Influence of the in vivo deregulation of the expression of ntrk3 (trkc) on cortical development of a murine model of panic/anxiety disorder

Alteracions durant el desenvolupament cerebral produirien canvis en la connectivitat neuronal i la bioquímica cel•lular que podrien resultar en una disfunció cognitiva i/o emocional, desembocant a trastorns psiquiàtrics. Les neurotrofines intervenen en els processos del neurodesenvolupament i en la funcionalitat del cervell adult i, conseqüentment, serien bons candidats com a factors de predisposició en diverses malalties mentals. S’ha suggerit la implicació del receptor de la neurotrofina 3, TrkC, en el trastorn de pànic. Nosaltres proposem que la sobreexpressió del gen NTRK3 (TrkC) és un mediador comú dels desencadenants genètics i ambientals d’aquest trastorn. Concretament, la seva desregulació podria produir canvis estructurals i funcionals a l’escorça cerebral dels pacients pel seu paper durant l’establiment dels circuïts corticals i la neuroplasticitat a l’adult, probablement esdevenint elements de predisposició a patir atacs de pànic. Els objectius principals d’aquest treball han estat: 1/determinar la contribució específica del gen NTRK3 a les alteracions de l’escorça cerebral observades en pacients, utilitzant un model murí modificat genèticament (TgNTRK3), i 2/analitzar l’impacte específic de la sobreexpressió de NTRK3 sobre la corticogènesi durant estadis embrionaris o postnatals estudiant la neurogènesi i la neuritogènesi. Els resultats indiquen que la sobreexpressió de NTRK3 als ratolins produeix una reducció del gruix de l’escorça frontal, recapitulant la hipofrontalitat dels pacients, que comportaria una menor inhibició dels nuclis subcorticals del sistema límbic com l’amígdala, i alteracions citoarquitectòniques a l’escorça prefrontal medial que recolzen la hipòtesi del seu mal funcionament. Tanmateix, els ratolins TgNTRK3 presenten canvis estructurals a l’escorça somatosensorial, suggerint que el processament de la informació sensorial podria estar alterat, el que encara no s’ha explorat en pacients. La sobreexpressió de NTRK3 també afecta la neuritogènesi en cultius primaris corticals i modifica la resposta de les neurones a l’estimulació amb neurotrofines. Per tant, el fenotip cortical adult dels TgNTRK3 podria dependre d’alteracions durant la corticogènesi.

Historical first descriptions of Cajal-Retzius cells: from pioneer studies to current knowledge

Santiago Ramón y Cajal developed a great body of scientific research during the last decade of 19th century, mainly between 1888 and 1892, when he published more than 30 manuscripts. The neuronal theory, the structure of dendrites and spines, and fine microscopic descriptions of numerous neural circuits are among these studies. In addition, numerous cell types (neuronal and glial) were described by Ramón y Cajal during this time using this 'reazione nera' or Golgi method. Among these neurons were the special cells of the molecular layer of the neocortex. These cells were also termed Cajal cells or Retzius cells by other colleagues. Today these cells are known as Cajal-Retzius cells. From the earliest description, several biological aspects of these fascinating cells have been analyzed (e.g., cell morphology, physiological properties, origin and cellular fate, putative function during cortical development, etc). In this review we will summarize in a temporal basis the emerging knowledge concerning this cell population with specific attention the pioneer studies of Santiago Ramón y Cajal.

Different effects of hyperlipidic diets in human lactation and adulthood: growth versus the development of obesity

After birth, the body shifts from glucose as primary energy substrate to milk-derived fats, with sugars from lactose taking a secondary place. At weaning, glucose recovers its primogeniture and dietary fat role decreases. In spite of human temporary adaptation to a high-fat (and sugars and protein) diet during lactation, the ability to thrive on this type of diet is lost irreversibly after weaning. We could not revert too the lactating period metabolic setting because of different proportions of brain/muscle metabolism in the total energy budget, lower thermogenesis needs and capabilities, and absence of significant growth in adults. A key reason for change was the limited availability of foods with high energy content at weaning and during the whole adult life of our ancestors, which physiological adaptations remain practically unchanged in our present-day bodies. Humans have evolved to survive with relatively poor diets interspersed by bouts of scarcity and abundance. Today diets in many societies are largely made up from choice foods, responding to our deeply ingrained desire for fats, protein, sugars, salt etc. Consequently our diets are not well adjusted to our physiological needs/adaptations but mainly to our tastes (another adaptation to periodic scarcity), and thus are rich in energy roughly comparable to milk. However, most adult humans cannot process the food ingested in excess because our cortical-derived craving overrides the mechanisms controlling appetite. This is produced not because we lack the biochemical mechanisms to use this energy, but because we are unprepared for excess, and wholly adapted to survive scarcity. The thrifty mechanisms compound the effects of excess nutrients and damage the control of energy metabolism, developing a pathologic state. As a consequence, an overflow of energy is generated and the disease of plenty develops.

Cortistain is expressed in a distinct subset of cortical interneurons

Cortistatin is a presumptive neuropeptide that shares 11 of its 14 amino acids with somatostatin. In contrast to somatostatin, administration of cortistatin into the rat brain ventricles specifically enhances slow wave sleep, apparently by antagonizing the effects of acetylcholine on cortical excitability. Here we show that preprocortistatin mRNA is expressed in a subset of GABAergic cells in the cortex and hippocampus that partially overlap with those containing somatostatin. A significant percentage of cortistatin-positive neurons is also positive for parvalbumin. In contrast, no colocalization was found between cortistatin and calretinin, cholecystokinin, or vasoactive intestinal peptide. During development there is a transient increase in cortistatin-expressing cells in the second postnatal week in all cortical areas and in the dentate gyrus. A transient expression of preprocortistatin mRNA in the hilar region at P16 is paralleled by electrophysiological changes in dentate granule cells. Together, these observations suggest mechanisms by which cortistatin may regulate cortical activity.

Neurites regrowth of cortical neurons by GSK3b inhibition independently of Nogo Receptor 1

Lesioned axons do not regenerate in the adult mammalian central nervous system, owing to the overexpression of inhibitory molecules such as myelin-derived proteins or chondroitin sulphate proteoglycans. In order to overcome axon inhibition, strategies based on extrinsic and intrinsic treatments have been developed. For myelin-associated inhibition, blockage with NEP1-40, receptor bodies or IN-1 antibodies has been used. In addition, endogenous blockage of cell signalling mechanisms induced by myelin-associated proteins is a potential tool for overcoming axon inhibitory signals. We examined the participation of glycogen synthase kinase 3 (GSK3) and ERK1/2 in axon regeneration failure in lesioned cortical neurons. We also investigated whether pharmacological blockage of GSK3 and ERK1/2 activities facilitates regeneration after myelin-directed inhibition in two models: i) cerebellar granule cells and ii) lesioned entorhino-hippocampal pathway in slice cultures, and whether the regenerative effects are mediated by Nogo Receptor 1 (NgR1). We demonstrate that, in contrast to ERK1/2 inhibition, the pharmacological treatment of GSK3 inhibition strongly facilitated regrowth of cerebellar granule neurons over myelin independently of NgR1. Lastly these regenerative effects were corroborated in the lesioned EHP in NgR1 -/- mutant mice. These results provide new findings for the development of new assays and strategies to enhance axon regeneration in injured cortical connections.

The natural hallucinogen 5-MeO-DMT, component of Ayahuasca, disrupts cortical function in rats: reversal by antipsychotic drugs

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen component of Ayahuasca, an Amazonian beverage traditionally used for ritual, religious and healing purposes that is being increasingly used for recreational purposes in US and Europe. 5MeO-DMT is of potential interest for schizophrenia research owing to its hallucinogenic properties. Two other psychotomimetic agents, phencyclidine and 2,5-dimethoxy-4-iodo-phenylisopropylamine (DOI), markedly disrupt neuronal activity and reduce the power of low frequency cortical oscillations (<4 Hz, LFCO) in rodent medial prefrontal cortex (mPFC). Here we examined the effect of 5-MeO-DMT on cortical function and its potential reversal by antipsychotic drugs. Moreover, regional brain activity was assessed by blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). 5-MeO-DMT disrupted mPFC activity, increasing and decreasing the discharge of 51 and 35% of the recorded pyramidal neurons, and reducing (−31%) the power of LFCO. The latter effect depended on 5-HT1A and 5-HT2A receptor activation and was reversed by haloperidol, clozapine, risperidone, and the mGlu2/3 agonist LY379268. Likewise, 5-MeO-DMT decreased BOLD responses in visual cortex (V1) and mPFC. The disruption of cortical activity induced by 5-MeO-DMT resembles that produced by phencyclidine and DOI. This, together with the reversal by antipsychotic drugs, suggests that the observed cortical alterations are related to the psychotomimetic action of 5-MeO-DMT. Overall, the present model may help to understand the neurobiological basis of hallucinations and to identify new targets in antipsychotic drug development.