TRPV1 channels are critical brain inflammation detectors and neuropathic pain biomarkers in mice

The capsaicin receptor TRPV1 has been widely characterized in the sensory system as a key component of pain and inflammation. A large amount of evidence shows that TRPV1 is also functional in the brain although its role is still debated. Here we report that TRPV1 is highly expressed in microglial cells rather than neurons of the anterior cingulate cortex and other brain areas. We found that stimulation of microglial TRPV1 controls cortical microglia activation per se and indirectly enhances glutamatergic transmission in neurons by promoting extracellular microglial microvesicles shedding. Conversely, in the cortex of mice suffering from neuropathic pain, TRPV1 is also present in neurons affecting their intrinsic electrical properties and synaptic strength. Altogether, these findings identify brain TRPV1 as potential detector of harmful stimuli and a key player of microglia to neuron communication

Defective microglial development in the hippocampus of Cx3cr1 deficient mice

Microglial cells participate in brain development and influence neuronal loss and synaptic maturation. Fractalkine is an important neuronal chemokine whose expression increases during development and that can influence microglia function via the fractalkine receptor, CX3CR1. Mice lacking Cx3cr1 show a variety of neuronal defects thought to be the result of deficient microglia function. Activation of CX3CR1 is important for the proper migration of microglia to sites of injury and into the brain during development. However, little is known about how fractalkine modulates microglial properties during development. Here we examined microglial morphology, response to ATP, and K(+) current properties in acute brain slices from Cx3cr1 knockout mice across postnatal hippocampal development. We found that fractalkine signaling is necessary for the development of several morphological and physiological features of microglia. Specifically, we found that the occurrence of an outward rectifying K(+) current, typical of activated microglia, that peaked during the second and third postnatal week, was reduced in Cx3cr1 knockout mice. Fractalkine signaling also influenced microglial morphology and ability to extend processes in response to ATP following its focal application to the slice. Our results reveal the developmental profile of several morphological and physiological properties of microglia and demonstrate that these processes are modulated by fractalkine signaling

Early hippocampal hyperexcitability in PS2APP mice: role of mutant PS2 and APP

Alterations of brain network activity are observable in Alzheimer's disease (AD) together with the occurrence of mild cognitive impairment, before overt pathology. However, in humans as well in AD mouse models, identification of early biomarkers of network dysfunction is still at its beginning. We performed in vivo recordings of local field potential activity in the dentate gyrus of PS2APP mice expressing the human amyloid precursor protein (APP) Swedish mutation and the presenilin-2 (PS2) N141I. From a frequency-domain analysis, we uncovered network hyper-synchronicity as early as 3 months, when intracellular accumulation of amyloid beta was also observable. In addition, at 6 months of age, we identified network hyperactivity in the beta/gamma frequency bands, along with increased theta-beta and theta-gamma phase-amplitude cross-frequency coupling, in coincidence with the histopathological traits of the disease. Although hyperactivity and hypersynchronicity were respectively detected in mice expressing the PS2-N141I or the APP Swedish mutant alone, the increase in cross-frequency coupling specifically characterized the 6-month-old PS2APP mice, just before the surge of the cognitive decline

Role of Intra-Aortic Balloon Pump and Extracorporeal Membrane Oxygenation in Early Graft Failure After Cardiac Transplantation

Early graft failure (EGF) is a major risk factor for death after heart transplantation (Htx). We investigated the predictive risk factors for moderate-to-severe EGF requiring an intra-aortic balloon pump (IABP) or extracorporeal membrane oxygenation (ECMO) circulatory support as treatment after Htx. Between January 2000 and December 2014, 412 consecutive adult patients underwent isolated Htx at our institution. Moderate and severe EGF were defined as the need for IABP and ECMO support, respectively, within 24 h after Htx. All available recipient and donor variables were analyzed to assess the risk of EGF occurrence. Overall, moderate-to-severe EGF occurred in 46 (11.1%) patients. Twenty-nine (63.04%) patients required peripheral or central ECMO support in the treatment of severe EGF and 17 (36.9%) patients required IABP support for the treatment of moderate EGF. The predictive risk factors for moderate-to-severe EGF in recipients, as assessed by logistic regression analysis, were a preoperative transpulmonary gradient\u2009>\u200912 mm\ua0Hg (odds ratio [OR] 5.2; P\u2009=\u20090.023), a preoperative inotropic score\u2009>\u200910 (OR 8.5; P\u2009=\u20090.0001), and preoperative ECMO support (OR 4.2; P\u2009=\u20090.012). For donors, the predictive risk factor was a donor score\u2009 65\u200917 (OR 8.3; P\u2009=\u20090.006). The absence of EGF was correlated with improved long-term survival: 94% at 1 year and 81% at 5 years without EGF versus 76% and 36% at 1 year (P\u2009<\u20090.001), and 70% and 28% at 5 years (P\u2009<\u20090.001) with EGF requiring IABP and ECMO support, respectively. In-hospital weaned and survived patients after IABP or ECMO treatment for moderate-to-severe EGF had a similar 5-year conditional survival rate as transplant patients who had not suffered EGF: 88% without EGF versus 84% with EGF treated with mechanical circulatory support devices (P\u2009=\u20090.08). The occurrence of EGF is a multifactorial deleterious event that depends on donor and recipient profiles. IABP and ECMO support are reliable treatment strategies, depending on the grade of EGF. Furthermore, surviving patients treated with IABP or ECMO have the same long-term conditional survival rate as patients who have not suffered EGF

Defective microglial development in the hippocampus of Cx3cr1 deficient mice

Microglial cells participate in brain development and influence neuronal loss and synaptic maturation. Fractalkine is an important neuronal chemokine whose expression increases during development and that can influence microglia function via the fractalkine receptor, CX3CR1. Mice lacking Cx3cr1 show a variety of neuronal defects thought to be the result of deficient microglia function. Activation of CX3CR1 is important for the proper migration of microglia to sites of injury and into the brain during development. However, little is known about how fractalkine modulates microglial properties during development. Here we examined microglial morphology, response to ATP, and K+ current properties in acute brain slices from Cx3cr1 knockout mice across postnatal hippocampal development. We found that fractalkine signaling is necessary for the development of several morphological and physiological features of microglia. Specifically, we found that the occurrence of an outward rectifying K+ current, typical of activated microglia, that peaked during the second and third postnatal week, was reduced in Cx3cr1 knockout mice. Fractalkine signaling also influenced microglial morphology and ability to extend processes in response to ATP following its focal application to the slice. Our results reveal the developmental profile of several morphological and physiological properties of microglia and demonstrate that these processes are modulated by fractalkine signalin

Independent hypothalamic circuits for social and predator fear

The neural circuits mediating fear to naturalistic threats are poorly understood. We found that functionally independent populations of neurons in the ventromedial hypothalamus (VMH), a region that has been implicated in feeding, sex and aggression, are essential for predator and social fear in mice. Our results establish a critical role for VMH in fear and have implications for selective intervention in pathological fear in humans