RESUMEN
In apes and humans, neutrophil to lymphocyte ratio (NLR) can be used as a predictive indicator of a variety of clinical conditions, longevity, and physiological stress. In chimpanzees specifically, NLR systematically varies with age, rearing, sex, and premature death, indicating that NLR may be a useful diagnostic tool in assessing primate health. To date, just one very recent study has investigated NLR in old world monkeys and found lower NLR in males and nursery-reared individuals, as well as a negative relationship between NLR and disease outcomes. Given that baboons are increasingly used as research models, we aimed to characterize NLR in baboons by providing descriptive data and examinations of baboon NLR heritability, and of the relationships between NLR, age, rearing, and sex in 387 olive baboons (Papio anubis) between 6 months and 19 years of age. We found that (1) mother-reared baboons had higher NLRs than nursery-reared baboons; (2) females had higher NLRs than males; and (3) there was a quadratic relationship between NLR and age, such that middle-aged individuals had the highest NLR values. We also examined NLR as a function of transport to a new facility using a subset of the data. Baboons exhibited significantly higher transport NLRs compared to routine exam NLRs. More specifically, adult baboons had higher transport NLRs than routine NLRs, whereas juveniles showed no such difference, suggesting that younger animals may experience transport stress differently than older animals. We also found that transport NLR was heritable, whereas routine NLR was not, possibly suggesting that stress responses (as indicated in NLR) have a strong genetic component. Consistent with research in humans and chimpanzees, these findings suggest that NLR varies with important biological and life history variables and that NLR may be a useful health biomarker in baboons.
Asunto(s)
Linfocitos , Neutrófilos , Papio anubis , Estrés Fisiológico , Animales , Femenino , Papio anubis/genética , Papio anubis/fisiología , Masculino , Embarazo , Factores de Edad , Factores SexualesRESUMEN
SH3 and multiple ankyrin repeat domains 3 (SHANK3) haploinsufficiency is causative for the neurological features of Phelan-McDermid syndrome (PMDS), including a high risk of autism spectrum disorder (ASD). We used unbiased, quantitative proteomics to identify changes in the phosphoproteome of Shank3-deficient neurons. Down-regulation of protein kinase B (PKB/Akt)-mammalian target of rapamycin complex 1 (mTORC1) signaling resulted from enhanced phosphorylation and activation of serine/threonine protein phosphatase 2A (PP2A) regulatory subunit, B56ß, due to increased steady-state levels of its kinase, Cdc2-like kinase 2 (CLK2). Pharmacological and genetic activation of Akt or inhibition of CLK2 relieved synaptic deficits in Shank3-deficient and PMDS patient-derived neurons. CLK2 inhibition also restored normal sociability in a Shank3-deficient mouse model. Our study thereby provides a novel mechanistic and potentially therapeutic understanding of deregulated signaling downstream of Shank3 deficiency.
Asunto(s)
Trastorno del Espectro Autista/tratamiento farmacológico , Proteínas del Tejido Nervioso/genética , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Trastorno del Espectro Autista/enzimología , Trastorno del Espectro Autista/genética , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 22/genética , Modelos Animales de Enfermedad , Regulación hacia Abajo , Técnicas de Silenciamiento del Gen , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Proteínas de Microfilamentos , Datos de Secuencia Molecular , Complejos Multiproteicos/metabolismo , Neuronas/enzimología , Fosforilación , Proteína Fosfatasa 2/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Proteómica , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Scratching has been widely used as an indicator of anxiety in many primate species. However, a handful of studies have shown no change in scratching under anxiety-provoking circumstances. In addition, the existing literature has investigated scratching only in relation to negative arousal (i.e., anxiety), even though anxiety and excitement (positive arousal) share important physiological and behavioral correlates, including increased heart rate, blood pressure, and locomotion. In the current study, we scored all instances of scratching in 11 outdoor-housed captive common marmosets (Callithrix jacchus) during three contexts that were intended to be negatively arousing and three contexts that were intended to be positively arousing during a baseline, manipulation, and post-induction period. Summed across the three negative arousal contexts, the results showed that subjects exhibited significantly lower scratching rates during the manipulation than during either the baseline or post-induction periods, and the pattern of means was the same for all three of those contexts. Under the three contexts of positive arousal, subjects exhibited different patterns of scratching rates during the manipulation periods (play = increases, foraging = decreases, food anticipation = no change). Data from the current study, and a close examination of data from studies showing no change in scratching under anxiety-provoking circumstances, suggest that the anxiety-scratching relationship may be more complex than has been reported previously. Our results raise a potential concern about the unchallenged use of scratching as a behavioral indicator of anxiety in captive non-human primates, with important implications for welfare and management of these species.
Asunto(s)
Ansiedad , Nivel de Alerta , Callithrix/fisiología , Animales , Femenino , MasculinoRESUMEN
Autism is a complex spectrum of disorders characterized by core behavioral deficits in social interaction, communication, repetitive stereotyped behaviors and restricted interests. Autism frequently presents with additional cognitive symptoms, including attentional deficits and intellectual disability. Preclinical models are important tools for studying the behavioral domains and biological underpinnings of autism, and potential treatment targets. The inbred BTBR T+tf/J (BTBR) mouse strain has been used as an animal model of core behavioral deficits in autism. BTBR mice exhibit repetitive behaviors and deficits in sociability and communication, but other aspects of their cognitive phenotype, including attentional performance, are not well characterized. We examined the attentional abilities of BTBR mice in the 5-choice serial reaction time task (5-CSRTT) using an automated touchscreen testing apparatus. The 5-CSRTT is an analogue of the human continuous performance task of attention, and so both the task and apparatus have translational relevance to human touchscreen cognitive testing. We also measured basal extracellular levels of a panel of neurotransmitters within the medial prefrontal cortex, a brain region critically important for performing the 5-CSRTT. We found that BTBR mice have increased impulsivity, defined as an inability to withhold responding, and decreased motivation, as compared to C57Bl/6J mice. Both of these features characterize attentional deficit disorders in humans. BTBR mice also display decreased accuracy in detecting short stimuli, lower basal levels of extracellular acetylcholine and higher levels of kynurenic acid within the prefrontal cortex. Intact cholinergic transmission in prefrontal cortex is required for accurate performance of the 5-CSRTT, consequently this cholinergic deficit may underlie less accurate performance in BTBR mice. Based on our findings that BTBR mice have attentional impairments and alterations in a key neural substrate of attention, we propose that they may be valuable for studying mechanisms for treatment of cognitive dysfunction in individuals with attention deficits and autism.
Asunto(s)
Acetilcolina/metabolismo , Atención , Trastornos Generalizados del Desarrollo Infantil/metabolismo , Trastornos Generalizados del Desarrollo Infantil/fisiopatología , Ácido Quinurénico/metabolismo , Aprendizaje , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiopatología , Animales , Modelos Animales de Enfermedad , Aseo Animal , Humanos , Masculino , Ratones , Ratones Endogámicos , Neurotransmisores/metabolismo , Desempeño Psicomotor , Tiempo de ReacciónRESUMEN
A series of 3-(pyridin-2-yl-ethynyl)benzamide negative allosteric modulators of the metabotropic glutamate receptor 5 (mGluR5 NAMs) have been prepared. Starting from HTS hit 1 (IC(50): 926 nM), potent mGluR5 NAMs showing excellent potencies (IC(50)s<50 nM) and good physicochemical profiles were prepared by monitoring LipE values. One compound 26 showed excellent mGluR5 binding (K(i): 21 nM) and antagonism (IC(50): 8 nM), an excellent rat PK profile (CL: 12 mL/min/kg, %F: 85) and showed oral activity in a mouse 4-Plate Behavioral model of anxiety (MED: 30 mpk) and a mouse Stress Induced Hyperthermia model of anxiety (MED 17.8 mpk).
Asunto(s)
Benzamidas/química , Piridinas/química , Receptores de Glutamato Metabotrópico/química , Regulación Alostérica , Animales , Trastornos de Ansiedad/tratamiento farmacológico , Benzamidas/farmacocinética , Benzamidas/uso terapéutico , Modelos Animales de Enfermedad , Ensayos Analíticos de Alto Rendimiento , Ratones , Piridinas/farmacocinética , Piridinas/uso terapéutico , Ratas , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/metabolismoRESUMEN
RATIONALE: Acid sensing ion channels (ASICs) are proton-gated ion channels located in the central and peripheral nervous systems. Of particular interest is ASIC1a, which is located in areas associated with fear and anxiety behaviors. Recent reports suggest a role for ASIC1a in preclinical models of fear conditioning and anxiety. OBJECTIVES: The present experiments evaluated various ASIC inhibitors in preclinical models of autonomic and behavioral parameters of anxiety. In addition, neurochemical studies evaluated the effects of an ASIC inhibitor (A-317567) on neurotransmitter levels in the amygdala. RESULTS: In electrophysiological studies using hippocampal primary neuronal cultures, three ASIC inhibitors (PcTX-1, A-317567, and amiloride) produced concentration-dependent inhibition of acid-evoked currents. In the stress-induced hyperthermia model, acute administration of psalmotoxin 1 (PcTX-1; 10-56 ng, i.c.v.), A-317567 (0.1-1.0 mg/kg, i.p.), and amiloride (10-100 mg/kg, i.p.) prevented stress-induced elevations in core body temperature. In the four-plate test, acute treatment with PcTX-1 (10-56 ng, i.c.v.) and A-317567 (0.01-0.1 mg/kg, i.p.), but not amiloride (3-100 mg/kg, i.p.), produced dose-dependent and significant increases in the number of punished crossings relative to vehicle-treated animals. Additionally, PcTX-1 (56-178 ng, i.c.v.), A-317567 (0.1-10 mg/kg, i.p.), and amiloride (10-100 mg/kg, i.p.) lacked significant anxiolytic-like activity in the elevated zero maze. In neurochemical studies, an infusion of A-317567 (100 microM) into the amygdala significantly elevated the extracellular levels of GABA, but not glutamate, in this brain region. CONCLUSIONS: These findings demonstrate that ASIC inhibition produces anxiolytic-like effects in some behavioral models and indicate a potential role for GABAergic mechanisms to underlie these anxiolytic-like effects.
Asunto(s)
Ansiolíticos/farmacología , Ansiedad/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Bloqueadores de los Canales de Sodio/farmacología , Canales Iónicos Sensibles al Ácido , Amilorida/farmacología , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Ansiedad/metabolismo , Ansiedad/psicología , Conducta Animal/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Conducta Exploratoria/efectos de los fármacos , Fiebre/metabolismo , Fiebre/prevención & control , Fiebre/psicología , Ácido Glutámico/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/embriología , Hipocampo/metabolismo , Isoquinolinas/farmacología , Masculino , Potenciales de la Membrana , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Microdiálisis , Naftalenos/farmacología , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Péptidos , Ratas , Ratas Sprague-Dawley , Canales de Sodio/metabolismo , Venenos de Araña/farmacología , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
RATIONALE: Neuropeptide S (NPS) and its receptor (NPSR) comprise a recently deorphaned G protein-coupled receptor system. Recent reports implicate NPS in the mediation of anxiolytic-like activity in rodents. OBJECTIVES: To extend the characterization of NPS, the present studies examined the in vitro pharmacology of mouse NPSR and the in vivo pharmacology of NPS in three preclinical mouse models predictive of anxiolytic action: the four-plate test (FPT), elevated zero maze (EZM), and stress-induced hyperthermia (SIH). The ability of NPS to produce antidepressant-like effects in the tail suspension test (TST) was also investigated. RESULTS: In vitro, mouse NPS 1-20 (mNPS 1-20) and the C-terminal glutamine-truncated mouse NPS 1-19 bound mNPSR with high affinity (Ki = 0.203 +/- 0.060, 0.635 +/- 0.141 nM, respectively) and potently activated intracellular calcium release (EC50 = 3.73 +/- 1.08, 4.10 +/- 1.25 nM). NPS produced effects in vivo consistent with anxiolytic-like activity. In FPT, NPS increased punished crossings (minimal effective dose [MED]: mNPS 1-20 = 0.2 microg, mNPS(1-19) = 0.02 microg), similar to the reference anxiolytic, alprazolam (MED 0.5 microg). NPS increased the percentage of time spent in the open quadrants of EZM (MED: mNPS 1-20 = 0.1 microg, mNPS 1-19 = 1.0 microg), like the reference anxiolytic, chlordiazepoxide (MED 56 microg). In SIH, NPS attenuated stress-induced increases in body temperature similar to alprazolam but with a large potency difference between the NPS peptides (MED: mNPS 1-20 = 2.0 microg, mNPS 1-19 = 0.0002 microg) and mNPS 1-20 increased baseline temperature. Unlike fluoxetine, NPS did not effect immobility time in TST, indicating a lack of antidepressant-like activity. CONCLUSIONS: These data provide an important confirmation and expansion of the anxiolytic-like effects of NPS and implicate the NPS system as a novel target for anxiolytic drug discovery.