Somatostatin interneurons activated by 5-HT_2Areceptor suppress slow oscillations in medial entorhinal cortex

Abstract

1 Serotonin (5-HT) affects multiple physiological processes in the brain and is involved in a 2 number of psychiatric disorders. 5-HT axons reach all cortical areas; however, the precise 3 mechanism by which 5-HT modulates cortical network activity is not yet fully understood. We 4 investigated the effects of 5-HT on slow oscillations (SO), a synchronized cortical network 5 activity universally present across species. SO are observed during slow-wave sleep and 6 anesthesia and are considered the default cortical activity pattern. Combining opto-and 7 pharmacogenetic manipulations with electrophysiological recordings, we discovered that 5-8 HT inhibits SO within the entorhinal cortex (EC) by activating somatostatin-expressing (Som) 9interneurons via the 5-HT2A receptor (5-HT2AR). This receptor is involved in the etiology of 10 different psychiatric disorders and mediates the psychological effects of many psychoactive 11 serotonergic drugs, suggesting that 5-HT targeting of Som interneurons may play an 12 important role in these processes. 13 14 5-HT is one of the most important neuromodulators in the central nervous system. Projections 15 originating from the Raphe nuclei, the brain-stem structure that comprises the majority of 5-16HT releasing neurons in the brain, reach all cortical and sub-cortical area (Descarries et al., 17 2010). Consequentially, it is not surprising that 5-HT is involved in the regulation of a myriad 18 of physiological functions (e.g. circadian rhythm, mood, memory formation, reward encoding, 19 sexual behavior) and psychiatric disorders including depression, autism, schizophrenia, and 20 anxiety disorders (Monti, 2011, Underwood et al., 2018, Hayes and Greenshaw, 2011, Teixeira et al., 21 2018, Uphouse and Guptarak, 2010, Nakai et al., 2017. 22 5-HT levels in the brain are closely linked to the sleep-wake cycle. Activity of serotonergic 23 raphe neurons is increased during wakefulness, decreased during slow-wave sleep and 24 virtually silent during REM sleep (McGinty and Harper, 1976, Oikonomou et al., 2019). Cortical 25 activity is also influenced by the behavioral state of the animal: slow-wave sleep (SWS) is 26 generally associated to "synchronized" patterns of activity, characterized by low-frequency 27 global fluctuations, whereas active wakefulness and REM sleep features "desynchronized" 28 network activity in which low-frequency fluctuations are absent. The shifting of cortical 29 networks between different patterns of activity is controlled, at least in part, by 30 neuromodulators (Lee and Dan, 2012). For instance, Acetylcholine (Ach) can profoundly alter 31 cortical network activity by inducing desynchronization via activation of Som interneurons 32 (Chen et al. , 2015). However, it is not solely responsible for cortical desynchronization as lesions 33 of cholinergic neurons are not sufficient to abolish desynchronization (Kaur et al., 2008). On the 34 other hand, blocking Ach and 5-HT transmission at the same time causes a complete 35 suppression of cortical desynchronizat...