Biology subjects

Murphy, K. R.

Publications and source records attributed to Murphy, K. R..

7 recordsLinked to original sources

bioRxiv2025

Focused ultrasound to the bilateral thalamus causally modulates human cognitive attention in a frequency- and intensity-dependent manner

The centromedian nucleus of the thalamus (CMT) is a core arousal center with potential for enhancing cognitive attention. While emergent focused ultrasound can reach this area, the stimulation paradigms which may enhance function in humans remain unknown. Here we performed bilateral stimulation of the CMT using a novel ultrasound neuromodulation wearable device using 3 distinct pulse frequencies. We found that a brief 25Hz stimulation enhanced reaction time in a in a directed attention Oddball task for at least 40 minutes. Pre-post task electrocortical EEG revealed a correlation between reaction time and the prevalence of arousal related alpha and theta cortical activity. Examination of dose dependence revealed bidirectional modulation of arousal state, with lower intensities preferentially enhancing cognitive function. Pre- and post-MRI scans showed no neuroradiological changes due to stimulation. Collectively, these findings demonstrate that targeted LIFU stimulation of the CMT can safely enhance cognitive function in healthy individuals with carefully designed parameters.

neuroscience↗

bioRxiv2024

Energy Deficit is a Key Driver of Sleep Homeostasis

Sleep and feeding are vital homeostatic behaviors, and disruptions in either can result in substantial metabolic consequences. Distinct neuronal manipulations in Drosophila can dissociate sleep loss from subsequent homeostatic rebound, offering an optimal platform to examine the precise interplay between these fundamental behaviors. Here, we investigate concomitant changes in sleep and food intake in individual animals, as well as respiratory metabolic expenditure, that accompany behavioral and genetic manipulations that induce sleep loss in Drosophila melanogaster. We find that sleep disruptions resulting in energy deficit through increased metabolic expenditure and manifested as increased food intake were consistently followed by rebound sleep. In contrast, "soft" sleep loss, which does not induce rebound sleep, is not accompanied by increased metabolism and food intake. Our results demonstrate that homeostatic sleep rebound is linked to energy deficit accrued during sleep loss. Collectively, these findings support the notion that sleep functions to conserve energy and highlight the need to examine the effects of metabolic therapeutics on sleep.

neuroscience↗

bioRxiv2023

Brain-wide mapping of neuronal architecture controlling torpor

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 during torpor is controlled by the brain, the underlying neural circuits remain largely unknown. 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 found that Trpm2-positive neurons in the preoptic area and Vgat-positive neurons in the dorsal medial hypothalamus are activated during torpor. Genetic silencing shows 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 body temperature and metabolic rate during torpor and identify critical nodes of the torpor-regulatory network.

neuroscience↗

bioRxiv2020

Mitochondrial CaMKII causes metabolic reprogramming, energetic insufficiency, and dilated cardiomyopathy

Despite the clear association between myocardial injury, heart failure and depressed myocardial energetics, little is known about upstream signals responsible for remodeling myocardial metabolism after pathological stress. We found increased mitochondrial calmodulin kinase II (CaMKII) activation and left ventricular dilation in mice one week after myocardial infarction (MI) surgery. In contrast, mice with genetic mitochondrial CaMKII inhibition were protected from left ventricular dilation and dysfunction after MI. Mice with myocardial and mitochondrial CaMKII over-expression (mtCaMKII) had severe dilated cardiomyopathy and decreased ATP that caused elevated cytoplasmic resting (diastolic) Ca2+ concentration and reduced mechanical performance. We mapped a metabolic pathway that allowed us to rescue disease phenotypes in mtCaMKII mice, providing new insights into physiological and pathological metabolic consequences of CaMKII signaling in mitochondria. Our findings suggest myocardial dilation, a disease phenotype lacking specific therapies, can be prevented by targeted replacement of mitochondrial creatine kinase, or mitochondrial-targeted CaMKII inhibition.

molecular biology↗

bioRxiv2019

Neurofibromin regulates metabolic rate via neuronal mechanisms in Drosophila

Neurofibromatosis type 1 (NF1) is a genetic disorder predisposing patients to a range of features, the most characteristic of which include areas of abnormal skin pigmentation and benign tumors associated with peripheral nerves, termed neurofibromas. Less common, but more serious symptoms also include malignant peripheral nerve sheath tumors, other malignancies, and learning disabilities. The NF1 gene encodes neurofibromin, a large protein that functions as a negative regulator of Ras signaling and mediates pleiotropic cellular and organismal function. Recent evidence suggests NF1 may regulate metabolism, though the mechanisms are unknown. Here we show that the Drosophila ortholog of NF1, dNf1 regulates metabolic homeostasis in fruit flies by functioning within a discrete brain circuit. Loss of dNf1 increases metabolic rate and feeding, enhances starvation susceptibility, and decreases lipid stores while increasing lipid turnover rate. The increase in metabolic rate is independent of locomotor activity (grooming), and maps to a subset of neurons in the ventral nervous system. The feeding and metabolic rate effects are due to loss of dNf1 in the same set of neurons, suggesting that increased feeding may be a compensatory effect driven by the increase in metabolic rate and lipid turnover. Finally, we show that the Ras GAP-related domain of neurofibromin is required for normal metabolism, demonstrating that Ras signaling downstream of dNf1 mediates the metabolic effects. These data demonstrate that dNf1 regulates metabolic rate via neuronal mechanisms, suggest that cellular and systemic metabolic alterations may represent a pathophysiological mechanism in NF1, and provide a platform for investigating the cellular role of neurofibromin in metabolic homeostasis.

neuroscience↗

bioRxiv2019

CaMKII oxidation is a performance/disease trade-off in vertebrate evolution

Reactive oxygen species (ROS) contribute to health and disease. CaMKII is a widely expressed enzyme whose activation by oxidation of regulatory domain methionines (ox-CaMKII) contributes to cardiovascular disease, asthma, and cancer. Here we integrate comparative genomic and experimental data to show that CaMKII activation by ROS arose more than half-a-billion years ago on the vertebrate stem lineage where it constituted a bridge between ROS and increased intracellular Ca2+ release, exercise responsive gene transcription, and improved performance in skeletal muscle. These enhancements to fight-or-flight physiology were likely key in facilitating a well-evidenced shift in the behavioural ecology of our immediate chordate ancestors, and, in turn, the evolutionary success of vertebrates. Still, the ox-CaMKII innovation for augmenting performance must be considered a critical evolutionary trade-off, as it rendered us more susceptible to common and often fatal diseases linked to excessive ROS.

evolutionary biology↗

bioRxiv2019

Phospholipase D Transduces Force to TREK-1 Channels in a Biological Membrane

Rapid conversion of force into a biological signal enables living cells to respond to mechanical forces in their environment. The force is believed to initially affect the plasma membrane and then alter the behavior of membrane proteins. Phospholipase D2 (PLD2) is a mechanosensitive enzyme that is regulated by a structured membrane-lipid site comprised of cholesterol and saturated ganglioside (GM1). Here we show stretch activation of TWIK-related K+ channel (TREK-1) is mechanically evoked by PLD2 and spatial patterning involving ordered GM1 and 4,5- bisphosphate (PIP2) clusters. First, mechanical force deforms the ordered lipids, which lowers membrane cholesterol, disrupts the interaction of PLD2 with the GM1 lipids, and allows a complex of TREK-1 and PLD2 to associate with PIP2 clusters. The association with PIP2 activates the enzyme, which produces the second messenger phosphatidic acid (PA) that gates the channel. Co-expression of catalytically inactive PLD2 inhibits TREK-1 stretch currents in a biological membrane. Cellular uptake of cholesterol inhibits TREK-1 currents in culture and depletion of cholesterol from astrocytes releases TREK-1 from GM1 lipids in mouse brain. Depletion of the PLD2 ortholog in flies results in hypersensitivity to mechanical force. We conclude PLD2 mechanosensitivity combines with TREK-1 ion permeability to elicit a mechanically evoked response. SummaryShear thinning activates TREK-1 through a second messenger.

neuroscience↗