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The similarities and differences between nervous systems of various species result from developmental constraints and specific adaptations.sup.1-4. Comparative analyses of the prefrontal cortex (PFC), a cerebral cortex region involved in higher-order cognition and complex social behaviours, have identified true and potential human-specific structural and molecular specializations.sup.4-8, such as an exaggerated PFC-enriched anterior-posterior dendritic spine density gradient.sup.5. These changes are probably mediated by divergence in spatiotemporal gene regulation.sup.9-17, which is particularly prominent in the midfetal human cortex.sup.15,18-20. Here we analysed human and macaque transcriptomic data.sup.15,20 and identified a transient PFC-enriched and laminar-specific upregulation of cerebellin 2 (CBLN2), a neurexin (NRXN) and glutamate receptor-[delta] GRID/GluD-associated synaptic organizer.sup.21-27, during midfetal development that coincided with the initiation of synaptogenesis. Moreover, we found that species differences in level of expression and laminar distribution of CBLN2 are, at least in part, due to Hominini-specific deletions containing SOX5-binding sites within a retinoic acid-responsive CBLN2 enhancer. In situ genetic humanization of the mouse Cbln2 enhancer drives increased and ectopic laminar Cbln2 expression and promotes PFC dendritic spine formation. These findings suggest a genetic and molecular basis for the anterior-posterior cortical gradient and disproportionate increase in the Hominini PFC of dendritic spines and a developmental mechanism that may link dysfunction of the NRXN-GRID-CBLN2 complex to the pathogenesis of neuropsychiatric disorders. The authors identify deletions in a retinoic acid signalling responsive genetic element that leads to disproportionate increase of dendritic spines on neurons of the human prefrontal cortex., Author(s): Mikihito Shibata [sup.1] , Kartik Pattabiraman [sup.1] [sup.2] , Sydney K. Muchnik [sup.1] [sup.3] , Navjot Kaur [sup.1] , Yury M. Morozov [sup.1] , Xiaoyang Cheng [sup.4] [sup.5] [sup.6] [...]

The brains of humans and other mammals are highly vulnerable to interruptions in blood flow and decreases in oxygen levels. Here we describe the restoration and maintenance of microcirculation and molecular and cellular functions of the intact pig brain under ex vivo normothermic conditions up to four hours post-mortem. We have developed an extracorporeal pulsatile-perfusion system and a haemoglobin-based, acellular, non-coagulative, echogenic, and cytoprotective perfusate that promotes recovery from anoxia, reduces reperfusion injury, prevents oedema, and metabolically supports the energy requirements of the brain. With this system, we observed preservation of cytoarchitecture; attenuation of cell death; and restoration of vascular dilatory and glial inflammatory responses, spontaneous synaptic activity, and active cerebral metabolism in the absence of global electrocorticographic activity. These findings demonstrate that under appropriate conditions the isolated, intact large mammalian brain possesses an underappreciated capacity for restoration of microcirculation and molecular and cellular activity after a prolonged post-mortem interval. A specialized technology can restore and preserve microcirculation and cellular functions hours post-mortem in an isolated pig brain., Author(s): Zvonimir Vrselja [sup.1] [sup.2] , Stefano G. Daniele [sup.1] [sup.2] [sup.3] , John Silbereis [sup.1] [sup.2] , Francesca Talpo [sup.1] [sup.2] [sup.4] , Yury M. Morozov [sup.1] [sup.2] , [...]

Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (C[B.sub.1]R) is critical for the central regulation of food intake. Here we test whether C[B.sub.1]R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of C[B.sub.1]R activity increases feeding, and notably, C[B.sub.1]R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for C[B.sub.1]R -induced feeding, because designer-receptors-exclusively-activated-by-designer-drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD-mediated activation of POMC neurons enhances C[B.sub.1]R-driven feeding. The Pomc gene encodes both the anorexigenic peptide a-melanocyte-stimulating hormone, and the opioid peptide β-endorphin. C[B.sub.1]R activation selectively increases β-endorphin but not α- melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute C[B.sub.1]R -induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish C[B.sub.1]R -induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids., Feeding behaviour is under the control of hypothalamic circuits (1). In the hypothalamic arcuate nucleus (ARC), Agouti-related peptide (AgRP)expressing neurons, when activated, promote food intake (2,3), whereas POMC-producing neurons promote [...]