Photoperiodic Programming of Monoamine Brain Circuits

项目总结

PROJECT SUMMARY A fundamental question in neurobiology is how environmental signals – both developmental and ongoing– induce plasticity in neural circuits and networks to shape behavior. Circadian photoperiod, the proportion of daylight in a solar day, is a pervasive environmental signal that varies substantially with latitude and season, and drives acute and long-term effects on mood regulation in humans and in animal models. The associations of the molecular circadian clock and photoperiod with mood disorders are clear, but the neurobiological mechanisms remain incompletely understood. The serotonergic dorsal raphe nuclei (DRN) are a critical nexus for integrating circadian photoperiodic input with mood and reward. They receive light input from the circadian visual system and polysynaptic input from the biological clock nuclei and make widespread outputs, including to midbrain nuclei mediating motivation and reward through dopaminergic transmission. Seasonal photoperiods (winter–like “short days” vs. summer-like “long days”) induce enduring changes in mouse DRN serotonin neurons - programming their excitability and intrinsic electrical properties, their serotonin content, as well as anxiety and depressive-like behaviors. We have previously shown that the TREK-1 K+ channel mRNA expression is photoperiodically regulated in DRN 5- HT neurons, and therefore may play a key role in photoperiodic programming of serotonin excitability. A number of independent lines of evidence indicate that TREK-1 in DRN neurons impact mood regulation and mood disorders. We now also report intriguing sex-dependent photoperiodic regulation of dopamine uptake and release downstream of the DRN in the NAc of female mice, indicating photoperiodic impact on circuitry for motivation and reward that mirrors the reported female bias of Seasonal Affective Disorder (SAD) in humans. We propose as our overall hypothesis that DRN 5-HT neurons are a primary site of photoperiodic programing – in which transcriptional regulation of TREK-1 plays a key role in regulating neuronal excitability. In congruence with the NIMH RDOC paradigm, we envision photoperiod programing as an extended circuit for positive valence system behaviors in which the output of the programmed serotonergic DRN induces convergent drive by the DRN and VTA inputs to alter NAc function, driving changes in the output of reinforcement/motivated behaviors. We will further elucidate a mechanistic basis of photoperiodic programming of 5-HT neurons involving TREK-1, and downstream effects of this programming on positive valence systems, including NAc dopamine release and uptake, NAc synaptic plasticity, and NAc-driven motivation behavior. Completion of these Aims will enhance understanding of key neurobiological mechanisms underlying photoperiodic regulation of mood, motivation, and reinforcement.