. Most neuropsychiatric disorders have developmental origins. Such vulnerability is often restricted to sensitive periods, but affected behaviors, modulating factors, and underlying mechanisms are scarcely understood. We have identified an early postnatal 5-HT-sensitive period in mice that affects adult anxiety/depression-related behaviors and cognitive function. Altered adult behaviors are associated with reduced anatomical connectivity between the raphe, the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) in this mouse model, but it remains unknown what the consequences are on physiological connectivity and how alterations causally impact behavior. In wildtype mice, it is well established that raphe-mPFC-BLA circuitry regulates anxiety and depression-related behaviors and cognitive function. But also here, mechanistic insight especially at the level of 5-HTergic circuitry remains superficial. Hence, in the context of understanding normal brain function as well as developmental vulnerability, we view it as critical to elucidate the role of 5-HT input into postsynaptic circuits and its relationship with behavior. We furthermore believe that such insight into circuit function is needed to improve diagnosis and treatment strategies for neuropsychiatric disorders. Our proposal focuses on studying the raphe-mPFC-BLA circuit because of its central role in mediating and modulating emotional behaviors. Through optogenetics, we will directly investigate reciprocal circuit nodes at the physiological and behavioral level in WT mice and after developmental 5-HT interference. Furthermore, our developmental mouse models demonstrate that pharmacologic and genetic interventions to serotonin transporter or MAOA function produce comparable effects on behavior. Here we investigate the critical question if this vulnerability extends to 5-HTergic neuronal activity, using a pharmacogenetic approach. Our research will impact the understanding of the pathophysiology in depression/anxiety and cognitive impairment. Our research will likewise impact our understanding of how to treat these same conditions. We find that increased 5-HT signaling during development leads to functionally blunted 5-HTergic and mPFC pathways in adulthood, which in turn cause deficits in stress adaptation and fear extinction, and increase amygdala reactivity and fear conditioned learning. Conversely, 5-HT terminal activity in the BLA selectively reduces fear conditioning learning. These findings already indicate that terminal 5-HT activity in the BLA might be a promising biological target for the treatment of fear-related symptomatology. 5-HT receptors within the amygdala that relay the 5-HTergic signal to the postsynaptic circuitry might be interesting molecular targets for drug development. Furthermore, altered activity patterns identified here, might become measurable through non-invasive methods in humans to aid diagnosis. While more research is needed to increase confidence in such ideas, these examples provide strong evidence that the novel insight our studies will provide could in fact lead to improved diagnosis, prevention and treatment strategies in psychiatry.
Serotonin signaling modulates behaviors, which are abnormal in depression and anxiety disorders, but mechanistic insight at the level of the underlying neural circuitry remains superficial. Using optogenetic and pharmacogenetic tools we propose to investigate the raphe-mPFC-BLA circuit under normal conditions and in a developmental hypo-serotonergic mouse model displaying increased anxiety-like behavior and cognitive impairment. Experiments are designed to reveal causal relationships between neuronal activity, postsynaptic neurophysiology and behavior, to improve diagnosis, prevention, and treatment strategies in psychiatry.
|Gingrich, Jay A; Malm, Heli; Ansorge, Mark S et al. (2017) New Insights into How Serotonin Selective Reuptake Inhibitors Shape the Developing Brain. Birth Defects Res 109:924-932|
|Harmon, Jennifer L; Wills, Lauren P; McOmish, Caitlin E et al. (2016) 5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists. J Pharmacol Exp Ther 357:1-9|
|McOmish, Caitlin E; Demireva, Elena Y; Gingrich, Jay A (2016) Developmental expression of mGlu2 and mGlu3 in the mouse brain. Gene Expr Patterns 22:46-53|
|Suri, Deepika; Teixeira, Cátia M; Cagliostro, Martha K Caffrey et al. (2015) Monoamine-sensitive developmental periods impacting adult emotional and cognitive behaviors. Neuropsychopharmacology 40:88-112|
|Yu, Q; Teixeira, C M; Mahadevia, D et al. (2014) Optogenetic stimulation of DAergic VTA neurons increases aggression. Mol Psychiatry 19:635|
|Goodfellow, Nathalie M; Sargin, Derya; Ansorge, Mark S et al. (2014) Mice with compromised 5-HTT function lack phosphotyrosine-mediated inhibitory control over prefrontal 5-HT responses. J Neurosci 34:6107-11|
|Rebello, Tahilia J; Yu, Qinghui; Goodfellow, Nathalie M et al. (2014) Postnatal day 2 to 11 constitutes a 5-HT-sensitive period impacting adult mPFC function. J Neurosci 34:12379-93|
|Yu, Q; Teixeira, C M; Mahadevia, D et al. (2014) Dopamine and serotonin signaling during two sensitive developmental periods differentially impact adult aggressive and affective behaviors in mice. Mol Psychiatry 19:688-98|
|Muller, J M; Morelli, E; Ansorge, M et al. (2011) Serotonin transporter deficient mice are vulnerable to escape deficits following inescapable shocks. Genes Brain Behav 10:166-75|
|Oberlander, T F; Gingrich, J A; Ansorge, M S (2009) Sustained neurobehavioral effects of exposure to SSRI antidepressants during development: molecular to clinical evidence. Clin Pharmacol Ther 86:672-7|