Dziubek, J. | Search bioRxiv

bioRxiv2024

Reverse engineering placebo analgesia

Placebo analgesia is a widely observed clinical phenomenon. Establishing a robust mouse model of placebo analgesia is needed for careful dissection of the underpinning circuit mechanisms. However, previous studies failed to observe consistent placebo effects in rodent models of chronic pain. We wondered whether strong placebo analgesia can be reverse engineered using general anesthesia-activated neurons in the central amygdala (CeAGA) that can potently suppress pain. Indeed, in both acute and chronic pain models, pairing a context with CeAGA-mediated pain relief produced robust context-dependent analgesia, exceeding that induced by morphine in the same paradigm. We reasoned that if the analgesic effect was dependent on reactivation of CeAGA neurons by conditioned contextual cues, the analgesia would still be an active treatment, rather than a placebo effect. CeAGA neurons indeed receive monosynaptic inputs from temporal lobe areas that could potentially relay contextual cues directly to CeAGA. However, in vivo imaging showed that CeAGA neurons were not re-activated in the conditioned context, despite mice displaying a strong analgesic phenotype, supporting the notion that the cue-induced pain relief is true placebo analgesia. Our results show that conditioning with activation of a central pain-suppressing circuit is sufficient to engineer placebo analgesia, and that purposefully linking a context with an active treatment could be a means to harness the power of placebo for pain relief.

neuroscience↗

bioRxiv2023

A subcortical switchboard for exploratory, exploitatory, and disengaged states

To survive in evolving environments with uncertain resources, animals need to dynamically adapt their behavior and exhibit flexibility in choosing appropriate behavioral strategies, for example, to exploit familiar choices, to explore and acquire novel information, or to disengage altogether. Previous studies have mainly investigated how forebrain regions represent choice costs and values as well as optimal decision strategies during explore/exploit trade-offs. However, the neural mechanisms by which the brain implements alternative behavioral strategies such as exploiting, exploring or disengaging from the environment, remains poorly understood. Here we identify a neural hub critical for flexible switching between behavioral strategies, the median raphe nucleus (MRN). Using cell-type specific optogenetic manipulations, calcium fiber photometry and circuit tracing in mice performing diverse instinctive and learnt behavioral tasks, we found that the MRNs main cell types, GABAergic, glutamatergic (VGluT2-positive), and serotonergic neurons, have complementary functions and drive exploitation, exploration and disengagement, respectively. Suppression of MRN GABAergic neurons, for instance through inhibitory input from lateral hypothalamus which conveys strong positive valence to the MRN, leads to perseverance in current actions and goals, and thus promotes exploitatory behavior. In contrast, activation of MRN VGluT2+ neurons drives exploratory behavior. Activity of serotonergic MRN neurons is necessary for general task engagement. Input from the lateral habenula conveying negative valence suppresses serotonergic MRN neurons, leading to disengagement. These findings establish the MRN as a central behavioral switchboard, uniquely positioned to flexibly control behavioral strategies. These circuits thus may also play an important role in the etiology and possible treatment of major mental pathologies such as depressive or obsessive-compulsive disorders.

neuroscience↗