An orbitocortical-thalamic circuit suppresses binge alcohol-drinking.

Alcohol consumption remains a significant global health challenge, causing millions of direct and indirect deaths annually. Intriguingly, recent work has highlighted the prefrontal cortex, a major brain area that regulates inhibitory control of behaviors, whose activity becomes dysregulated upon alcohol abuse. However, whether an endogenous mechanism exists within this brain area that limits alcohol consumption is unknown. Here we identify a discrete GABAergic neuronal ensemble in the medial orbitofrontal cortex (mOFC) that is selectively recruited during binge alcohol-drinking and intoxication. Upon alcohol intoxication, this neuronal ensemble suppresses binge drinking behavior. Optogenetically silencing of this population, or its ablation, results in uncontrolled binge alcohol consumption. We find that this neuronal ensemble is specific to alcohol and is not recruited by other rewarding substances. We further show, using brain-wide analysis, that this neuronal ensemble projects widely, and that its projections specifically to the mediodorsal thalamus are responsible for regulating binge alcohol drinking. Together, these results identify a brain circuit in the mOFC that serves to protect against binge drinking by halting alcohol intake. These results provide valuable insights into the complex nature of alcohol abuse and offers potential avenues for the development of mOFC neuronal ensemble-targeted interventions.

Pathophysiological and pharmacological relevance of TLR4 in peripheral immune cells after stroke.

Stroke is a very common disease being the leading cause of death and disability worldwide. The immune response subsequent to an ischemic stroke is a crucial factor in its physiopathology and outcome. This response is not limited to the injury site. In fact, the immune response to the ischemic process mobilizes mainly circulating cells which upon activation will be recruited to the injury site. When a stroke occurs, molecules that are usually retained inside the cell bodies are released into the extracellular space by uncontrolled cell death. These molecules can bind to the Toll-like receptor 4 (TLR4) in circulating immune cells which are then activated, eliciting, although not exclusively, the inflammatory response to the stroke. In this review, we present an up-to-date summary of the role of the different peripheral immune cells in stroke as well as the role of TLR4 in the function of each cell type in ischemia. Also, we summarize the different antagonists developed against TLR4 and their potential as a pharmacological tool for stroke treatment.

Specific Features of SVZ Neurogenesis After Cortical Ischemia: a Longitudinal Study.

Stroke is a devastating disease with an increasing prevalence. Part of the current development in stroke therapy is focused in the chronic phase, where neurorepair mechanisms such as neurogenesis, are involved. In the adult brain, one of the regions where neurogenesis takes place is the subventricular zone (SVZ) of the lateral ventricles. Given the possibility to develop pharmacological therapies to stimulate this process, we have performed a longitudinal analysis of neurogenesis in a model of cortical ischemia in mice. Our results show an initial decrease of SVZ proliferation at 24 h, followed by a recovery leading to an increase at 14d and a second decrease 28d after stroke. Coinciding with the 24 h proliferation decrease, an increase in the eutopic neuroblast migration towards the olfactory bulb was observed. The analysis of the neuroblast ectopic migration from the SVZ toward the lesion showed an increase in this process from day 14 after the insult. Finally, our data revealed an increased number of new cortical neurons in the peri-infarct cortex 65d after the insult. In summary, we report here critical check-points about post-stroke neurogenesis after cortical infarcts, important for the pharmacological modulation of this process in stroke patients.