Biology subjects

Cheadle, L. M.

Publications and source records attributed to Cheadle, L. M..

3 recordsLinked to original sources

bioRxiv2026

Deciphering epileptogenic and activity-dependent gene programs in the human brain

Neuronal activity is fundamental to brain function, yet chronically elevated activity underlies neurological disorders such as drug-resistant epilepsy (DRE). In animal models, activity induces defined transcriptional programs within activated neurons; however, the nature, cellular specificity, and pathological relevance of such programs in the human brain remain poorly understood. Here, we apply single-nucleus and spatial transcriptomics to epileptogenic, non-epileptogenic, and intraoperatively stimulated non-epileptogenic cortical tissue obtained from individuals with DRE. Across 26 cell types profiled, glutamatergic neurons projecting from cortical layers 2/3, 5, and 6 to intratelencephalic targets exhibit pronounced sensitivity to the epileptogenic microenvironment, inducing shared immediate-early genes alongside cell-type-specific programs linked to synaptic remodeling and cellular stress. Approximately one-third of transcripts enriched in the epileptogenic microenvironment were also induced by acute stimulation, suggesting that a fraction of epilepsy-associated gene expression reflects conserved responses to heightened activity rather than disease-specific programs. While transcripts induced by both epileptogenic and acute activity converged upon immediate-early genes and heat-shock proteins, only acute stimulation triggered a rapid, multicellular induction of transcripts involved in mitochondrial ATP synthesis. This divergence suggests that neurons within epileptogenic cortex may be unable to mount appropriate metabolic adaptations to sustained energetic demands. In parallel, both microglia and circulating CD14+ monocytes exhibit signs of immune activation in epilepsy, suggesting myeloid-driven inflammatory rewiring that extends beyond the brain. Together, these findings illuminate human activity-dependent gene programs and reveal signatures of neuronal vulnerability and inflammation in DRE.

neuroscience↗

bioRxiv2024

A brain-body feedback loop driving HPA-axis dysfunction in breast cancer

Breast cancer patients often exhibit disrupted circadian rhythms in circulating glucocorticoids (GCs), such as cortisol. This disruption correlates with reduced quality of life and higher cancer mortality1-3. The exact cause of this phenomenon -- whether due to treatments, stress, age, co-morbidities, lifestyle factors, or the cancer itself remains unclear. Here, we demonstrate that primary breast cancer alone blunts host GC rhythms by disinhibiting neurons in the hypothalamus, and that circadian phase-specific neuromodulation of these neurons can attenuate tumor growth by enhancing anti-tumor immunity. We find that mice with mammary tumors exhibit blunted GC rhythms before tumors are palpable, alongside increased activity in paraventricular hypothalamic neurons expressing corticotropin-releasing hormone (i.e., PVNCRH neurons). Tumor-bearing mice have fewer inhibitory synapses contacting PVNCRH neurons and reduced miniature inhibitory post-synaptic current (mIPSC) frequency, leading to net excitation. Tumor-bearing mice experience impaired negative feedback on GC production, but adrenal and pituitary gland functions are largely unaffected, indicating that alterations in PVNCRH neuronal activity are likely a primary cause of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in breast cancer. Using chemogenetics (hM3Dq) to stimulate PVNCRH neurons at different circadian phases, we show that stimulation just before the light-to-dark transition restores normal GC rhythms and reduces tumor progression. These mice have significantly more effector T cells (CD8+) within the tumor than non-stimulated controls, and the anti-tumor effect of PVNCRH neuronal stimulation is absent in mice lacking CD8+ T cells. Our findings demonstrate that breast cancer distally regulates neurons in the hypothalamus that control output of the HPA axis and provide evidence that therapeutic targeting of these neurons could mitigate tumor progression.

neuroscience↗

bioRxiv2024

The cytokine receptor Fn14 is a molecular brake on neuronal activity that mediates circadian function in vivo

To survive, organisms must adapt to a staggering diversity of environmental signals, ranging from sensory information to pathogenic infection, across the lifespan. At the same time, organisms intrinsically generate biological oscillations, such as circadian rhythms, without input from the environment. While the nervous system is well-suited to integrate extrinsic and intrinsic cues, how the brain balances these influences to shape biological function system-wide is not well understood at the molecular level. Here, we demonstrate that the cytokine receptor Fn14, previously identified as a mediator of sensory experience-dependent synaptic refinement during brain development, regulates neuronal activity and function in adult mice in a time-of-day-dependent manner. We show that a subset of excitatory pyramidal (PYR) neurons in the CA1 subregion of the hippocampus increase Fn14 expression when neuronal activity is heightened. Once expressed, Fn14 constrains the activity of these same PYR neurons, suggesting that Fn14 operates as a molecular brake on neuronal activity. Strikingly, differences in PYR neuron activity between mice lacking or expressing Fn14 were most robust at daily transitions between light and dark, and genetic ablation of Fn14 caused aberrations in circadian rhythms, sleep-wake states, and sensory-cued and spatial memory. At the cellular level, microglia contacted fewer, but larger, excitatory synapses in CA1 in the absence of Fn14, suggesting that these brain-resident immune cells may dampen neuronal activity by modifying synaptic inputs onto PYR neurons. Finally, mice lacking Fn14 exhibited heightened susceptibility to chemically induced seizures, implicating Fn14 in disorders characterized by hyperexcitation, such as epilepsy. Altogether, these findings reveal that cytokine receptors that mediates inflammation in the periphery, such as Fn14, can also play major roles in healthy neurological function in the adult brain downstream of both extrinsic and intrinsic cues. HighlightsO_LINeuronal activity induces Fn14 expression in pyramidal neurons of the hippocampus C_LIO_LIFn14 constrains neuronal activity near daily transitions between light and dark C_LIO_LILoss of Fn14 lengthens the endogenous circadian period and disrupts sleep-wake states and memory C_LIO_LIMicroglia contact excitatory synapses in an Fn14-dependent manner C_LI

neuroscience↗