Highlights d Chemo-connectomics combines chemogenetics (DREADDs) with resting-state fMRI d Locus coeruleus (LC) activation rapidly increases brain-wide functional connectivity d Connectivity changes correlate positively with adrenergic receptor distribution d LC activation shifts large-scale network connectivity toward salience processing

The locus coeruleus (LC) supplies norepinephrine (NE) to the entire forebrain, regulates many fundamental brain functions, and is implicated in several neuropsychiatric diseases. Although selective manipulation of the LC is not possible in humans, studies have suggested that strong LC activation might shift network connectivity to favor salience processing. To test this hypothesis, we use a mouse model to study the impact of LC stimulation on large-scale functional connectivity by combining chemogenetic activation of the LC with resting-state fMRI, an approach we term "chemo-connectomics". LC activation rapidly interrupts ongoing behavior and strongly increases brain-wide connectivity, with the most profound effects in the salience and amygdala networks. We reveal a direct correlation between functional connectivity changes and transcript levels of alpha-1, alpha-2, and beta-1 adrenoceptors across the brain, and a positive correlation between NE turnover and functional connectivity within select brain regions. These results represent the first brain-wide functional connectivity mapping in response to LC activation, and demonstrate a causal link between receptor expression, brain states and functionally connected large-scale networks at rest. We propose that these changes in large-scale network connectivity are critical for optimizing neural processing in the context of increased vigilance and threat detection. RESULTSTo selectively target the LC, we used transgenic mice that express codon-improved Crerecombinase (iCre) under the dopamine-beta-hydroxylase (DBH) promoter (DBH-iCre mice, Figure 1A) 33 . We stereotactically delivered floxed excitatory DREADDs 34 (AAV5-hSyn-DIO-hM3Dq-mCherry; hM3Dq-mCh) or a control virus (AAV5-hSyn-DIO-mCherry; mCh) to the LC, thus restricting virus expression to DBH-positive noradrenergic neurons of the LC (Figure 1B). We assessed successful LC activation using pupillometry, a highly sensitive and clinically relevant readout of LC activation [35][36][37] . After two minutes of baseline recording under light isoflurane anesthesia, we activated LC neurons by administering the potent DREADD activator clozapine at an ultra-low dose (0.03 mg/kg, i.p., Figure 1C) 38 . Within a minute of clozapine injection, we observed a strong increase in pupil diameter in the hM3Dq-mCh group, while pupil diameter of mCh mice did not change in response to clozapine injection and remained stable throughout the 10-minute recording session (Figure 1D-F). To show that our LC activation protocol is behaviorally relevant, we subjected mice to an open field test (OFT) immediately after clozapine injection and recorded their behavior for 30 minutes. In comparison to mCh mice, clozapine injection had profound effects on the behavior of hM3Dq-mCh mice. Several minutes after clozapine administration, hM3Dq-mCh mice showed strongly suppressed locomotor activity ( Figure 1G, H), spent less time in the (more aversive) center of the open field (Figure 1I, J), performed less activity-related supported rears (Figure 1...

These findings underscore the importance of considering dorsal and ventral hippocampus separately when conducting high-throughput molecular analyses, which has important implications for fundamental research as well as clinical studies.

Honeybees, like other insects, accumulate electric charge in flight, and when their body parts are moved or rubbed together. We report that bees emit constant and modulated electric fields when flying, landing, walking and during the waggle dance. The electric fields emitted by dancing bees consist of low-and high-frequency components. Both components induce passive antennal movements in stationary bees according to Coulomb's law. Bees learn both the constant and the modulated electric field components in the context of appetitive proboscis extension response conditioning. Using this paradigm, we identify mechanoreceptors in both joints of the antennae as sensors. Other mechanoreceptors on the bee body are potentially involved but are less sensitive. Using laser vibrometry, we show that the electrically charged flagellum is moved by constant and modulated electric fields and more strongly so if sound and electric fields interact. Recordings from axons of the Johnston organ document its sensitivity to electric field stimuli. Our analyses identify electric fields emanating from the surface charge of bees as stimuli for mechanoreceptors, and as biologically relevant stimuli, which may play a role in social communication.