Faculty Bibliography

Seventy % of mammals copulate using repeated pelvic thrusting, while the transfer of sperm requires just a single intromission. Why did thrusting evolve to be the dominant form of sexual intercourse? In this study, we investigate how the rate of sexual pelvic thrusting changes with body size. By analyzing films of copulating mammals, from mice Mus musculus to elephants Elephantidae, we find that bigger animals thrust slower. The rate of pelvic thrusting decreases from 6 Hz for the pocket mouse Pergonathus to 1.3-1.8 Hz for humans to an absence of thrusting for the rhino Rhinocerotidae and elephant Elephantidae families. To understand this dependence on body size, we consider the spring-like behavior of the legs, which is associated with the elasticity of the body's muscles, tendons, and ligaments. For both running and thrusting, a maximum amplitude and great energy savings can be achieved if the system is oscillated at its resonant or natural frequency. Resonant frequencies, as measured through previous studies of running in dogs Canis familiaris and horses Equus ferus caballus, show good agreement with sexual thrusting frequencies. Running and sexual thrusting have nothing in common from a behavioral perspective, but from a physical perspective, they are both constrained by the same musculoskeletal systems, and both take advantage of resonance. Our findings may provide improved treatments for human sexual dysfunction as well as improving breeding strategies for domestic mammals.

Widespread hyperalgesia, characterized by pain sensitivity beyond the primary pain site, is a common yet under-characterized feature across chronic pain conditions, including chronic pancreatitis (CP). In this exploratory study, we identified a candidate neural biosignature of widespread hyperalgesia using high-density electroencephalography (EEG) in patients with chronic low back pain (cLBP). Specifically, stimulus-evoked delta, theta, and alpha oscillatory activity in the bilateral medial orbitofrontal cortex (mOFC) differentiated cLBP patients with widespread hyperalgesia from healthy controls. To examine cross-condition generalizability and advance predictive biomarker development for CP, we applied this mOFC-derived EEG biosignature to an independent cohort of patients with CP. The biosignature distinguished CP patients with widespread hyperalgesia and predicted individual treatment responses to peripherally targeted endoscopic therapy. These preliminary findings provide early support for a shared cortical signature of central sensitization across pain conditions and offer translational potential for developing EEG-based predictive tools for treatment response in CP.

OBJECTIVE:To evaluate urinalysis testing patterns within the Veterans Health Administration (VHA), estimate the proportion and likelihood of patients who completed a urinalysis to have microscopic hematuria (MH), and explore how urinalysis testing patterns may influence MH detection. METHODS:This was a retrospective cross-sectional study using VHA data. We identified adult patients without a known urologic cancer history who had at least 1 outpatient visit at any VHA site and at least 1 interpretable urinalysis performed in 2015. The factors associated with the number or urinalyses performed on each patient and associations with the presence of MH were investigated. RESULTS:Among 5,719,966 adults, 39% completed a urinalysis. Variation in the proportion of patients who completed urinalyses was highest by age, among patients with hypertension and diabetes, and by region. Of patients who underwent urinalysis and had no prior genitourinary cancer history, 54% did not have an interpretable urinalysis result. Among patients with at least one interpretable microscopic urinalysis, 37% had MH. This was more common among older patients, females, current smokers, and patients with more comorbidities. Variation in the likelihood of patients having MH remained after adjusting for multiple factors and when contextualized by urinalysis completion and interpretability patterns. CONCLUSION/CONCLUSIONS:The number of urinalyses performed in the VHA system is remarkably high. Detection of MH is influenced by the frequency of urinalysis testing and interpretability of results. The presence and detection of MH varies by factors which should be considered when adjudicating the need for further evaluation of MH.

Beyond the vast array of functional roles attributed to serotonin (5-HT) in the brain, changes in 5-HT levels have been shown to accompany changes in behavioral states, including WAKE, NREM, and REM sleep. Whether 5-HT dynamics at shorter time scales can be seen to delineate substates within these larger brain states remains an open question. Here, we performed simultaneous recordings of extracellular 5-HT using a recently developed G-Protein-Coupled Receptor-Activation-Based 5-HT sensor (GRAB5-HT3.0) and local field potential in the hippocampal CA1 of mice, which revealed the presence of prominent ultraslow (<0.05 Hz) 5-HT oscillations both during NREM and WAKE states. Interestingly, the phase of these ultraslow 5-HT oscillations was found to distinguish substates both within and across larger behavioral states. Hippocampal ripples occurred preferentially on the falling phase of ultraslow 5-HT oscillations during both NREM and WAKE, with higher power ripples concentrating near the peak specifically during NREM. By contrast, hippocampal-cortical coherence was strongest, and microarousals and intracranial EMG peaks were most prevalent during the rising phase in both wake and NREM. Overall, ultraslow 5-HT oscillations delineate substates within the larger behavioral states of NREM and WAKE, thus potentially temporally segregating internal memory consolidation processes from arousal-related functions.

Sharp wave-ripples (SPW-Rs) are critical to hippocampal function, and the same is true of gonadal steroids, but the interactions are unclear. We find that surgical removal of the gonads greatly reduces SPW rates in both sexes. Ripples are greatly reduced also. Testosterone treatment rescues SPW and ripple rates in males, and 17β-estradiol restores SPW rates in females. We also find that male SPW rates are higher than females but have less power. Furthermore, in intact females, SPW rates fluctuate with the stage of the ovarian cycle. These data demonstrate that hippocampal SPWs are significantly affected by gonadal removal, testosterone, and 17β-estradiol. In addition, there are sex differences. The data are consistent with past demonstrations that testosterone and 17β-estradiol play central roles in hippocampus and significantly expand the views of hormone action and SPW-Rs.

Precision-targeted ultrasonic neuromodulation offers immense potential for studying brain function and treating neurological diseases. Yet, its application has been limited by challenges in achieving precise spatio-temporal control and monitoring of ultrasound effects on brain circuits. Here we show that transcranial ultrasound elicits direct and highly focal responses, which can be dynamically steered at spatio-temporal scales relevant for neural function. Furthermore, holographic transcranial ultrasound stimulation allows direct control of the stimulated volume and actively modulates local and mid-range network projections, effectively lowering the activation threshold by an order of magnitude. To better understand this previously unexplored excitability regime not fully explained by the conventional pressure-frequency dyad, we developed a dual modelling framework, where both an empirical and a mechanistic model were constructed to capture the intricacies of holographic transcranial ultrasound stimulation. These models achieve qualitative agreement with our experimental results, suggesting that these findings are predominantly driven by putative network interactions. Our results bring insight on the complex interaction mechanisms of ultrasound with neural tissue and highlight its potential for the noninvasive interfacing of distributed brain networks.

Most offspring are born helpless, requiring intense caregiving from parents especially during the first few days of neonatal life. For many species, infant cries are a primary signal used by parents to provide caregiving. Previously we and others documented how maternal left auditory cortex rapidly becomes sensitized to pup calls over hours of parental experience, enabled by oxytocin. The speed and robustness of this maternal plasticity suggests cortical pre-tuning or initial bias for pup call stimulus features. Here we examine the circuit basis of left-lateralized tuning to vocalization features with whole-cell recordings in brain slices. We found that layer 2/3 pyramidal cells of female left auditory cortex show selective suppression of inhibitory inputs with repeated stimulation at the fundamental pup call rate (inter-stimulus interval ∼150 msec) in pup-naïve females and expanded with maternal experience. However, optogenetic stimulation of cortical inhibitory cells showed that inputs from somatostatin-positive and oxytocin-receptor-expressing interneurons were less suppressed at these rates. This suggested that disynaptic inhibition rather than monosynaptic depression was a major mechanism underlying pre-tuning of cortical excitatory neurons, confirmed with simulations. Thus cortical interneuron specializations can augment neuroplasticity mechanisms to ensure fast appropriate caregiving in response to infant cries.

Social behaviors, including parental care, mating, and fighting, all depend on the hormonal milieu of an organism. Decades of work highlighted estrogen as a key hormonal controller of social behaviors, exerting its influence primarily through binding to estrogen receptor alpha (ERα). Recent technological advances in chemogenetics, optogenetics, gene editing, and transgenic model organisms have allowed for a detailed understanding of the neuronal subpopulations and circuits for estrogen action across Esr1-expressing interconnected brain regions. Focusing on rodent studies, in this review we examine classical and contemporary research demonstrating the multifaceted role of estrogen and ERα in regulating social behaviors in a sex-specific and context-dependent manner. We highlight gaps in knowledge, particularly a missing link in the molecular cascade that allows estrogen to exert such a diverse behavioral repertoire through the coordination of gene expression changes. Understanding the molecular and cellular basis of ERα's action in social behaviors provides insights into the broader mechanisms of hormone-driven behavior modulation across the lifespan.