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In times of stress or danger, the autonomic nervous system (ANS) signals the fight or flight response. A canonical function of ANS activity is to globally mobilize metabolic resources, preparing the organism to respond to threat. Yet a body of research has demonstrated that, rather than displaying a homogenous pattern across the body, autonomic responses to arousing events, as measured through changes in electrodermal activity (EDA), can differ between right and left body locations. Surprisingly, an attempt to identify a function of ANS asymmetry consistent with its metabolic role has not been investigated. In the current study, we investigated whether asymmetric autonomic responses could be induced through limb-specific aversive stimulation. Participants were given mild electric stimulation to either the left or right arm while EDA was monitored bilaterally. In a group-level analyses, an ipsilateral EDA response bias was observed, with increased EDA response in the hand adjacent to the stimulation. This effect was observable in ∼50% of individual participants. These results demonstrate that autonomic output is more complex than canonical interpretations suggest. We suggest that, in stressful situations, autonomic outputs can prepare either the whole-body fight or flight response, or a simply a limb-localized flick, which can effectively neutralize the threat while minimizing global resource consumption. These findings are consistent with recent theories proposing evolutionary leveraging of neural structures organized to mediate sensory responses for processing of cognitive emotional cues.

In times of stress or danger, the autonomic nervous system (ANS) signals the fight or flight response. A canonical function of ANS activity is to globally mobilize metabolic resources, preparing the organism to respond to threat. Yet a body of research has demonstrated that, rather than displaying a homogenous pattern across the body, autonomic responses to arousing events — as measured through changes in electrodermal activity (EDA) — can differ between right and left body locations. Surprisingly, the metabolic function of such ANS asymmetry has not been investigated. In the current study, we investigated whether asymmetric autonomic responses could be induced through limb-specific aversive stimulation. Participants were given mild electric stimulation to either the left or right arm while EDA was monitored bilaterally. Across participants, a strong ipsilateral EDA response bias was observed, with increased EDA response in the hand adjacent to the stimulation. This effect was observable in over 50% of individual subjects. These results demonstrate that autonomic output is more complex than canonical interpretations suggest. We suggest that, in stressful situations, autonomic outputs can prepare either the whole-body fight or flight response, or a simply a limb-localized flick, which can effectively neutralize the threat while minimizing global resource consumption. These findings provide insight into the evolutionary pathway of neural systems processing general arousal by linking observed asymmetry in the peripheral arousal response to a historical leveraging of neural structures organized to mediate responses to localized threat.

Isolation and proteomic profiling of brain cell types, particularly neurons, pose several technical challenges which limit our ability to resolve distinct cellular phenotypes in neurological diseases. Therefore, we generated a novel mouse line that enables cell type-specific expression of a biotin ligase, TurboID, via Cre-lox strategy for in vivo proximity-dependent biotinylation of proteins. Using adenoviral-based and transgenic approaches, we show striking protein biotinylation in neuronal cell bodies and axons throughout the mouse brain. We quantified more than 2,000 neuron-derived proteins following enrichment that mapped to numerous subcellular compartments. Synaptic, transmembrane transporters, ion channel subunits, and disease-relevant druggable targets were among the most significantly enriched proteins. Remarkably, we resolved brain region-specific proteomic profiles of Camk2a neurons with distinct functional molecular signatures and disease associations that may underlie regional neuronal vulnerability. Leveraging the neuronal specificity of this in vivo biotinylation strategy, we used an antibody-based approach to uncover regionally unique patterns of neuron-derived signaling phospho-proteins and cytokines, particularly in the cortex and cerebellum. Our work provides a proteomic framework to investigate cell type-specific mechanisms driving physiological and pathological states of the brain as well as complex tissues beyond the brain.

Proteomic profiling of brain cell types using isolation-based strategies pose limitations in resolving cellular phenotypes representative of their native state. We describe a mouse line for cell type-specific expression of biotin ligase TurboID, for in vivo biotinylation of proteins. Using adenoviral and transgenic approaches to label neurons, we show robust protein biotinylation in neuronal soma and axons throughout the brain, allowing quantitation of over 2000 neuron-derived proteins spanning synaptic proteins, transporters, ion channels and disease-relevant druggable targets. Next, we contrast Camk2a-neuron and Aldh1l1-astrocyte proteomes and identify brain region-specific proteomic differences within both cell types, some of which might potentially underlie the selective vulnerability to neurological diseases. Leveraging the cellular specificity of proteomic labeling, we apply an antibody-based approach to uncover differences in neuron and astrocyte-derived signaling phospho-proteins and cytokines. This approach will facilitate the characterization of cell-type specific proteomes in a diverse number of tissues under both physiological and pathological states.