Keith Richard Murphy

All Publications

• High-throughput ultrasound neuromodulation in awake and freely behaving rats. Brain stimulation Di Ianni, T., Morrison, K. P., Yu, B., Murphy, K. R., de Lecea, L., Airan, R. D. 2023; 16 (6): 1743-1752

  Abstract

  Transcranial ultrasound neuromodulation is a promising potential therapeutic tool for the noninvasive treatment of neuropsychiatric disorders. However, the expansive parameter space and difficulties in controlling for peripheral auditory effects make it challenging to identify ultrasound sequences and brain targets that may provide therapeutic efficacy. Careful preclinical investigations in clinically relevant behavioral models are critically needed to identify suitable brain targets and acoustic parameters. However, there is a lack of ultrasound devices allowing for multi-target experimental investigations in awake and unrestrained rodents. We developed a miniaturized 64-element ultrasound array that enables neurointerventional investigations with within-trial active control targets in freely behaving rats. We first characterized the acoustic field with measurements in free water and with transcranial propagation. We then confirmed in vivo that the array can target multiple brain regions via electronic steering, and verified that wearing the device does not cause significant impairments to animal motility. Finally, we demonstrated the performance of our system in a high-throughput neuromodulation experiment, where we found that ultrasound stimulation of the rat central medial thalamus, but not an active control target, promotes arousal and increases locomotor activity.

  View details for DOI 10.1016/j.brs.2023.11.014

  View details for PubMedID 38052373

• A cluster of neuropeptide S neurons regulates breathing and arousal. Current biology : CB Angelakos, C. C., Girven, K. S., Liu, Y., Gonzalez, O. C., Murphy, K. R., Jennings, K. J., Giardino, W. J., Zweifel, L. S., Suko, A., Palmiter, R. D., Clark, S. D., Krasnow, M. A., Bruchas, M. R., de Lecea, L. 2023

  Abstract

  Neuropeptide S (NPS) is a highly conserved peptide found in all tetrapods that functions in the brain to promote heightened arousal; however, the subpopulations mediating these phenomena remain unknown. We generated mice expressing Cre recombinase from the Nps gene locus (NpsCre) and examined populations of NPS+ neurons in the lateral parabrachial area (LPBA), the peri-locus coeruleus (peri-LC) region of the pons, and the dorsomedial thalamus (DMT). We performed brain-wide mapping of input and output regions of NPS+ clusters and characterized expression patterns of the NPS receptor 1 (NPSR1). While the activity of all three NPS+ subpopulations tracked with vigilance state, only NPS+ neurons of the LPBA exhibited both increased activity prior to wakefulness and decreased activity during REM sleep, similar to the behavioral phenotype observed upon NPSR1 activation. Accordingly, we found that activation of the LPBA but not the peri-LC NPS+ neurons increased wake and reduced REM sleep. Furthermore, given the extended role of the LPBA in respiration and the link between behavioral arousal and breathing rate, we demonstrated that the LPBA but not the peri-LC NPS+ neuronal activation increased respiratory rate. Together, our data suggest that NPS+ neurons of the LPBA represent an unexplored subpopulation regulating breathing, and they are sufficient to recapitulate the sleep/wake phenotypes observed with broad NPS system activation.

  View details for DOI 10.1016/j.cub.2023.11.018

  View details for PubMedID 38056461

• Dorsomedial and preoptic hypothalamic circuits control torpor. Current biology : CB Yamaguchi, H., Murphy, K. R., Fukatsu, N., Sato, K., Yamanaka, A., de Lecea, L. 2023

  Abstract

  Endotherms can survive low temperatures and food shortage by actively entering a hypometabolic state known as torpor. Although the decrease in metabolic rate and body temperature (Tb) during torpor is controlled by the brain, the specific neural circuits underlying these processes have not been comprehensively elucidated. In this study, we identify the neural circuits involved in torpor regulation by combining whole-brain mapping of torpor-activated neurons, cell-type-specific manipulation of neural activity, and viral tracing-based circuit mapping. We find that Trpm2-positive neurons in the preoptic area and Vgat-positive neurons in the dorsal medial hypothalamus are activated during torpor. Genetic silencing shows that the activity of either cell type is necessary to enter the torpor state. Finally, we show that these cells receive projections from the arcuate and suprachiasmatic nucleus and send projections to brain regions involved in thermoregulation. Our results demonstrate an essential role of hypothalamic neurons in the regulation of Tb and metabolic rate during torpor and identify critical nodes of the torpor regulatory network.

  View details for DOI 10.1016/j.cub.2023.10.076

  View details for PubMedID 37992720

• Cell type specific focused ultrasound neuromodulation in preclinical models of sleep and psychiatric disorders. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Murphy, K. R., de Lecea, L. 2023

  View details for DOI 10.1038/s41386-023-01662-9

  View details for PubMedID 37463978

• A tool for monitoring cell type-specific focused ultrasound neuromodulation and control of chronic epilepsy. Proceedings of the National Academy of Sciences of the United States of America Murphy, K. R., Farrell, J. S., Gomez, J. L., Stedman, Q. G., Li, N., Leung, S. A., Good, C. H., Qiu, Z., Firouzi, K., Butts Pauly, K., Khuri-Yakub, B. P., Michaelides, M., Soltesz, I., de Lecea, L. 2022; 119 (46): e2206828119

  Abstract

  Focused ultrasound (FUS) is a powerful tool for noninvasive modulation of deep brain activity with promising therapeutic potential for refractory epilepsy; however, tools for examining FUS effects on specific cell types within the deep brain do not yet exist. Consequently, how cell types within heterogeneous networks can be modulated and whether parameters can be identified to bias these networks in the context of complex behaviors remains unknown. To address this, we developed a fiber Photometry Coupled focused Ultrasound System (PhoCUS) for simultaneously monitoring FUS effects on neural activity of subcortical genetically targeted cell types in freely behaving animals. We identified a parameter set that selectively increases activity of parvalbumin interneurons while suppressing excitatory neurons in the hippocampus. A net inhibitory effect localized to the hippocampus was further confirmed through whole brain metabolic imaging. Finally, these inhibitory selective parameters achieved significant spike suppression in the kainate model of chronic temporal lobe epilepsy, opening the door for future noninvasive therapies.

  View details for DOI 10.1073/pnas.2206828119

  View details for PubMedID 36343238