Biology subjects

Goldstein, N.

Publications and source records attributed to Goldstein, N..

3 recordsLinked to original sources

bioRxiv2024

A parabrachial hub for the prioritization of survival behavior

Long-term sustained pain in the absence of acute physical injury is a prominent feature of chronic pain conditions. While neurons responding to noxious stimuli have been identified, understanding the signals that persist without ongoing painful stimuli remains a challenge. Using an ethological approach based on the prioritization of adaptive survival behaviors, we determined that neuropeptide Y (NPY) signaling from multiple sources converges on parabrachial neurons expressing the NPY Y1 receptor to reduce sustained pain responses. Neural activity recordings and computational modeling demonstrate that activity in Y1R parabrachial neurons is elevated following injury, predicts functional coping behavior, and is inhibited by competing survival needs. Taken together, our findings suggest that parabrachial Y1 receptor-expressing neurons are a critical hub for endogenous analgesic pathways that suppress sustained pain states.

neuroscience↗

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

General Anesthesia Activates a Central Anxiolytic Center in the BNST

Low doses of general anesthetics like ketamine and dexmedetomidine have anxiolytic properties independent of their sedative effects. How these different drugs exert these anxiolytic effects is not well understood. We discovered a population of GABAergic neurons in the oval division of the bed nucleus of the stria terminalis that is activated by multiple anesthetics and the anxiolytic drug diazepam (ovBNSTGA). A majority of ovBNSTGA neurons express neurotensin receptor 1 (Ntsr1) and innervate brain regions known to regulate anxiety and stress responses. Optogenetic activation ovBNSTGA or ovBNSTNtsr1 neurons significantly attenuated anxiety-like behaviors in both naive animals and mice with inflammatory pain, while inhibition of these cells increased anxiety. Notably, activation of these neurons decreased heart rate and increased heart rate variability, suggesting that they reduce anxiety through modulation of the autonomic nervous system. Our study identifies ovBNSTGA/ovBNSTNtsr1 neurons as one of the brains endogenous anxiolytic centers and a potential therapeutic target for treating anxiety-related disorders. HIGHLIGHTSO_LIGeneral anesthetics and anxiolytics activate a population of neurons in the ovBNST C_LIO_LIAnesthesia-activated ovBNST neurons bidirectionally modulate anxiety-like behavior C_LIO_LIMost anesthesia-activated ovBNST neurons express neurotensin receptor 1 C_LIO_LIovBNSTNtsr1 neuron activation shifts autonomic responses to an anxiolytic state C_LI

neuroscience↗