title: Vesicular acetylcholine transporter knock down-mice are more susceptible to inflammation, c-Fos expression and sickness behavior induced by lipopolysaccharide.
abstract: In addition to the well-known functions as a neurotransmitter, acetylcholine (ACh) can modulate of the immune system. Nonetheless, how endogenous ACh release inflammatory responses is still not clear. To address this question, we took advantage of an animal model with a decreased ACh release due a reduction (knockdown) in vesicular acetylcholine transporter (VAChT) expression (VAChT-KD(HOM)). These animals were challenged with lipopolysaccharide (LPS). Afterwards, we evaluated sickness behavior and quantified systemic and cerebral inflammation as well as neuronal activation in the dorsal vagal complex (DVC). VAChT-KD(HOM) mice that were injected with LPS (10mg/kg) showed increased mortality rate as compared to control mice. In line with this result, a low dose of LPS (0.1mg/kg) increased the levels of pro-inflammatory (TNF-α, IL-1β, and IL-6) and anti-inflammatory (IL-10) cytokines in the spleen and brain of VAChT-KD(HOM) mice in comparison with controls. Similarly, serum levels of TNF-α and IL-6 were increased in VAChT-KD(HOM) mice. This excessive cytokine production was completely prevented by administration of a nicotinic receptor agonist (0.4mg/kg) prior to the LPS injection. Three hours after the LPS injection, c-Fos expression increased in the DVC region of VAChT-KD(HOM) mice compared to controls. In addition, VAChT-KD(HOM) mice showed behavioral changes such as lowered locomotor and exploratory activity and reduced social interaction after the LPS challenge, when compared to control mice. Taken together, our results show that the decreased ability to release ACh exacerbates systemic and cerebral inflammation and promotes neural activation and behavioral changes induced by LPS. In conclusion, our findings support the notion that activity of cholinergic pathways, which can be modulated by VAChT expression, controls inflammatory and neural responses to LPS challenge.
authors.affiliation: Laboratório de Inflamação e Metabolismo (LIM), Programa de Pós-graduação em Ciências Fisiológicas, Centro Integrado de Pesquisa e Pós-Graduação em Saúde - CIPq-Saúde, Universidade Federal dos Vales do Jequitinhonha e Mucuri (UFVJM), Campus JK, Alto da Jacuba, Minas Gerais 39100 000, Brazil; Núcleo de Neurociências (NNC), Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos, Pampulha, n° 6627, Belo Horizonte, Minas Gerais 31270 901, Brazil. Electronic address: hercules.leite@ufvjm.edu.br.
authors.forename: Hércules Ribeiro
authors.initials: HR
authors.lastname: Leite
authors.affiliation: Núcleo de Neurociências (NNC), Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos, Pampulha, n° 6627, Belo Horizonte, Minas Gerais 31270 901, Brazil.
authors.forename: Onésia Cristina de
authors.initials: OC
authors.lastname: Oliveira-Lima
authors.affiliation: Núcleo de Neurociências (NNC), Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos, Pampulha, n° 6627, Belo Horizonte, Minas Gerais 31270 901, Brazil.
authors.forename: Luciana de Melo
authors.initials: LM
authors.lastname: Pereira
authors.affiliation: Núcleo de Neurociências (NNC), Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos, Pampulha, n° 6627, Belo Horizonte, Minas Gerais 31270 901, Brazil.
authors.forename: Vinícius Elias de Moura
authors.initials: VEM
authors.lastname: Oliveira
authors.affiliation: Molecular Medicine, Robarts Research Institute, Department of Physiology and Pharmacology, Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario N6A 5K8, Canada.
authors.forename: Vania Ferreira
authors.initials: VF
authors.lastname: Prado
authors.affiliation: Molecular Medicine, Robarts Research Institute, Department of Physiology and Pharmacology, Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario N6A 5K8, Canada.
authors.forename: Marco Antônio Máximo
authors.initials: MAM
authors.lastname: Prado
authors.affiliation: Núcleo de Neurociências (NNC), Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos, Pampulha, n° 6627, Belo Horizonte, Minas Gerais 31270 901, Brazil.
authors.forename: Grace Schenatto
authors.initials: GS
authors.lastname: Pereira
authors.affiliation: Núcleo de Neurociências (NNC), Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos, Pampulha, n° 6627, Belo Horizonte, Minas Gerais 31270 901, Brazil. Electronic address: massen@icb.ufmg.br.
authors.forename: André Ricardo
authors.initials: AR
authors.lastname: Massensini
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D055809:Illness Behavior / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018722:Nicotinic Agonists / Q000494:pharmacology; D015398:Signal Transduction; D050494:Vesicular Acetylcholine Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D018722:Nicotinic Agonists; D050494:Vesicular Acetylcholine Transport Proteins; D000109:Acetylcholine
keywords: Acetylcholine; Inflammation; Lipopolysaccharide; Sickness behavior; Vesicular acetylcholine transporter