Faculty Bibliography

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.

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.

Around 40% of the US population and 1 in 6 individuals worldwide have obesity, with the incidence surging globally^1,2. Various dietary interventions, including carbohydrate, fat and, more recently, amino acid restriction, have been explored to combat this epidemic^3-6. Here we investigated the impact of removing individual amino acids on the weight profiles of mice. We show that conditional cysteine restriction resulted in the most substantial weight loss when compared to essential amino acid restriction, amounting to 30% within 1 week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, partly explaining the phenotype^7-9. Notably, we observed lower levels of tissue coenzyme A (CoA), which has been considered to be extremely stable¹⁰, resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective tricarboxylic acid cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen-rich compounds and amino acids. In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism and stress signalling compared with other amino acid restrictions. These findings suggest strategies for addressing a range of metabolic diseases and the growing obesity crisis.

Ultra low-field (ULF) MRI is an accessible neuroimaging modality that can bridge healthcare disparities and advance population-level brain health research. However, the inherently low signal-to-noise ratio of ULF-MRI often necessitates reductions in spatial resolution and, combined with the field-dependency of MRI contrast, challenges the accurate extraction of clinically relevant brain morphology. We evaluate the current state of ULF-MRI brain volumetry utilizing techniques for enhancing spatial resolution and leveraging recent advancements in brain segmentation. This is based on the agreement between ULF and corresponding high-field (HF) MRI brain volumes, and test-retest repeatability for multiple ULF scans. In this study, we find that accurate brain volumes can be measured from ULF-MRIs when combining orthogonal imaging directions for T₂-weighted images to form a higher resolution image volume. We also demonstrate that not all orthogonal imaging directions contribute equally to volumetric accuracy and provide a recommended scan protocol given the constraints of the current technology.

BACKGROUND:Complex Regional Pain Syndrome (CRPS) is a challenging and often disabling condition marked by persistent pain, most commonly in a limb following injury or surgery. It presents with a wide array of symptoms, including intense pain, swelling, alterations in skin color and temperature, motor dysfunction, and trophic changes such as skin and tissue atrophy. While the precise cause of CRPS is not fully understood, it is thought to stem from abnormal nervous system activity, leading to heightened pain sensitivity and inflammatory responses. A thorough understanding of CRPS is essential for accurate diagnosis, effective treatment, and enhancing patients' quality of life.Although attempts have been made to distinguish between acute and chronic CRPS, there are currently no established diagnostic criteria specific to chronic CRPS in medical literature. OBJECTIVE:This ASIPP guidance document offers updated, evidence-based recommendations for the diagnosis and management of Chronic Complex Regional Pain Syndrome (CRPS), with a primary focus on introducing novel, time-based diagnostic criteria specific to the chronic phase. These proposed criteria address significant gaps in the current literature, where existing standards, such as the Budapest Criteria, do not sufficiently differentiate between the acute and chronic stages of the condition. METHODS:An expert panel convened by the American Society of Interventional Pain Physicians (ASIPP) conducted a comprehensive literature review and employed a structured consensus process to develop recommendations. Acknowledging that the clinical and pathological characteristics of CRPS change significantly beyond 12 months, the panel proposed chronic-specific diagnostic criteria based on disease duration, clinical history, physical examination findings, and optional diagnostic tests. These draft criteria were refined through multidisciplinary input and expert consensus. RESULTS:The diagnostic framework for chronic CRPS consists of four key components:General Criteria - Require fulfillment of the Budapest Criteria for at least 12 months, continued recognition of CRPS as a diagnosis of exclusion, and differentiation from generalized nociplastic pain syndromes.History-Based Criteria - Mandate the presence of at least three out of five specific historical features.Physical Examination Criteria - Include asymmetric limb findings, sensory disturbances, and musculoskeletal changes.Optional Diagnostic Testing - May involve assessments such as intraepidermal nerve fiber density (IENFD) and imaging evidence of regional bone demineralization.This framework builds upon the Budapest Criteria by incorporating time-dependent features of chronic CRPS, including musculoskeletal dystrophy, neurogenic inflammation, and sympathetic dysfunction. Emerging objective tools-such as quantitative sensory testing (QST), skin biopsy for IENFD, functional MRI, and serum biomarkers of neuroinflammation-may further support diagnosis in complex or uncertain cases.Treatment recommendations highlight a multimodal strategy that integrates physical rehabilitation, pharmacologic management of neuropathic pain, sympathetic nerve blocks, and advanced neuromodulation. Emphasis is placed on individualized care pathways tailored to disease stage and patient-specific characteristics. CONCLUSIONS:This article presents the first structured, time-sensitive diagnostic criteria for chronic CRPS, aimed at improving diagnostic accuracy and informing treatment strategies. Adoption of these criteria may enhance clinical outcomes and promote further research into the natural history and pathophysiology of CRPS progression.

Astrocytes, the bushy, star-shaped glial cells of the brain and spinal cord, support the proper development and function of many cells in the central nervous system. In response to disease or injury they transform, adopting varied morphologies, molecular signatures, and functions-this state of transformation is known as reactivity. For over a century, the reactivity of astrocytes has been recognized, but it is the recent surge in technological innovation that has shed light on the diverse nature of this reactivity. It is this developing understanding of the heterogeneity of reactive astrocytes across disease-specific contexts and a spatiotemporal gradient that now excites the astrocyte field. In this review, we discuss the current understanding of reactive astrocyte heterogeneity, highlight the biological implications of this heterogeneity, and propose future approaches to aid in fully understanding the heterogeneity of reactive astrocytes.

In nearly all mammalian species, newborn pups are weak and vulnerable, relying heavily on care and protection from parents for survival. Thus, developmentally hardwired neural circuits are in place to ensure the timely expression of parental behaviors. Furthermore, several neurochemical systems, including estrogen, oxytocin, and dopamine, facilitate the emergence and expression of parental behaviors. However, stress can adversely affect these systems, impairing parental behaviors. In this review, we will summarize our current knowledge regarding the impact of stress on pup-directed behavior circuits that lead to infant neglect, abuse, and, in extreme cases, killing. We will discuss various stressors that influence parental behaviors at different life stages and how stress induces changes in the neurochemical systems that support parental care, ultimately leading to its poor performance.

Many chemotherapeutic agents impair cancer growth by inducing DNA damage. The impact of these agents on mutagenesis in normal cells, including sperm, is largely unknown. Here, we applied high-fidelity duplex sequencing to 94 samples from 36 individuals exposed to diverse chemotherapies and 32 controls. We found that many of the sperm samples from men exposed to chemotherapy, the mutation burden was elevated as compared to controls and the expected burden based on trio studies, with one subject having >10-fold increase over expected for age. Saliva from this same individual also had a markedly higher mutation burden. We then validated this finding using other tissues, also finding an increased mutation burden in the blood and liver of many subjects exposed to chemotherapy as compared to unexposed controls. Similarly, mice treated with three cycles of cisplatin had an increased mutation burden in sperm but also in the liver, and hematopoietic progenitor cells. These results suggest an association between cancer therapies and mutation burden, with implications for counseling cancer patients considering banking sperm prior to therapy and for cancer survivors considering the tradeoffs of using banked sperm as compared to conceiving naturally.

Alston's singing mice (Scotinomys teguina) are highly vocal Central American rodents that produce structured "songs" (duration: 5-10 s),¹

Immunotherapies have revolutionized cancer care for many tumor types, but their potential long-term cognitive impacts are incompletely understood. Here, we demonstrated in mouse models that chimeric antigen receptor (CAR) T cell therapy for both central nervous system (CNS) and non-CNS cancers impaired cognitive function and induced a persistent CNS immune response characterized by white matter microglial reactivity, microglial chemokine expression, and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis were disrupted. Single-nucleus sequencing studies of human frontal lobe from patients with or without previous CAR T cell therapy for brainstem tumors confirmed reactive states of microglia and oligodendrocytes following treatment. In mice, transient microglial depletion or CCR3 chemokine receptor blockade rescued oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function following CAR T cell therapy. Taken together, these findings illustrate targetable neural-immune mechanisms underlying immunotherapy-related cognitive impairment.