Local inhibitory GABAergic and excitatory glutamatergic neurons are important for midbrain dopaminergic and hindbrain serotonergic pathways controlling motivation, mood, and voluntary movements. Such neurons reside both within the dopaminergic nuclei, and in adjacent brain structures, including the rostromedial and laterodorsal tegmental nuclei. Compared with the monoaminergic neurons, the development, heterogeneity, and molecular characteristics of these regulatory neurons are poorly understood. We show here that different GABAergic and glutamatergic subgroups associated with the monoaminergic nuclei express specific transcription factors. These neurons share common origins in the ventrolateral rhombomere 1, where the postmitotic selector genes Tal1, Gata2 and Gata3 control the balance between the generation of inhibitory and excitatory neurons. In the absence of Tal1, or both Gata2 and Gata3, the GABAergic precursors adopt glutamatergic fates and populate the glutamatergic nuclei in excessive numbers. Together, our results uncover developmental regulatory mechanisms, molecular characteristics, and heterogeneity of central regulators of monoaminergic circuits.

Delayed delivery of MANF to rat brain after ischemic stroke promotes functional recovery and recruits phagocytic immune cells.

Stroke is the leading cause of disability in adults. Drug treatments that target stroke-induced pathological mechanisms and promote recovery are desperately needed. In the brain, an ischemic event triggers major inflammatory responses that are mediated by the resident microglial cells. In this review, we focus on the microglia activation after ischemic brain injury as a target of immunomodulatory therapeutics. We divide the microglia-mediated events following ischemic stroke into three categories: acute, subacute, and long-term events. This division encompasses the spatial and temporal dynamics of microglia as they participate in the pathophysiological changes that contribute to the symptoms and sequela of a stroke. The importance of Toll-like receptor (TLR) signaling in the outcomes of these pathophysiological changes is highlighted. Increasing evidence shows that microglia have a complex role in stroke pathophysiology and they mediate both detrimental and beneficial effects on stroke outcome. So far, most of the pharmacological studies in experimental models of stroke have focused on neuroprotective strategies which are impractical for clinical applications. Post-ischemic inflammation is long lasting and thus, could provide a therapeutic target for novel delayed drug treatment. However, more studies are needed to elucidate the role of microglia in the recovery process from an ischemic stroke and to evaluate the therapeutic potential of modulating post-ischemic inflammation to promote functional recovery.