Treffer: Conserved brain-wide emergence of emotional response from sensory experience in humans and mice.

Emotional responses to sensory experience are central to the human condition in health and disease. We hypothesized that principles governing the emergence of emotion from sensation might be discoverable through their conservation across the mammalian lineage. We therefore designed a cross-species neural activity screen, applicable to humans and mice, combining precise affective behavioral measurements, clinical medication administration, and brain-wide intracranial electrophysiology. This screen revealed conserved biphasic dynamics in which emotionally salient sensory signals are swiftly broadcast throughout the brain and followed by a characteristic persistent activity pattern. Medication-based interventions that selectively blocked persistent dynamics while preserving fast broadcast selectively inhibited emotional responses in humans and mice. Mammalian emotion appears to emerge as a specifically distributed neural context, driven by persistent dynamics and shaped by a global intrinsic timescale. Editor's summary: Many animal species have been shown to display distinct emotional states. However, little is known about the neuronal mechanisms underlying the emergence of emotional responses to discrete events. Kauvar et al. performed parallel behavioral, pharmacological, and electrophysiological experiments in mice and humans and identified evolutionarily conserved brain signals forming a basis of sensory and emotional processing of salient aversive stimuli (see the Perspective by Karamihalev and Gogolla). After stimulus-specific (sensory) information is rapidly disseminated throughout the mammalian brain, a slower and more persistent (emotional) activation of brainwide networks occurs. These translational results enhance our understanding of the neural substrates of affective states across species. —Mattia Maroso INTRODUCTION: Emotional states are central to the human condition in health and disease, yet the neural processes by which emotions emerge from experience remain mysterious. In mammals, lasting emotional responses may serve to integrate external and internal information spread across the brain, to guide contextually appropriate behaviors. We hypothesized that common structural and functional constraints on sensory integration into emotional states in the mammalian lineage could yield conserved dynamical principles governing the establishment and maintenance of emotional responses. RATIONALE: To identify broadly conserved patterns of neural activity, we first developed unbiased brain-wide activity screens spanning widely divergent mammalian species. Specifically, we explored when, where, and how emotional states emerge, using high-speed, invasive, and global methods in human and mouse subjects carrying out the same task. While recognizing and leveraging the value of obtaining verbal descriptions of subjective emotional experience from human subjects for this question, we also explicitly bridged human and mouse systems with temporally precise affective behavioral measures, clinically compatible pharmacological interventions, and deep brain-spanning intracranial electrophysiological readouts, designed to be similarly carried out in parallel in both human and mouse subjects, to investigate conserved principles underlying the emergence of lasting emotional states from brief sensory input. RESULTS: We determined that sequences of air puffs, directed at the cornea of human or mouse subjects, elicit both fast/reflexive and sustained/affective eye closure behaviors; the latter (in both species) is characterized by negative valence, persistence, generalization, and ablation by the dissociative agent ketamine. We performed a brain-wide neural activity screen of this temporally precise behavioral response, using intracranial stereo-electroencephalography (iEEG) in humans and multiprobe Neuropixels single-unit electrophysiology in mice. This brain-wide screen revealed a biphasic process in which emotionally salient sensory signals are swiftly broadcast throughout the mammalian brain and directly followed by a slower and widely distributed persistent signal. We discovered that the persistent signal could be selectively and similarly blocked by ketamine while preserving the fast sensory broadcast in both species, and that emergence of a behaviorally defined emotional state could be selectively blocked by this intervention. We found that the accumulation and decay pattern of persistent population neural activity was consistent with first-order system dynamics, and that the dose-dependent pharmacological impact on the emotional response could be well-modeled by varying a single decay timescale parameter, with emotion-blunting dissociative drugs accelerating the decay. We furthermore found (in both humans and mice) that ketamine accelerated the intrinsic timescale of baseline spontaneous activity and reduced brain-wide population coupling in networks with puff-triggered persistent activity. Control experiments in mice with a neutral auditory stimulus (while operating on faster timescales than emotionally salient stimuli) revealed that the pharmacological effect of sharpening response dynamics and reducing capacity to maintain persistent information across the brain was generalizable, highlighting the importance of signal persistence in the establishment of brain-wide responses. CONCLUSION: We find that mammalian emotional states, in a conserved pattern spanning divergent species, are integrated from sensory experiences through persistent activity dynamics that can be shaped by a global and tunable intrinsic timescale, akin to the action of a piano sustain pedal. Functioning as a distributed neural context, adaptive emotional states appear to depend upon brain-wide mechanisms of signal persistence in specific networks. Furthermore, consistent with our measurements of intrinsic timescale modulation by clinically relevant intervention, aspects of the etiology and treatment of certain neuropsychiatric disorders may be governed by altered stability of brain states linked to maladaptively fast or slow intrinsic timescales. Brain-wide emergence of emotional response in humans and mice.: (A) A repeatable, temporally precise, and cross-species measure of emotional response. (B) Broad, fast, and spatially resolved neural activity mapping across species with intracranial electrical recording. (C) The aversive stimulus signal is rapidly and widely broadcast, and from this, a sustained and distributed emotional state emerges. Ketamine selectively blocks the sustained response by accelerating the decay rate of system dynamics. [ABSTRACT FROM AUTHOR]

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