Highlights Extracellular levels of norepinephrine display dynamic changes during NREM and REM sleep  Phasic activity of locus coeruleus neurons during NREM underlies slow norepinephrine oscillations  Spindles occur at norepinephrine troughs and are abolished by norepinephrine increases  Increased spindles prior to REM reflect the beginning of a long-lasting norepinephrine decline  REM episodes are characterized by a sub-threshold continuous norepinephrine decline  The responsiveness of astrocytic Ca 2+ to norepinephrine is reduced during sleep

Functional imaging and gene expression studies both implicate the medial prefrontal cortex (mPFC), particularly deep-layer projection neurons, as a potential locus for autism pathology. Here, we explored how specific deep-layer prefrontal neurons contribute to abnormal physiology and behavior in mouse models of autism. First, we find that across three etiologically distinct models-in utero valproic acid (VPA) exposure, CNTNAP2 knockout and FMR1 knockout-layer 5 subcortically projecting (SC) neurons consistently exhibit reduced input resistance and action potential firing. To explore how altered SC neuron physiology might impact behavior, we took advantage of the fact that in deep layers of the mPFC, dopamine D2 receptors (D2Rs) are mainly expressed by SC neurons, and used D2-Cre mice to label D2R+ neurons for calcium imaging or optogenetics. We found that social exploration preferentially recruits mPFC D2R+ cells, but that this recruitment is attenuated in VPA-exposed mice. Stimulating mPFC D2R+ neurons disrupts normal social interaction. Conversely, inhibiting these cells enhances social behavior in VPA-exposed mice. Importantly, this effect was not reproduced by nonspecifically inhibiting mPFC neurons in VPA-exposed mice, or by inhibiting D2R+ neurons in wild-type mice. These findings suggest that multiple forms of autism may alter the physiology of specific deep-layer prefrontal neurons that project to subcortical targets. Furthermore, a highly overlapping population-prefrontal D2R+ neurons-plays an important role in both normal and abnormal social behavior, such that targeting these cells can elicit potentially therapeutic effects.

SUMMARY Both the medial prefrontal cortex (mPFC) and serotonin play key roles in anxiety, however, specific mechanisms through which serotonin might act on the mPFC to modulate anxiety-related behavior remain unknown. Here, we use a combination of optogenetics and synaptic physiology to show that serotonin acts presynaptically via 5-HT1B receptors to selectively suppress inputs from the contralateral mPFC and ventral hippocampus (vHPC), while sparing those from mediodorsal thalamus. To elucidate how these actions could potentially regulate prefrontal circuit function, we infused a 5-HT1B agonist into the mPFC of freely behaving mice. Consistent with previous studies that have optogenetically inhibited vHPC-mPFC projections, activating prefrontal 5-HT1B receptors suppressed theta-frequency (4–12 Hz) mPFC activity, and also reduced avoidance of anxiogenic regions in the elevated plus maze. These findings suggest a potential mechanism, linking specific receptors, synapses, patterns of circuit activity, and behavior, through which serotonin may regulate prefrontal circuit function including anxiety-related behaviors.

SummaryWe normally regard sleep and wake as two distinct opposing brain states, where sleep requires silence of wake-promoting structures such as the locus coeruleus (LC)-norepinephrine (NE) system. We set out to investigate how cortical NE dynamics and NE-related astrocytic activity relates to LC population activity during sleep states.We show that LC displays regular phasic activity bouts during NREM sleep leading to a slow oscillatory pattern of prefrontal NE levels of which the majority of NE increases does not lead to awakening. NE troughs link to sleep spindles and continued NE decline transitions into REM sleep. Last, we show that prefrontal astrocytes have reduced sensitivity towards NE during sleep.Our results suggest that dynamic changes in the activity of wake-promoting systems during sleep create alternation between crucial sleep processes and broadening of sensitivity towards incoming sensory input.HighlightsExtracellular levels of norepinephrine display dynamic changes during NREM and REM sleepPhasic activity of locus coeruleus neurons during NREM underlies slow norepinephrine oscillationsSpindles occur at norepinephrine troughs and are abolished by norepinephrine increasesIncreased spindles prior to REM reflect the beginning of a long-lasting norepinephrine declineREM episodes are characterized by a sub-threshold continuous norepinephrine declineThe responsiveness of astrocytic Ca2+ to norepinephrine is reduced during sleep