The Importance of Ventral Hippocampal Dopamine and Norepinephrine in Recognition Memory.

Dopaminergic neurons originating from the ventral tegmental area (VTA) and the locus coeruleus are innervating the ventral hippocampus and are thought to play an essential role for efficient cognitive function. Moreover, these VTA projections are hypothesized to be part of a functional loop, in which dopamine regulates memory storage. It is hypothesized that when a novel stimulus is encountered and recognized as novel, increased dopamine activity in the hippocampus induces long-term potentiation and long-term storage of memories. We here demonstrate the importance of increased release of dopamine and norepinephrinein the rat ventral hippocampus on recognition memory, using microdialysis combined to a modified novel object recognition test. We found that presenting rats to a novel object significantly increased dopamine and norepinephrine output in the ventral hippocampus. Two hours after introducing the first object, a second object (either novel or familiar) was placed in the same position as the first object. Presenting the animals to a second novel object significantly increased dopamine and norepinephrine release in the ventral hippocampus, compared to a familiar object. In conclusion, this study suggests that dopamine and norepinephrine output in the ventral hippocampus has a crucial role in recognition memory and signals novelty.

Intrinsic electrophysiological properties predict variability in morphology and connectivity among striatal Parvalbumin-expressing Pthlh-cells.

Determining the cellular content of the nervous system in terms of cell types and the rules of their connectivity represents a fundamental challenge to the neurosciences. The recent advent of high-throughput techniques, such as single-cell RNA-sequencing has allowed for greater resolution in the identification of cell types and/or states. Although most of the current neuronal classification schemes comprise discrete clusters, several recent studies have suggested that, perhaps especially, within the striatum, neuronal populations exist in continua, with regards to both their molecular and electrophysiological properties. Whether these continua are stable properties, established during development, or if they reflect acute differences in activity-dependent regulation of critical genes is currently unknown. We set out to determine whether gradient-like molecular differences in the recently described Pthlh-expressing inhibitory interneuron population, which contains the Pvalb-expressing cells, correlate with differences in morphological and connectivity properties. We show that morphology and long-range inputs correlate with a spatially organized molecular and electrophysiological gradient of Pthlh-interneurons, suggesting that the processing of different types of information (by distinct anatomical striatal regions) has different computational requirements.

Heterogeneous somatostatin-expressing neuron population in mouse ventral tegmental area.

The cellular architecture of the ventral tegmental area (VTA), the main hub of the brain reward system, remains only partially characterized. To extend the characterization to inhibitory neurons, we have identified three distinct subtypes of somatostatin (Sst)-expressing neurons in the mouse VTA. These neurons differ in their electrophysiological and morphological properties, anatomical localization, as well as mRNA expression profiles. Importantly, similar to cortical Sst-containing interneurons, most VTA Sst neurons express GABAergic inhibitory markers, but some of them also express glutamatergic excitatory markers and a subpopulation even express dopaminergic markers. Furthermore, only some of the proposed marker genes for cortical Sst neurons were expressed in the VTA Sst neurons. Physiologically, one of the VTA Sst neuron subtypes locally inhibited neighboring dopamine neurons. Overall, our results demonstrate the remarkable complexity and heterogeneity of VTA Sst neurons and suggest that these cells are multifunctional players in the midbrain reward circuitry.

Zilpaterol hydrochloride lowers marbling score by dilution of marbling and depression of intramuscular adipocyte volume in M. longissimus dorsi of beef steers.

We hypothesized that zilpaterol hydrochloride (ZH) depresses marbling scores in beef cattle by dilution of the intramuscular (i.m.) adipose tissue in the longissimus thoracis (LT) by increased muscle cross-sectional area. Crossbred steers were treated with ractopamine hydrochloride (RH; 28 d) or ZH (20 d) or no ß-adrenergic agonist (CON). ZH increased LT cross-sectional area (P < .001) and depressed rib fat depth (P < .001), USDA marbling score (P < .05), percent LT lipid (P < .02), total lipid in a 2.54 cm-thick LM steak (P < .05) and most LT lipid fatty acids (P ≤ .05),but had no effect on mean i.m. adipocyte volume (P = .15). ZH increased the relative volume proportion of smaller i.m. adipocytes (250 to 500 pL) and decreased the proportion of larger i.m. adipocytes (2000 and 3000 pL) (P < .05). We conclude that ZH reduces marbling score both by dilution of the marbling and a depression of i.m. adipocyte relative volumes.

Toma de decisiones y consideraciones éticas en el soporte ventilatorio en áreas críticas hospitalarias en el contexto de pandemia COVID-19 / Decision-making and ethical considerations in ventilatory support in critical hospital areas in the context of the COVID-19 pandemic

Objetivo. Los recursos hospitalarios resultan insuficientes ante la demanda de pacientes graves con COVID-19. La adecuada gestión de recursos es esencial para brindar la mejor atención posible. Se revisaron criterios que ayuden a tomar decisiones adecuadas y oportunas, siguiendo principios éticos. La priorización del soporte ventilatorio invasivo debe hacerse de manera transparente y objetiva, evaluando integralmente al paciente y basado en criterios objetivos como escalas de pronóstico, ciclo de vida o compromiso clínico. El tratamiento sintomático (incluyendo cuidados paliativos) es indispensable en esta pandemia y la comunicación con el aciente o la familia permiten humanizar la atención del personal de salud.

Objetive. Hospital resources are insufficient given the demand for seriously ill patients with COVID-19. Proper resource management is essential to provide the best possible care. Criteria to help make appropriate and timely decisions were reviewed, following ethical principles. The prioritization of invasive ventilatory support must be done in a transparent and objective manner, comprehensively evaluating the patient and based on objective criteria such as prognostic scales, life cycle or clinical commitment. Symptomatic treatment (including palliative care) is essential in this pandemic and communication with the patient or family makes it possible to humanize the care of health personnel.

Transcriptomic correlates of electrophysiological and morphological diversity within and across excitatory and inhibitory neuron classes.

In order to further our understanding of how gene expression contributes to key functional properties of neurons, we combined publicly accessible gene expression, electrophysiology, and morphology measurements to identify cross-cell type correlations between these data modalities. Building on our previous work using a similar approach, we distinguished between correlations which were "class-driven," meaning those that could be explained by differences between excitatory and inhibitory cell classes, and those that reflected graded phenotypic differences within classes. Taking cell class identity into account increased the degree to which our results replicated in an independent dataset as well as their correspondence with known modes of ion channel function based on the literature. We also found a smaller set of genes whose relationships to electrophysiological or morphological properties appear to be specific to either excitatory or inhibitory cell types. Next, using data from PatchSeq experiments, allowing simultaneous single-cell characterization of gene expression and electrophysiology, we found that some of the gene-property correlations observed across cell types were further predictive of within-cell type heterogeneity. In summary, we have identified a number of relationships between gene expression, electrophysiology, and morphology that provide testable hypotheses for future studies.

Exploring the Interneuron Canopy Atop the 'Impenetrable Jungle'.

The multifaceted functions of the brain are borne through seemingly infinite spatiotemporal interactions between its resident neural elements. Using a combinatorial approach, Schuman and colleagues (J. Neurosci. 2018;39:125-139) recently identify four layer 1 cortical interneuron subtypes, including a hitherto uncharacterized neuron they term the 'canopy' cell. Properties unique to each of the subtypes likely endow them with distinct roles in top-down processing.

Diversity of Interneurons in the Dorsal Striatum Revealed by Single-Cell RNA Sequencing and PatchSeq.

Striatal locally projecting neurons, or interneurons, act on nearby circuits and shape functional output to the rest of the basal ganglia. We performed single-cell RNA sequencing of striatal cells enriching for interneurons. We find seven discrete interneuron types, six of which are GABAergic. In addition to providing specific markers for the populations previously described, including those expressing Sst/Npy, Th, Npy without Sst, and Chat, we identify two small populations of cells expressing Cck with or without Vip. Surprisingly, the Pvalb-expressing cells do not constitute a discrete cluster but rather are part of a larger group of cells expressing Pthlh with a spatial gradient of Pvalb expression. Using PatchSeq, we show that Pthlh cells exhibit a continuum of electrophysiological properties correlated with expression of Pvalb. Furthermore, we find significant molecular differences that correlate with differences in electrophysiological properties between Pvalb-expressing cells of the striatum and those of the cortex.

Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics.

Understanding any brain circuit will require a categorization of its constituent neurons. In hippocampal area CA1, at least 23 classes of GABAergic neuron have been proposed to date. However, this list may be incomplete; additionally, it is unclear whether discrete classes are sufficient to describe the diversity of cortical inhibitory neurons or whether continuous modes of variability are also required. We studied the transcriptomes of 3,663 CA1 inhibitory cells, revealing 10 major GABAergic groups that divided into 49 fine-scale clusters. All previously described and several novel cell classes were identified, with three previously described classes unexpectedly found to be identical. A division into discrete classes, however, was not sufficient to describe the diversity of these cells, as continuous variation also occurred between and within classes. Latent factor analysis revealed that a single continuous variable could predict the expression levels of several genes, which correlated similarly with it across multiple cell types. Analysis of the genes correlating with this variable suggested it reflects a range from metabolically highly active faster-spiking cells that proximally target pyramidal cells to slower-spiking cells targeting distal dendrites or interneurons. These results elucidate the complexity of inhibitory neurons in one of the simplest cortical structures and show that characterizing these cells requires continuous modes of variation as well as discrete cell classes.

miR-183 cluster scales mechanical pain sensitivity by regulating basal and neuropathic pain genes.

Nociception is protective and prevents tissue damage but can also facilitate chronic pain. Whether a general principle governs these two types of pain is unknown. Here, we show that both basal mechanical and neuropathic pain are controlled by the microRNA-183 (miR-183) cluster in mice. This single cluster controls more than 80% of neuropathic pain-regulated genes and scales basal mechanical sensitivity and mechanical allodynia by regulating auxiliary voltage-gated calcium channel subunits α2δ-1 and α2δ-2. Basal sensitivity is controlled in nociceptors, and allodynia involves TrkB+ light-touch mechanoreceptors. These light-touch-sensitive neurons, which normally do not elicit pain, produce pain during neuropathy that is reversed by gabapentin. Thus, a single microRNA cluster continuously scales acute noxious mechanical sensitivity in nociceptive neurons and suppresses neuropathic pain transduction in a specific, light-touch-sensitive neuronal type recruited during mechanical allodynia.

Effects of age and acute ethanol on glutamatergic neurotransmission in the medial prefrontal cortex of freely moving rats using enzyme-based microelectrode amperometry.

Ethanol abuse during adolescence may significantly alter development of the prefrontal cortex which continues to undergo structural remodeling into adulthood. Glutamatergic neurotransmission plays an important role during these brain maturation processes and is modulated by ethanol. In this study, we investigated glutamate dynamics in the medial prefrontal cortex of freely moving rats, using enzyme-based microelectrode amperometry. We analyzed the effects of an intraperitoneal ethanol injection (1 g/kg) on cortical glutamate levels in adolescent and adult rats. Notably, basal glutamate levels decreased with age and these levels were found to be significantly different between postnatal day (PND) 28-38 vs PND 44-55 (p<0.05) and PND 28-38 vs adult animals (p<0.001). We also observed spontaneous glutamate release (transients) throughout the recordings. The frequency of transients (per hour) was significantly higher in adolescent rats (PND 28-38 and PND 44-55) compared to those of adults. In adolescent rats, post-ethanol injection, the frequency of glutamate transients decreased within the first hour (p<0.05), it recovered slowly and in the third hour there was a significant rebound increase of the frequency (p<0.05). Our data demonstrate age-dependent differences in extracellular glutamate levels in the medial prefrontal cortex and suggest that acute ethanol injections have both inhibitory and excitatory effects in adolescent rats. These effects of ethanol on the prefrontal cortex may disturb its maturation and possibly limiting individuals´ control over addictive behaviors.

What is missing in health informatics standardization for pHealth?

Health systems turn everywhere, but with different speed, from organization-centered to personalized eHealth or pHealth, i.e. ubiquitous care delivery independent of time and location of the resources involved. As interoperability is an important issue in such distributed, fully integrated, intelligent and individualized environment, pHealth solutions have to comply with advanced architectural solutions based on international standards. Representing concepts and their interrelations, such architectural framework perspectives' system architecture, domains, and development process can be described by the domains' ontologies. Therefore, advanced interoperability approaches have to refer to ontology principles, finally resulting in ontology-driven approaches to semantically interoperable and sustainable health information systems. The paper investigates functional requirements, interoperability levels, architectural approaches to pHealth systems, thereby analyzing and classifying related existing or emerging standards.

PCI-24781, a Novel Hydroxamic Acid HDAC Inhibitor, Exerts Cytotoxicity and Histone Alterations via Caspase-8 and FADD in Leukemia Cells.

Histone deacetylase inhibitors (HDACi) have become a promising new avenue for cancer therapy, and many are currently in Phase I/II clinical trials for various tumor types. In the present study, we show that apoptosis induction and histone alterations by PCI-24781, a novel hydroxamic acid-based HDAC inhibitor, require caspase-8 and the adaptor molecule, Fas-associated death domain (FADD), in acute leukemia cells. PCI-24781 treatment also causes an increase in superoxide levels, which has been reported for other HDACi. However, an antioxidant does not reverse histone alterations caused by PCI-24781, indicating that ROS generation is likely downstream of the effects that PCI-24781 exerts on histone H3. Taken together, these results provide insight into the mechanism of apoptosis induction by PCI-24781 in leukemia by highlighting the roles of caspase-8, FADD and increased superoxide levels.

La neuritis óptica y su seguimiento con tomografía óptica de coherencia (OCT) Informe de caso / Optic neuritis followed by optical coherente tomography (OCT). Case report

Objetivo: Describir las formas de presentación de la neuritis óptica, haciendo énfasis en el síndrome postviral y la neurítis óptica postviral, entidades que van de la mano, mostrando sus asociaciones de tipo local y sistémico. Adicionalmente, se muestra el seguimiento imaginológico realizado con tomografía óptica de coherencia, lo cual permite la observación clara del episodio agudo pero más allá de su diagnóstico por medio de la observación del fondo de ojo. Metodología: Se presenta un caso de neuritis óptica en una mujer de 25 años quien consulta por visión borrosa y fotofobia; se encontró en el fondo de ojo borramiento e hiperemia marcada del disco óptico asociado a pérdida marcada de agudeza visual en el ojo izquierdo; tiene historia de un episodio viral inespecífico, por lo que se hace diagnóstico de neuritis óptica anterior, posiblemente de origen postviral. Se descarta clínicamente enfermedad desmielinizante. Conclusiones: La neuritis óptica es una patología poco frecuente que tiene implicaciones serias en cuanto a pérdida irreversible de la agudeza visual si no se realiza diagnóstico y tratamiento oportuno; en este caso particular se sospechó origen viral aunque no fue confirmado.

Aim: To describe the different ways of clinic presentation of optic neuritis, empathizing in postviral syndrome and postviral optic neuritis; these entities are related in local and systemic compromises. In this case, the patient was ollowed with coherence optic tomography, which allowed a clear observation of the acute event and its evolution. Methodology: We present a case report of optic neuritis in a 25 years old woman, who complains for blurry vision and photophobia. Clinical examination showed blurring of the disk margin and marked hyperemia, associated with visual oss in left eye. This patient had an unexpected episode of viral infection, carrying us to a possible diagnosis of anterior optic neuritis from viral origin. Conclusions: Optic neuritis is an unfrequented condition that may have serious implications related to irreversible visual loss without opportune diagnosis and treatment.