Biology subjects

Campbell, J. N.

Publications and source records attributed to Campbell, J. N..

12 recordsLinked to original sources

bioRxiv2026

PKCδ mediates high-fat diet-induced increased tonic GABAA receptor current in cardiac vagal motor neurons in the DMV

Consumption of high fat diet (HFD) is linked to reduced cardiac vagal motor output, a main contributor to progression of cardiovascular disease. HFD for 15 days increases extrasynaptic or tonic gamma aminobutyric acid (GABA) current in cardiac projecting neurons in the dorsal motor nucleus of the vagus (CVNDMV), which contributes to dampening cardiac parasympathetic output. However, the mechanism underlying this increased inhibition is unknown. Here, we hypothesize that increased activity of protein kinase C {delta} isoform (PKC{delta}) enhances tonic GABA current in CVNDMV after HFD. Whole-cell patch-clamp recording of retrogradely labeled CVNDMV demonstrated that pan inhibition of PKC activity with GFX, and isoform specific inhibition of PKC{delta} with rottlerin normalize 15-day HFD-induced increases in tonic GABA current, suggesting that PKC{delta} mediates enhanced tonic inhibition. This effect persisted in the presence of dynasore, a clathrin-mediated endocytosis blocker, indicating that the normalization effect of PKC{delta} inhibition on tonic current in HFD is likely independent of clathrin-mediated endocytosis. Furthermore, no differences in PKC{delta} mRNA or protein expression were observed between NFD and HFD, suggesting a post-translational mechanism underpinning increased tonic GABA current after 15 days of HFD. Altogether, this study provides evidence that HFD-induces increased PKC{delta} activity, but not expression, leading to increased tonic GABAergic inhibition in CVNDMV. This increase PKC{delta} activity could explain the cardiac vagal motor output dampening in CVD and be developed into treatments targeting PKC{delta} for CVD.

neuroscience↗

bioRxiv2025

BDNF receptor balance gates AgRP-to-PVH fiber density and stimulation evoked feeding across caloric states

Agouti-related peptide (AgRP) neurons show opposite pairings of anatomy and output across caloric states. In mice, 24-h caloric restriction (CR) increases AgRP-to-paraventricular hypothalamus (PVH) fiber density without increasing stimulation-evoked feeding, whereas 5-day high-fat diet (HFD) reduces fiber density yet increases stimulation-evoked feeding, including during PVH terminal stimulation. PVH Bdnf rises acutely under both challenges and remains elevated with sustained HFD. Receptor expression shifts with state: in AgRP neurons, CR increases TrkB transcripts, whereas HFD increases p75NTR transcripts. AgRP-specific deletions define directional roles: TrkB loss reduces AgRP-to-PVH fiber density and yields larger stimulation-evoked feeding, whereas p75NTR loss increases fiber density and limits responses. Thus, a TrkB/p75NTR balance in AgRP neurons provides rheostat-like control over the relationship between circuit structure and stimulation-evoked feeding across caloric states, identifying TrkB and p75NTR as tractable molecular handles for probing state-dependent control of AgRP circuit output. HighlightsO_LICR increases AgRP[->]PVH fibers without boosting evoked feeding C_LIO_LIHFD retracts AgRP[->]PVH fibers and amplifies evoked feeding C_LIO_LIPVH Bdnf rises acutely in response to CR or HFD; elevation persists only with HFD C_LIO_LIAgRP TrkB{uparrow} with CR, p75NTR{uparrow} with HFD; AgRP specific knockouts of these receptors define floor and ceiling PVH axon innervation/evoked feeding C_LI

neuroscience↗

bioRxiv2025

Co-Conservation of Synaptic Gene Expression and Circuitry in Collicular Neurons

The superior colliculus (SC), a midbrain sensorimotor hub, is anatomically and functionally similar across vertebrates, but how its cell types have evolved is unclear. Using single-nucleus transcriptomics, we compared the SCs molecular and cellular organization in mice, tree shrews, and humans. Despite over 96 million years of evolutionary divergence, we identified [~]30 consensus neuronal subtypes, including Cbln2+ neurons that form the SC-pulvinar circuit in mice and tree shrews. Synapse-related genes were among the most conserved, unlike neocortex, suggesting co-conservation of synaptic genes and circuitry. In contrast, cilia-related genes diverged significantly across species, highlighting the potential importance of the neuronal primary cilium in SC evolution. Additionally, we identified a novel inhibitory SC neuron in tree shrews and humans but not mice. Our findings reveal that the SC has evolved by conserving neuron subtypes, synaptic genes, and circuitry, while diversifying ciliary gene expression and an inhibitory neuron subtype.

neuroscience↗

bioRxiv2024

A Brain Reward Circuit Inhibited By Next-Generation Weight Loss Drugs

Glucagon-like peptide-1 receptor agonists (GLP1RAs) effectively reduce body weight and improve metabolic outcomes, yet established peptide-based therapies require injections and complex manufacturing. Small-molecule GLP1RAs promise oral bioavailability and scalable manufacturing, but their selective binding to human versus rodent receptors has limited mechanistic studies. Here, we developed humanized GLP1R mouse models to investigate how small-molecule GLP1RAs influence feeding behavior. This approach revealed that these compounds regulate both homeostatic and hedonic feeding through parallel neural circuits. Beyond engaging canonical hypothalamic and hindbrain networks that control metabolic homeostasis, GLP1RAs recruit a discrete population of Glp1r-expressing neurons in the central amygdala, which selectively suppress the consumption of palatable foods by reducing dopamine release in the nucleus accumbens. Stimulating these central amygdalar neurons curtail hedonic feeding, whereas targeted deletion of the receptor in this cell population specifically diminishes the anorectic efficacy of GLP1RAs for reward-driven intake. These findings reveal a dedicated neural circuit through which small molecule GLP1RAs modulate reward processing, suggesting broad therapeutic potential in conditions of dysregulated dopamine signaling including substance use disorder and binge eating.

neuroscience↗

bioRxiv2024

The ambiguity of "hybrid swarm": inconsistent definitions and applications in existing research

1Hybridization is common in wild taxa and often increases in frequency following anthropogenic disturbance to an environment. Next-generation sequencing techniques make genomic analysis of a large number of individuals feasible, vastly improving the analysis for and promoting a greater frequency of studies on hybridization. However, terminology surrounding hybridization can be inconsistent; in particular, the term "hybrid swarm" has been used extensively in the literature but lacks a consistent definition. In this paper, we conducted a comprehensive review of the literature that uses the term "hybrid swarm" in reference to hybridization between taxa and challenged putative definitions of the term. We found that the term "hybrid swarm" is used in a variety of contexts, including some contradictory to other literature, and that there is little consensus on what constitutes a hybrid swarm in terms of hybrid outcomes, frequency relative to disturbances, or duration of existence. We dissuade researchers from use of the term "hybrid swarm" and instead suggest more specific and clear terminology to describe aspects of hybridization. Consequently, we hope that this paper promotes consensus surrounding hybridization terminology and improves the quality of future research on hybridization.

evolutionary biology↗

bioRxiv2024

Test of a conservation intervention highlights temporal variability in hybridization dynamics in Catostomus fishes

Non-native species are a leading threat to fish biodiversity. They pose risks to native populations through human-mediated introductions resulting in hybridization events, which could result in demographic or genetic swamping. Catostomus fishes in the Upper Colorado River Basin are an example of this. Extensive hybridization occurs between non-native white suckers (C. commersonii ) and native flannelmouth and bluehead suckers (C. latipinnis and C. discobolus). This system provides a suitable model for using genomic analyses to test the efficacy of an intervention to reduce the abundance of non-native species and production of hybrid offspring. This study implemented a Resistance Board Weir (RBW) as a fish barrier across Roubideau Creek, a tributary of the Gunnison River in Colorado (USA), to restrict non-native sucker participation in spawning events. Conducted over four years, the study gathered genomic data from larval fish samples, pre- and post-implementation of the RBW. We used genomic data to determine the efficacy of a RBW at limiting non-native and hybridized sucker larval production. We found no significant effect of the weir on the proportion of white sucker ancestry in larval fish across the four years of the study, which included three years of weir usage when access was successfully controlled for variable amounts of time. Overall, this work provides insight into the efficacy of a resistance board weir as a management tool for non-native suckers, and highlights interannual variability. This work contributes valuable information for policy and fisheries management in Colorado.

evolutionary biology↗

bioRxiv2024

Sarm1-Dependent Metabolic Reprogramming of Schwann Cells Following Nerve Injury

Schwann cells (SCs) transition into a Repair state after peripheral nerve injury; however, the early SC injury response preceding this transition remains poorly understood. We demonstrate that Sarm1, a key regulator of axon degeneration, is expressed and upregulated in SCs after nerve injury. Cell-type-specific Sarm1 knockout SCs exhibit enhanced axon protection in vitro, and SC- and glia-specific Sarm1 deletion confers axon protection in mouse sciatic nerve and Drosophila wing injury models. Single-nucleus RNA sequencing revealed that Sarm1-deficient SCs are enriched in a distinct cluster expressing genes with developmental roles in axon and myelin protection, with increased oxidative phosphorylation gene expression across all injured SC states. We propose that Sarm1 gates the transition from a Protection-Associated Schwann Cell (PASC) state to a Repair SC state, establishing Sarm1 as a multi-functional regulator with implications for peripheral neuropathies and neurodegenerative diseases.

neuroscience↗

bioRxiv2023

Molecular Disambiguation of Heart Rate Control by the Nucleus Ambiguus

The nucleus ambiguus (nAmb) provides parasympathetic control of cardiorespiratory functions as well as motor control of the upper airways and esophagus. A subset of nAmb neurons innervates the heart through the vagus nerve to control cardiac function at rest and during key autonomic reflexes such as the mammalian diving reflex. Yet, how these cardiovagal nAmb neurons differ from other nAmb neurons in the adult brain remains unclear. We therefore classified adult mouse nAmb neurons molecularly, anatomically, and functionally. First, our integrated analysis of single-nucleus RNA-sequencing data predicted multiple molecular subtypes of nAmb neurons. Mapping the axon projections of one nAmb neuron subtype, Npy2r-expressing nAmb neurons, showed that they innervate cardiac ganglia but not the upper airways or esophagus. Chemogenetically stimulating Npy2r+ nAmb neurons robustly decreased heart rate through peripheral muscarinic acetylcholine receptors. Finally, Npy2r+ nAmb neurons are activated during voluntary underwater diving, consistent with a cardiovagal function for this nAmb subtype. These results together reveal the molecular organization of nAmb neurons and its control of heart rate.

neuroscience↗

bioRxiv2023

Molecular organization of autonomic, respiratory, and spinally-projecting neurons in the mouse ventrolateral medulla

The ventrolateral medulla (VLM) is a crucial region in the brain for visceral and somatic control. It also serves as a significant source of synaptic input to the spinal cord. Experimental studies have shown that gene expression in individual VLM neurons is predictive of their function. However, the organizing principles of the VLM have remained uncertain. This study aimed to create a comprehensive dataset of VLM cells using single-cell RNA sequencing. The dataset was enriched with targeted sequencing of spinally-projecting and adrenergic/noradrenergic VLM neurons. Based on differentially expressed genes, the resulting dataset of 114,805 VLM cells identifies 23 subtypes of neurons, excluding those in the inferior olive, and 5 subtypes of astrocytes. Spinally-projecting neurons were found to be abundant in 7 subtypes of neurons, which were validated through in-situ hybridization. These subtypes included adrenergic/noradrenergic neurons, serotonergic neurons, and neurons expressing gene markers associated with pre-motor neurons in the ventromedial medulla. Further analysis of adrenergic/noradrenergic neurons and serotonergic neurons identified 9 and 6 subtypes, respectively, within each class of monoaminergic neurons. Marker genes that identify the neural network responsible for breathing were concentrated in 2 subtypes of neurons, delineated from each other by markers for excitatory and inhibitory neurons. These datasets are available for public download and for analysis with a user-friendly interface. Collectively, this study provides a fine-scale molecular identification of cells in the VLM, forming the foundation for a better understanding of the VLMs role in vital functions and motor control.

neuroscience↗

bioRxiv2023

Dorsal Motor Vagal Neurons Can Elicit Bradycardia and Reduce Anxiety-Like Behavior

Cardiovagal neurons (CVNs) innervate cardiac ganglia through the vagus nerve to control cardiac function. Although the cardioinhibitory role of CVNs in nucleus ambiguus (CVNNA) is well established, the nature and functionality of CVNs in dorsal motor nucleus of the vagus (CVNDMV) is less clear. We therefore aimed to characterize CVNDMV anatomically, physiologically, and functionally. Optogenetically activating cholinergic DMV neurons resulted in robust bradycardia through peripheral muscarinic (parasympathetic) and nicotinic (ganglionic) acetylcholine receptors, but not beta-1-adrenergic (sympathetic) receptors. Retrograde tracing from the cardiac fat pad labeled CVNNA and CVNDMV through the vagus nerve. Using whole cell patch clamp, CVNDMV demonstrated greater hyperexcitability and spontaneous action potential firing ex vivo despite similar resting membrane potentials, compared to CVNNA. Chemogenetically activating DMV also caused significant bradycardia with a correlated reduction in anxiety-like behavior. Thus, DMV contains uniquely hyperexcitable CVNs capable of cardioinhibition and robust anxiolysis.

neuroscience↗

bioRxiv2023

Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety

Liraglutide and other agonists of the glucagon-like peptide 1 receptor (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. One potential mechanism is by activating neurons which inhibit hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc). To identify these afferents, we developed a method combining rabies-based connectomics with single-nuclei transcriptomics. Applying this method to AgRP neurons predicted at least 21 afferent subtypes in the mouse mediobasal and paraventricular hypothalamus. Among these are Trh+ Arc neurons (TrhArc), inhibitory neurons which express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TrhArc neurons inhibits AgRP neurons and feeding in an AgRP neuron-dependent manner. Silencing TrhArc neurons causes over-eating and weight gain and attenuates liraglutides effect on body weight. Our results demonstrate a widely applicable method for molecular connectomics, comprehensively identify local inputs to AgRP neurons, and reveal a circuit through which GLP-1RAs suppress appetite.

neuroscience↗

bioRxiv2023

A leptin-responsive hypothalamic circuit inputs to the circadian feeding network

Salient cues, such as the rising sun or the availability of food, play a crucial role in entraining biological clocks, allowing for effective behavioral adaptation and ultimately, survival. While the light-dependent entrainment of the central circadian pacemaker (suprachiasmatic nucleus, SCN) is relatively well defined, the molecular and neural mechanisms underlying entrainment associated with food availability remains elusive. Using single nucleus RNA sequencing during scheduled feeding (SF), we identified a leptin receptor (LepR) expressing neuron population in the dorsomedial hypothalamus (DMH) that upregulates circadian entrainment genes and exhibits rhythmic calcium activity prior to an anticipated meal. We found that disrupting DMHLepR neuron activity had a profound impact on both molecular and behavioral food entrainment. Specifically, silencing DMHLepR neurons, mis-timed exogenous leptin administration, or mis-timed chemogenetic stimulation of these neurons all interfered with the development of food entrainment. In a state of energy abundance, repetitive activation of DMHLepR neurons led to the partitioning of a secondary bout of circadian locomotor activity that was in phase with the stimulation and dependent on an intact SCN. Lastly, we discovered that a subpopulation of DMHLepR neurons project to the SCN with the capacity to influence the phase of the circadian clock. This leptin regulated circuit serves as a point of integration between the metabolic and circadian systems, facilitating the anticipation of meal times.

neuroscience↗