Allosteric Control of Gating and Kinetics at P2X₄ Receptor Channels

The CNS abundantly expresses P2X receptor channels for ATP; of these the most widespread in the brain is the P2X₄ channel. We show that ivermectin (IVM) is a specific positive allosteric effector of heterologously expressed P2X₄ and possibly of heteromeric P2X₄/P2X₆channels, but not of P2X₂, P2X₃, P2X₂/P2X₃, or P2X₇ channels. In the submicromolar range (EC₅₀, ∼250 nM) the action of IVM was rapid and reversible, resulting in increased amplitude and slowed deactivation of P2X₄ channel currents evoked by ATP. IVM also markedly increased the potency of ATP and that of the normally low-potency agonist α,β-methylene-ATP in a use- and voltage-independent manner without changing the ion selectivity of P2X₄ channels. Therefore, IVM evokes a potent pharmacological gain-of-function phenotype that is specific for P2X₄ channels. We also tested whether IVM could modulate endogenously expressed P2X channels in the adult trigeminal mesencephalic nucleus and hippocampal CA1 neurons. Surprisingly, IVM produced no significant effect on the fast ATP-evoked inward currents in either type of neuron, despite the fact that IVM modulated P2X₄ channels heterologously expressed in embryonic hippocampal neurons. These results suggest that homomeric P2X₄ channels are not the primary subtype of P2X receptor in the adult trigeminal mesencephalic nucleus and in hippocampal CA1 neurons

Chronic Nicotine Cell Specifically Upregulates Functional α4* Nicotinic Receptors: Basis for Both Tolerance in Midbrain and Enhanced Long-Term Potentiation in Perforant Path

Understanding effects of chronic nicotine requires identifying the neurons and synapses whose responses to nicotine itself, and to endogenous acetylcholine, are altered by continued exposure to the drug. To address this problem, we developed mice whose α4 nicotinic receptor subunits are replaced by normally functioning fluorescently tagged subunits, providing quantitative studies of receptor regulation at micrometer resolution. Chronic nicotine increased α4 fluorescence in several regions; among these, midbrain and hippocampus were assessed functionally. Although the midbrain dopaminergic system dominates reward pathways, chronic nicotine does not change α4* receptor levels in dopaminergic neurons of ventral tegmental area (VTA) or substantia nigra pars compacta. Instead, upregulated, functional α4* receptors localize to the GABAergic neurons of the VTA and substantia nigra pars reticulata. In consequence, GABAergic neurons from chronically nicotine-treated mice have a higher basal firing rate and respond more strongly to nicotine; because of the resulting increased inhibition, dopaminergic neurons have lower basal firing and decreased response to nicotine. In hippocampus, chronic exposure to nicotine also increases α4* fluorescence on glutamatergic axons of the medial perforant path. In hippocampal slices from chronically treated animals, acute exposure to nicotine during tetanic stimuli enhances induction of long-term potentiation in the medial perforant path, showing that the upregulated α4* receptors in this pathway are also functional. The pattern of cell-specific upregulation of functional α4* receptors therefore provides a possible explanation for two effects of chronic nicotine: sensitization of synaptic transmission in forebrain and tolerance of dopaminergic neuron firing in midbrain

Nicotine Activation of α4* Receptors: Sufficient for Reward, Tolerance, and Sensitization

The identity of nicotinic receptor subtypes sufficient to elicit both the acute and chronic effects of nicotine dependence is unknown. We engineered mutant mice with α4 nicotinic subunits containing a single point mutation, Leu^(9′) → Ala^(9′) in the pore-forming M2 domain, rendering α4* receptors hypersensitive to nicotine. Selective activation of α4* nicotinic acetylcholine receptors with low doses of agonist recapitulates nicotine effects thought to be important in dependence, including reinforcement in response to acute nicotine administration, as well as tolerance and sensitization elicited by chronic nicotine administration. These data indicate that activation of α4* receptors is sufficient for nicotine-induced reward, tolerance, and sensitization

On the recurrence and robust properties of Lorenz'63 model

Lie-Poisson structure of the Lorenz'63 system gives a physical insight on its dynamical and statistical behavior considering the evolution of the associated Casimir functions. We study the invariant density and other recurrence features of a Markov expanding Lorenz-like map of the interval arising in the analysis of the predictability of the extreme values reached by particular physical observables evolving in time under the Lorenz'63 dynamics with the classical set of parameters. Moreover, we prove the statistical stability of such an invariant measure. This will allow us to further characterize the SRB measure of the system.Comment: 44 pages, 7 figures, revised version accepted for pubblicatio

Sentido del humor en el adulto mayor

A sense of humor is a phenomenon not frequently studied in the context of psychology, let alone in the older adult, an age group that is constantly growing in Venezuela. This research, guided by the approaches of Carbelo (2007) and DAnello (2010) and titled Sense of Humor in Older Adults, aimed to determine the meaning this phenomenon has for the elderly. To accomplish this, qualitative research was conducted using an in-depth Interview as a data collection method. Informants were 4 seniors (2 men and 2 women) between 60 and 73 years of age, selected as a sample of purpose. For the analysis, grounded theory was used, concluding that for the older adult, when a sense of humor becomes part of the personality, it is a health-protective factor, gives a sense of belonging and positively changing the environment, bringing a better quality of life, the latter being the main signifier that emerged from the information analysis. Similarly, it was determined that a sense of humor is a social construct developed throughout life that locks in during this life stage.  El humor es un fenómeno poco estudiado dentro del contexto de la psicología, menos aún, en el adulto mayor, grupo etario que se encuentra en constante crecimiento dentro de nuestro país.En tal sentido, la investigación, guiada por los planteamientos de Carbelo (2007) y DAnello (2010), denominada sentido del humor en el adulto mayor, tuvo por objetivo, determinar el significado que tiene este fenómeno para el adulto mayor. Para ello, se realizó un estudio de corte cualitativo,donde se utilizó la Entrevista en Profundidad como método de recolección de la información. Los informantes fueron 4 adultos mayores (2 hombres y 2 mujeres) con edades comprendidas entre 60 y 73 años de edad, los cuales fueron seleccionados como una muestra de propósito. Para el análisis, se utilizó la Teoría Fundamentada, concluyéndose que para el adulto mayor, cuando el sentido del humor se convierte en parte de la personalidad, es un factor protector de la salud, da sentido de pertenencia y cambia positivamente el ambiente, trayendo como consecuencia una mejor calidad de vida, siendo esto último el principal significante que surgió del análisis de la información. Igualmente, se determinó que el sentido del humor es una construcción social que se va elaborando a lo largo de la vida y que se afianza en esta etapa vital. &nbsp

The structure of the tetrasialoganglioside from human brain

Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle- age onset. In nine families, we identified heterozygous C- terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias

Allosteric Control of Gating and Kinetics at P2X₄ Receptor Channels

The CNS abundantly expresses P2X receptor channels for ATP; of these the most widespread in the brain is the P2X₄ channel. We show that ivermectin (IVM) is a specific positive allosteric effector of heterologously expressed P2X₄ and possibly of heteromeric P2X₄/P2X₆channels, but not of P2X₂, P2X₃, P2X₂/P2X₃, or P2X₇ channels. In the submicromolar range (EC₅₀, ∼250 nM) the action of IVM was rapid and reversible, resulting in increased amplitude and slowed deactivation of P2X₄ channel currents evoked by ATP. IVM also markedly increased the potency of ATP and that of the normally low-potency agonist α,β-methylene-ATP in a use- and voltage-independent manner without changing the ion selectivity of P2X₄ channels. Therefore, IVM evokes a potent pharmacological gain-of-function phenotype that is specific for P2X₄ channels. We also tested whether IVM could modulate endogenously expressed P2X channels in the adult trigeminal mesencephalic nucleus and hippocampal CA1 neurons. Surprisingly, IVM produced no significant effect on the fast ATP-evoked inward currents in either type of neuron, despite the fact that IVM modulated P2X₄ channels heterologously expressed in embryonic hippocampal neurons. These results suggest that homomeric P2X₄ channels are not the primary subtype of P2X receptor in the adult trigeminal mesencephalic nucleus and in hippocampal CA1 neurons