Biology subjects

Heisler, L. K.

Publications and source records attributed to Heisler, L. K..

7 recordsLinked to original sources

bioRxiv2026

Stereotaxic targeting of the Dorsal Vagal Complex

The Dorsal Vagal Complex (DVC) is a critical brainstem relay for visceral sensory information, sympathetic regulation, and gut-brain communication. Current weight-reducing pharmacotherapies are reported to target this brainstem region to elicit their main satiety actions. Despite its importance, no published step-by-step protocol exists for stereotaxic targeting of this region in rodents. Here, we present a detailed protocol for bilateral administration of substances into the DVC of mice using the atlanto-occipital membrane approach. We describe the surgical access, obex-referenced coordinate system, injection parameters, and we provide a histological validation. This protocol is useful for the study of DVC cells and efferent and afferent neuronal DVC circuits using common neuroscience tools such as tracings, optogenetics or chemogenetics. For complete details on the use and execution of this protocol, please refer to Martinez de Morentin et al.(Martinez De Morentin et al., 2024)

neuroscience↗

bioRxiv2026

AAV-mediated delivery of leptin but not adiponectin improves metabolic health in a mouse model of congenital generalised lipodystrophy

Lipodystrophies are a group of disorders featuring reduced adipose tissue mass or function, which often leads to significant metabolic disease, reduced lifespan and impaired quality of life. Individuals with congenital generalised lipodystrophy (CGL) have severely reduced adipose tissue mass. The loss of healthy systemic lipid storage typically causes hepatic steatosis and lipoatrophic diabetes. In addition, adipocyte-secreted hormones including leptin and adiponectin are dramatically reduced. Leptin has critical roles regulating appetite and broader effects on lipid and glucose metabolism. Daily injection with recombinant leptin is currently the only specific, approved treatment for CGL. The consequences of adiponectin loss in these patients are not fully understood. Likewise, the potential therapeutic benefit of adiponectin delivery is unclear. Here we examine the effect of delivering leptin or adiponectin by adeno-associated virus (AAV) as potential gene therapy treatment for metabolic disease in CGL using a well-characterised murine model of the condition. AAV-mediated leptin delivery significantly improved hepatic steatosis and hyperinsulinemia. However, adiponectin delivery did not lead to any observed beneficial effects. This demonstrates the potential of gene therapy approaches for long-term delivery of leptin in individuals with lipodystrophy, without the need for continuous supply of perishable therapeutics and painful daily injections.

physiology↗

bioRxiv2025

Brain serotonin circuit reverses decline in physical activity with age

Physical inactivity increases with age and is the fourth leading risk factor for mortality. Establishing the mechanisms underpinning declining physical activity (PA) with age has remained both elusive and difficult to overcome. Older (50-70 years old) compared with younger (17-30 years old) UK participants showed reduced PA, and this profile was effectively modelled in mice. Analysis of brain serotonin (5-HT) neurons in the dorsal raphe (DR) revealed altered firing activity in older mice. Chemogenetically mimicking this 5-HTDR tone in young adult mice produced an older adult PA profile. Genetically blocking 5-HT activity at 5-HT2C receptors (5-HT2CRs) prevented the decline in PA with age. Importantly, barring 5-HT action at 5-HT2CRs specifically within the ventral tegmental area restored youthful PA levels and strength in older mice. These data fill a longstanding knowledge gap by defining brain circuitry programming the decline in PA with age, and importantly, a means to reverse it.

neuroscience↗

bioRxiv2025

Nucleus raphe magnus serotonin neurons bidirectionally control spinal mechanical pain transmission

BackgroundNoxious stimuli are conveyed to and integrated in the dorsal horn of the spinal cord (DHSC) before being transmitted to supraspinal centers, where pain perception is generated. Descending pathways from the brainstem dynamically modulate this integration, either facilitating or inhibiting nociceptive information based on physiological, emotional, genetic and environmental factors. Serotonergic neurons in the nucleus raphe magnus (NRM), activating different spinal 5-HT receptors, exert bidirectional control, both facilitatory and inhibitory, but the underlying mechanisms of this control remain unclear. MethodsWe investigated in adult mice, the NRM serotonergic modulation of nociception using imaging, behavioral, pharmacological, electrophysiological, chemogenetic and optogenetic approaches. ResultsWe have demonstrated that the action of serotonergic neurons in the NRM on spinal nociceptive transmission depends on their activation pattern, which targets different spinal 5-HT receptors likely associated with different spinal microcircuits. Serotonergic neurons of the NRM exert a tonic analgesic effect mediated by 5-HT2c receptor. Low increase in 5-HT activity leads to an increased analgesia through spinal inhibitory interneurons expressing 5-HT2c and 5-HT2A receptors. Finally, prolonged stimulation of serotonergic neurons led to hyperalgesia mediated by 5-HT3 receptor. Comparison of 5-HT receptors in spinal tissue from mice and human shows that 5-HT2c receptor has a very high expression level, comparable between both species. ConclusionsThese results propose a model of bidirectional action of serotonin neurons on nociceptive transmission depending on their level of activity and show that 5-HT2c receptor is the main mediator of serotonin-induced analgesia.

neuroscience↗

bioRxiv2023

Mesenchymal-specific Alms1 knockout in mice recapitulates key metabolic features of Alström Syndrome

BackgroundAlstrom Syndrome (AS), a multi-system disease caused by mutations in the ALMS1 gene, includes obesity with disproportionately severe insulin resistant diabetes, dyslipidemia, and hepatosteatosis. How loss of ALMS1 causes this phenotype is poorly understood, but prior studies have circumstancially implicated impaired adipose tissue expandability. We set out to test this by comparing the metabolic effects of selective Alms1 knockout in mesenchymal cells including preadipocytes to those of global Alms1 knockout. MethodsGlobal Alms1 knockout (KO) mice were generated by crossing floxed Alms1 and CAG-Cre mice. A Pdgfr-Cre driver was used to abrogate Alms1 function selectively in mesenchymal stem cells (MSCs) and their descendants, including preadipocytes. We combined metabolic phenotyping of global and Pdgfr+ Alms1-KO mice on a 45% fat diet with measurements of body composition and food intake, and histological analysis of metabolic tissues. ResultsGlobal Alms1 KO caused hyperphagia, obesity, insulin resistance, dyslipidaemia, and fatty liver. Pdgfr-cre driven KO of Alms1 (MSC KO) recapitulated insulin resistance, fatty liver, and dyslipidaemia in both sexes. Other phenotypes were sexually dimorphic: increased fat mass was only present in female Alms1 MSC KO mice. Hyperphagia was not evident in male Alms1 MSC KO mice, but was found in MSC KO females, despite no neuronal Pdgfr expression. ConclusionsMesenchymal deletion of Alms1 recapitulates the metabolic features of AS, including severe fatty liver. This confirms a key role for Alms1 in the adipose lineage, where its loss is sufficient to cause systemic metabolic effects and damage to remote organs. AS should be regarded as a forme fruste of lipodystrophy. Therapies should prioritise targeting positive energy balance.

physiology↗

bioRxiv2023

GLP-1 Receptor Agonist Improves Metabolic Disease in a Pre-clinical Model of Lipodystrophy

Individuals with lipodystrophies typically suffer from significant metabolic disease linked to adipose tissue dysfunction including severe insulin resistance and lipoatrophic diabetes, hepatic steatosis and hyperphagia. Current treatment options are limited and beter therapies for affected individuals are urgently needed. No systematic, detailed analyses exist of the effects of glucagon like peptide-1 receptor (GLP-1R) agonists in the treatment of lipoatrophic diabetes. Here we examined the effects of the GLP-1R agonist liraglutide in seipin knockout mice, a pre-clinical model of generalised lipodystrophy. Acute liraglutide treatment of seipin knockout mice significantly improved insulin, glucose and pyruvate tolerance. Once-daily injection of seipin knockout mice with liraglutide for 14 days led to a modest reduction in food intake but significant improvements in hepatomegaly associated with steatosis and significantly reduced markers of liver fibrosis. Detailed examination of the pancreas revealed that liraglutide enhanced insulin secretion in response to glucose challenge with concomitantly improved glucose control. Thus, GLP-1R agonist liraglutide significantly improved multiple aspects of lipoatrophic diabetes and hepatic steatosis in mice with congenital generalised lipodystrophy. This provides important insights regarding the benefits of GLP-1R agonists for treating lipodystrophy, informing more widespread use to improve the health of individuals with this condition.

pharmacology and toxicology↗

bioRxiv2023

A brainstem to hypothalamic arcuate nucleus GABAergic circuit drives feeding

The obesity epidemic is principally driven by the consumption of more calories than the body requires. It is therefore essential that the mechanisms underpinning feeding behavior are defined. The brainstem nucleus of the solitary tract (NTS) receives direct information from the digestive system and projects to second order regions in the brain. Though {gamma}-Aminobutyric acid is widely expressed in the NTS (GABANTS), its function has not been defined. Characterization of GABA cells using single nucleus RNA sequencing (Nuc-Seq) identified at least 19 clusters. Here we provide insight into the function of GABANTS cells, revealing that selective activation of GABANTS neurons significantly controls food intake and body weight. Optogenetic interrogation of GABANTS circuitry identified GABANTS[->]arcuate nucleus of the hypothalamus (ARC) projections as appetite suppressive without creating aversion. Electrophysiological analysis revealed GABANTS[->]ARC stimulation inhibits hunger promoting agouti-related protein/neuropeptide Y (AgRP/NPY) neurons via GABA release. Adopting an intersectional genetics strategy, we clarify that the GABANTS[->]ARC circuit induces satiety. These data identify GABANTS as a new modulator of feeding behavior, body weight and controller of orexigenic AgRP/NPY activity, thereby providing insight into the neural underpinnings of obesity. HighlightsO_LINucleus of the solitary tract (NTS) GABA neurons are responsive to nutritional status. C_LIO_LIChemogenetic GABANTS neuron activation reduces food intake and body weight. C_LIO_LIGABANTS projections to the hypothalamic arcuate nucleus (ARC) promote satiety. C_LIO_LIOptogenetic GABANTS[->]ARC stimulation inhibits orexigenic AgRP/NPY neurons. C_LI In BriefMartinez de Morentin et al. identify GABAergic neurons in the nucleus of the solitary tract as a new player in the circuit governing feeding behavior and body weight.

neuroscience↗