During early life, serotonin acts to modulate neurodevelopmental processes. Genetic and environmental factors that alter serotonin signaling can therefore impact brain maturation. We have identified a sensitive developmental period (postnatal day 2-11) during which elevated serotonin signaling elicits life-long increases in anxiety and depression-related behaviors as well as cognitive impairments in mice. We also identified an array of neural changes associated with these behavioral abnormalities: altered dendritic morphology of medial prefrontal cortex (mPFC) and hippocampal (HC) pyramidal neurons, altered excitability of mPFC neurons, increased inhibitory drive to 5-HTergic neurons of the dorsal raphe, and diminished axonal arborization of 5-HT neurons. Here we aim at furthering our knowledge of consequences elicited by increased developmental 5-HT signaling, focusing on mPFC function and testing their causal relationship with emotional behavior. This experimental choice is based on the importance of the mPFC in disorders of anxiety and depression. For example, the subgenual cortex is typically hyperactivated in depressive states - a condition reversed by successful treatment, including deep brain stimulation. Functional connectivity between the mPFC and the amygdala is inversely correlated with harm avoidance scores. In rodents, mPFC-amygdala circuits control extinction of learned fear and ventral hippocampal-mPFC theta activity coherence correlates with anxiety states. Lastly, we show (see preliminary data) that lesions of the infralimbic cortex (IL, an mPFC sub-region) phenocopy anxiety-related behaviors elicited by increased developmental 5-HT signaling. Taken together, these findings demonstrate a critical involvement of the mPFC and its circuitry engaging the HC and the amygdala in the modulation of depressive and anxiety states. Our proposal addresses the overarching hypothesis that increased 5-HT signaling during a sensitive developmental period permanently alters mPFC-circuitry that modulates emotional and cognitive processes.
In Aim1 we study the effect of developmental 5-HT signaling on membrane electrical properties of mPFC pyramidal neurons and their functional connectivity with the HC and amygdala. These data will set the stage for causality-testing experiments in Aim2, where we apply optogenetic and pharmacogenetic tools to modulate the activity of IL and/or PL pyramidal neurons directly or through afferents from the HC and amygdala.
In Aim3 we seek to identify 5-HT receptors mediating the developmental effects of increased 5-HT signaling on mPFC function. Together, Aims1-3 will impact the understanding of human risk factors for depression/anxiety and neuropsychiatric disorders with altered mPFC activity. Our preliminary data suggest that genetic or environmental factors, which act alone or in concert to increase 5-HT signaling during development, constitute risk factors for mPFC dysfunction. Together with the mechanistic insight we will provide, our data could lead to improved diagnosis, prevention and treatment strategies in psychiatry.
During early life, serotonin acts to modulate neurodevelopmental processes, and factors (genetic and environmental) that alter serotonin signaling can therefore impact brain maturation - for better or for worse. Having identified a sensitive period in mice during which elevated serotonin signaling increases adult depression and anxiety along with structural and electrophysiological changes in the medial prefrontal cortex, we now propose to study alterations at the level of mPFC-circuitry and test their causal relationship with emotional behavior. Our research will advance mechanistic insight on the role of serotonin during development and impact public health by increasing our knowledge on risk factors and intermediate phenotypes of neuropsychiatric disorders.
