Biology subjects

Filippi, B. M.

Publications and source records attributed to Filippi, B. M..

6 recordsLinked to original sources

bioRxiv2026

Insulin controls olfactory gain at the first central synapse by regulating periglomerular neuron excitability

Sensory processing is dynamically tuned by internal state, yet how metabolic signals reshape the earliest stages of sensory circuits remains poorly understood. Here we identify a circuit mechanism by which satiety suppresses olfactory sensitivity at the first central synapse in the mouse olfactory bulb. Using a within-animal paradigm modelling fasted and glucose-induced sated states, we show that satiety impairs food-finding behaviour and reduces olfactory receptor neuron input to the olfactory bulb. Periglomerular (PG) cells, which co-express insulin receptors and the potassium channel Kv1.3, mediate this effect: insulin inhibits the low-voltage-activated Kv1.3 current in PG cells, increasing their spontaneous and odour-evoked activity. This heightened PG cell activity drives enhanced presynaptic inhibition of olfactory receptor neuron terminals, dampening sensory input before it reaches mitral cells. These findings establish insulin-dependent presynaptic inhibition of PG cells as a key locus of state-dependent sensory gain control.

neuroscience↗

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↗

bioRxiv2024

Insulin evokes release of endozepines from astrocytes of the NTS to modulate glucose metabolism

The central nervous system (CNS) plays a key role in regulating metabolic functions, but conditions like obesity and diabetes can disrupt this balance. Within the CNS, the nucleus of the solitary tract (NTS) in the dorsal vagal complex (DVC) controls glucose metabolism and feeding behaviour. In rodents, the NTS senses insulin and communicates with the liver to regulate glucose production. Even short-term exposure to a high-fat diet (HFD) can lead to insulin resistance and impair NTS function. However, we still know little about which cells in the NTS are sensitive to insulin. Our study aimed to identify these insulin-sensitive cells and understand how they affect glucose metabolism. We found that insulin receptors in astrocytes are crucial for the NTSs ability to regulate glucose production in the liver. Insulin evokes the release of endozepines from astrocytes, and injecting endozepines into the NTS reduces glucose production. The effect of endozepines within the NTS is mimicked by GABAA antagonists and prevented by an agonist, suggesting that insulin prompts astrocytes to release endozepines, which then attenuate GABAA receptor activity, ultimately reducing glucose production in the liver. Our study is the first to show that insulin-dependent release of endozepines from NTS- astrocytes is fundamental to control blood glucose levels, providing valuable insights into the mechanisms underlying insulin function within this specific region of the CNS.

neuroscience↗

bioRxiv2023

Manipulating mitochondrial dynamics in the NTS prevents diet-induced deficits in brown fat morphology and activity

Brown adipose tissue (BAT) uptakes and metabolises both glucose and triglycerides to produce heat and is activated by the central nervous system (CNS) through direct noradrenergic sympathetic innervation. Dysregulation of signalling modules in selective CNS areas such as the nucleus of tractus solitarius (NTS) are linked with altered BAT activity, obesity and diabetes. High-fat diet (HFD)-feeding increases mitochondrial fragmentation in the NTS triggering insulin resistance, hyperphagia and weight gain. Here we sought to determine whether changes in mitochondrial dynamics in the NTS can affect BAT glucose uptake. Our findings demonstrated that short-term HFD feeding reduces BATs ability to take up glucose, as measured by PET/CT scan. However, inhibiting mitochondrial fragmentation in NTS-astrocytes of HFD-fed rats improved BAT glucose uptake while lowering blood glucose and insulin levels. Compared with HFD-fed rats, HFD fed animals, where mitochondrial fragmentation was inhibited in the NTS-astrocytes, had higher levels of catecholaminergic innervation of BAT, and did not present HFD-dependent infiltration of enlarged white fat droplets in the BAT. In regular chow-fed rats, increasing mitochondrial fragmentation in the NTS-astrocytes reduced BAT glucose uptake, catecholaminergic innervation and {beta}3-adrenergic receptor levels. Our data suggest that targeting mitochondrial dynamics in the NTS-astrocytes could be a beneficial strategy to increase glucose utilization and protect from developing obesity and diabetes.

neuroscience↗

bioRxiv2020

Signals Secreted by Infection Induce Transcriptional and Epigenetic Changes in Neurons

Infection with the protozoan Toxoplasma gondii induces changes in neurotransmission, neuroinflammation, and behavior, yet it remains elusive how these changes come about. In this study we investigated how norepinephrine levels are altered by infection. TINEV (Toxoplasma-induced neuronal extracellular vesicles) isolated from infected noradrenergic cells down-regulated dopamine {beta}-hydroxylase (DBH) gene expression in human and rodent cells. Here we report that intracerebral injection of TINEVs into the brain is sufficient to induce DBH down-regulation and distrupt catecholaminergic signalling. Further, TINEV treatment induced hypermethylation upstream of the DBH gene. An antisense lncRNA to DBH was found in purified TINEV preparations. Paracrine signalling to induce transcriptional gene silencing and DNA methylation may be a common mode to regulate neurologic function.

microbiology↗

bioRxiv2020

Inhibition of Mitochondrial Fission and iNOS in the Dorsal Vagal Complex Protects from Overeating and Weight Gain

The dorsal vagal complex (DVC) senses changes in insulin levels and controls glucose homeostasis, feeding behaviour and body weight. Three days of high-fat diet (HFD) in rats is sufficient to induce insulin resistance in the DVC and impair its ability to regulate feeding behaviour. HFD-feeding is associated with increased mitochondrial fission in the DVC and fission is regulated by dynamin-related protein 1 (Drp1). Higher Drp1 activity can inhibit insulin signalling, although the exact mechanisms controlling body weight remain elusive. Here we show that Drp1 activation in DVC leads to higher body weight in rats and Drp1 inhibition in HFD-fed rats reduced body weight gain, cumulative food intake and adipose tissue, and prevented insulin resistance. Rats expressing active Drp1 in the DVC had higher levels of inducible nitric oxide synthase (iNOS) and knockdown of iNOS in the DVC of HFD-fed rats led to a reduction in body weight gain, cumulative food intake and adipose tissue, and prevented insulin resistance. In obese insulin-resistant animals, inhibition of mitochondrial fission or DVC iNOS knockdown restored insulin sensitivity and decreased food intake, body weight and fat deposition. Finally, we show that inhibiting mitochondrial fission in DVC astrocytes is sufficient to protect rats from developing HFD-dependent insulin resistance, hyperphagia, body weight gain and fat deposition. Our study uncovers new molecular and cellular targets for brain regulation of whole-body metabolism, which could inform new strategies to combat obesity and diabetes.

neuroscience↗