliorative effects on PN-FLX phenotypes in the open field and shock escape tests.

In summary, these data demonstrate that 5-HT2A receptor signaling mediates some but not all consequences of increased P2-11 5-HT signaling. Taken together, in my thesis work I identified and characterized two sensitive developmental periods whereupon early-life perturbation of monoamine signaling alters adult behavior: an early postnatal (P2-P11) 5-HT-sensitive period that affects anxiety and depression-related behaviors and a later peri-adolescent (P22-P41) DA- and 5-HT-sensitive period altering aggression and behavioral sensitivity amphetamine. These data give insight into the etiology of neuropsychiatric disorders and should ultimately help improving diagnosis, prevention and treatment approaches.