Novel treatment approaches based on identification of molecular determinants in neuropsychiatric diseases

Es ist bekannt, dass bei bedeutenden neuropsychiatrischen Krankheiten, einschließlich Schizophrenie und manisch-depressiven Erkrankungen/bipolaren Störungen, höhere Gehirnfunktionen beeinträchtigt werden. Dies führt zu desorganisiertem Denken und kognitiven Verschlechterungen bei den Betroffenen. Vorhandene Behandlungsmöglichkeiten können zwar die Leitsymptome beider Krankheiten reduzieren, allerdings sind kognitive Beeinträchtigungen nicht behandelbar. Um die Bedeutung der Kognition und die damit zugrunde liegenden Mechanismen für wichtige neuropsychiatrische Krankheiten besser zu verstehen und neue Behandlunsgwege für diese zu entwickeln, haben wir Mausmodelle hierfür entwickelt. Wir haben gezeigt, dass Erythropoietin (EPO), ein hämatopoietischer Wachstumsfaktor mit vielseitigen neuroprotektiven Eigenschaften, sich auch positiv auf kognitive Leistungen auswirkt; dies trifft sowohl unter gesunden wie unter pathologischen Bedingungen zu. Eine dreiwöchige Behandlung von jungen (28 Tage alten), gesunden Mäusen mit EPO resultiert in einer signifikanten Verbesserung in Hippocampus abhängigen Kontext-Gedächtnis Aufgaben. Elektrophysiologische and histologische Analysen an hippocampalen Schnitten von EPO-behandelten Mäusen zeigen, dass EPO excitatorische und inhibitorische Neurotransmission moduliert ohne die Gesamtzahl der Synapsen zu beeinflussen. Um eine eingehende Untersuchung der EPO Effekte unter pathologischen Bedingungen zu ermöglichen, haben wir ein Tiermodell entwickelt, bei dem jungen Mäusen stereotaktisch eine standardisierte unilaterale parietale Verletzung zugefügt wird. Diese am rechten parietalen Cortex durchgeführte Kälteläsion führt zu kognitiven Beeinträchtigungen und bilateraler Gehirnatrophie; dies erinnert stark an die Pathophysiologie, die bei der Schizophrenie beobachtet wird. Während die Gesamtanzahl der Neuronen und Astrocyten in verschiedenen Gehirnregionen unverändert bleibt, was auf eine nicht-gliotische Neurodegeneration (wie bei Schizophrenie) hinweist, verursacht die Läsion dennoch einen eindeutigen Phänotyp. Es kommt zu einer frühen und bleibenden Aktivierung von Mikroglia Zellen, einer Erniedrigung von Oligodendroyten-/Myelin-assoziierten Proteinen, einem relativen Anstieg von Determinanten der GABAergen Neurotransmission und einer Reduktion eines präsynaptischen Proteins, Synapsin 1. Globale Gehirnatrophie und kognitive Verschlechterungen sowie die Veränderungen in der zellulären Zusammensetzung / Proteinexpression können durch frühe EPO Intervention verhindert werden. Obwohl der genaue Mechanismus noch geklärt werden muss, öffnen diese tiefgreifenden EPO Effekte neue Wege für Prophylaxe und Therapie neuropsychiatrischer Erkrankungen, wie z.B. Schizophrenie

Hot Air Drying of Green Table Olives

The characteristics of hot air-drying of green table olives (Domat variety) by using a tray dryer were studied. Air temperature varied from 40 to 70 °C with an air velocity of 1 m/s. Drying rate curves were determined and quality of dried green olives was evaluated by instrumental analysis (bulk density, particle density, porosity, shrinkage, moisture content, water activity, colour value, protein content, oil content, peroxide value and acidity). Consumers’ acceptance test and microbiological analysis were also applied

Hot Air Drying of Green Table Olives

The characteristics of hot air-drying of green table olives (Domat variety) by using a tray dryer were studied. Air temperature varied from 40 to 70 °C with an air velocity of 1 m/s. Drying rate curves were determined and quality of dried green olives was evaluated by instrumental analysis (bulk density, particle density, porosity, shrinkage, moisture content, water activity, colour value, protein content, oil content, peroxide value and acidity). Consumers’ acceptance test and microbiological analysis were also applied

Expression of constitutively active erythropoietin receptor in pyramidal neurons of cortex and hippocampus boosts higher cognitive functions in mice

<p>Abstract</p> <p>Background</p> <p>Erythropoietin (EPO) and its receptor (EPOR) are expressed in the developing brain and their transcription is upregulated in adult neurons and glia upon injury or neurodegeneration. We have shown neuroprotective effects and improved cognition in patients with neuropsychiatric diseases treated with EPO. However, the critical EPO targets in brain are unknown, and separation of direct and indirect effects has remained difficult, given the role of EPO in hematopoiesis and brain oxygen supply.</p> <p>Results</p> <p>Here we demonstrate that mice with transgenic expression of a constitutively active EPOR isoform (cEPOR) in pyramidal neurons of cortex and hippocampus exhibit enhancement of spatial learning, cognitive flexibility, social memory, and attentional capacities, accompanied by increased impulsivity. Superior cognitive performance is associated with augmented long-term potentiation of cEPOR expressing neurons in hippocampal slices.</p> <p>Conclusions</p> <p>Active EPOR stimulates neuronal plasticity independent of any hematopoietic effects and in addition to its neuroprotective actions. This property of EPOR signaling should be exploited for defining novel strategies to therapeutically enhance cognitive performance in disease conditions.</p

Erythropoietin enhances hippocampal long-term potentiation and memory

<p>Abstract</p> <p>Background</p> <p>Erythropoietin (EPO) improves cognition of human subjects in the clinical setting by as yet unknown mechanisms. We developed a mouse model of robust cognitive improvement by EPO to obtain the first clues of how EPO influences cognition, and how it may act on hippocampal neurons to modulate plasticity.</p> <p>Results</p> <p>We show here that a 3-week treatment of young mice with EPO enhances long-term potentiation (LTP), a cellular correlate of learning processes in the CA1 region of the hippocampus. This treatment concomitantly alters short-term synaptic plasticity and synaptic transmission, shifting the balance of excitatory and inhibitory activity. These effects are accompanied by an improvement of hippocampus dependent memory, persisting for 3 weeks after termination of EPO injections, and are independent of changes in hematocrit. Networks of EPO-treated primary hippocampal neurons develop lower overall spiking activity but enhanced bursting in discrete neuronal assemblies. At the level of developing single neurons, EPO treatment reduces the typical increase in excitatory synaptic transmission without changing the number of synaptic boutons, consistent with prolonged functional silencing of synapses.</p> <p>Conclusion</p> <p>We conclude that EPO improves hippocampus dependent memory by modulating plasticity, synaptic connectivity and activity of memory-related neuronal networks. These mechanisms of action of EPO have to be further exploited for treating neuropsychiatric diseases.</p

Submitted by

Novel treatment approaches based on identification of molecular determinants in neuropsychiatric disease

Opposing Cholinergic and Serotonergic Modulation of Layer 6 in Prefrontal Cortex

Prefrontal cortex is a hub for attention processing and receives abundant innervation from cholinergic and serotonergic afferents. A growing body of evidence suggests that acetylcholine (ACh) and serotonin (5-HT) have opposing influences on tasks requiring attention, but the underlying neurophysiology of their opposition is unclear. One candidate target population is medial prefrontal layer 6 pyramidal neurons, which provide feedback modulation of the thalamus, as well as feed-forward excitation of cortical interneurons. Here, we assess the response of these neurons to ACh and 5-HT using whole cell recordings in acute brain slices from mouse cortex. With application of exogenous agonists, we show that individual layer 6 pyramidal neurons are bidirectionally-modulated, with ACh and 5-HT exerting opposite effects on excitability across a number of concentrations. Next, we tested the responses of layer 6 pyramidal neurons to optogenetic release of endogenous ACh or 5-HT. These experiments were performed in brain slices from transgenic mice expressing channelrhodopsin in either ChAT-expressing cholinergic neurons or Pet1-expressing serotonergic neurons. Light-evoked endogenous neuromodulation recapitulated the effects of exogenous neurotransmitters, showing opposing modulation of layer 6 pyramidal neurons by ACh and 5-HT. Lastly, the addition of 5-HT to either endogenous or exogenous ACh significantly suppressed the excitation of pyramidal neurons in prefrontal layer 6. Taken together, this work suggests that the major corticothalamic layer of prefrontal cortex is a substrate for opposing modulatory influences on neuronal activity that could have implications for regulation of attention

Hypocretin/orexin neurons encode social discrimination and exhibit a sex-dependent necessity for social interaction

Summary: The hypothalamus plays a crucial role in the modulation of social behavior by encoding internal states. The hypothalamic hypocretin/orexin neurons, initially identified as regulators of sleep and appetite, are important for emotional and motivated behaviors. However, their role in social behavior remains unclear. Using fiber photometry and behavioral analysis, we show here that hypocretin neurons differentially encode social discrimination based on the nature of social encounters. The optogenetic inhibition of hypocretin neuron activity or blocking of hcrt-1 receptors reduces the amount of time mice are engaged in social interaction in males but not in females. Reduced hcrt-1 receptor signaling during social interaction is associated with altered activity in the insular cortex and ventral tegmental area in males. Our data implicating hypocretin neurons as sexually dimorphic regulators within social networks have significant implications for the treatment of neuropsychiatric diseases with social dysfunction, particularly considering varying prevalence among sexes