Ligand activation of the nociceptive TRPV1 ion channel by vanilloids is a proven and powerful pathway for pain management and serves as one of the best model systems for analyzing allosteric coupling in ion channels. However, vanilloid binding and activation have been mostly described only qualitatively in the past. We developed a novel method to isolate channel gating states with a specific number of bound ligands and bound configuration, which allowed direct measurement of binding affinity and gating energetics on a per subunit basis. We determined that capsaicin binds to a rat TRPV1 subunit with an association constant of 2.4X10^6 M^(-1), and found ligand binding to each subunit is nearly independent. Each ligand binding contributes 1.70 to 1.86 kcal/mol activation energy. Subunit contributions are nearly equal as postulated in the MWC model, with a minor deviation that two capsaicin molecules bound to diagonal subunits yield stronger cooperativity (by 0.3 to 0.4 kcal/mol) than those bound to neighboring subunits.

Swift detection and remembering of salient and emotional stimuli is critical for survival and adaptive fitness. Optimal emotional processing is central to mental health, abnormalities of which are frequently present across all forms of neuropsychiatric illness including major depression, post-traumatic stress disorder, and suicide. Despite the extent of the problem, our fundamental understanding of the neural circuitry underlying emotional processing remains limited, which has hindered therapeutic advances in neuropsychiatric diseases.

Here, we employed intracranial electrodes in drug-resistant epilepsy patients undergoing pre-surgical evaluation to directly record neural signals from the amygdala, the hippocampus and the orbitofrontal cortex, a neuroanatomical circuit core to emotional processing. First, we examined oscillatory activity within the medial temporal lobe during processing of fearful faces compared to neutral landscapes. We found early engagement of the amygdala and unidirectional influence from the amygdala to the hippocampus during processing of fearful faces. In addition, we showed that such modulation is mediated through cross frequency coupling between theta/alpha (4-10Hz) oscillations and high gamma activity (70-200 Hz). Next, we investigated the oscillatory mechanisms of emotional memory and asked how emotion influences the discrimination of similar mnemonic experiences (e.g. pattern separation). We observed frequency-specific interactions between the amygdala and the hippocampus, with theta (3-7Hz) synchrony facilitating correct mnemonic discrimination and alpha (8-13Hz) synchrony promoting incorrect recognition. Finally, we examined how past context modulates our future perception of facial expression. Using Bayesian decoding techniques, we showed that the high gamma activity is precisely aligned with the phase of theta oscillations, in which the probability densities of the reconstructed time showed that the descending theta phase encodes past context and ascending theta phase represents future face perception. In sum, intracranial recordings have provided critical insights on how oscillations coordinate circuit dynamics in the frontotemporal network to rapidly and flexibly organize emotional information in humans.