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Adult mammalian brains have largely lost neuroregeneration capability except for a few niches. Previous studies have converted glial cells into neurons, but the total number of neurons generated is limited and the therapeutic potential is unclear. Here, we demonstrate that NeuroD1-mediated in situ astrocyte-to-neuron conversion can regenerate a large number of functional new neurons after ischemic injury. Specifically, using NeuroD1 adeno-associated virus (AAV)-based gene therapy, we were able to regenerate one third of the total lost neurons caused by ischemic injury and simultaneously protect another one third of injured neurons, leading to a significant neuronal recovery. RNA sequencing and immunostaining confirmed neuronal recovery after cell conversion at both the mRNA level and protein level. Brain slice recordings found that the astrocyte-converted neurons showed robust action potentials and synaptic responses at 2 months after NeuroD1 expression. Anterograde and retrograde tracing revealed long-range axonal projections from astrocyte-converted neurons to their target regions in a time-dependent manner. Behavioral analyses showed a significant improvement of both motor and cognitive functions after cell conversion. Together, these results demonstrate that in vivo cell conversion technology through NeuroD1-based gene therapy can regenerate a large number of functional new neurons to restore lost neuronal functions after injury., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The paraventricular nucleus of the thalamus (PVT) is thought to regulate behavioral responses under emotionally arousing conditions. Reward-associated cues activate PVT neurons; however, the specific PVT efferents regulating reward seeking remain elusive. Using a cued sucrose-seeking task, we manipulated PVT activity under two emotionally distinct conditions: (1) when reward was available during the cue as expected or (2) when reward was unexpectedly omitted during the cue. Pharmacological inactivation of the anterior PVT (aPVT), but not the posterior PVT, increased sucrose seeking only when reward was omitted. Consistent with this, photoactivation of aPVT neurons abolished sucrose seeking, and the firing of aPVT neurons differentiated reward availability. Photoinhibition of aPVT projections to the nucleus accumbens or to the amygdala increased or decreased, respectively, sucrose seeking only when reward was omitted. Our findings suggest that PVT bidirectionally modulates sucrose seeking under the negative (frustrative) conditions of reward omission., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Although the developmental principles of sensory and cognitive processing have been extensively investigated, their synergy has been largely neglected. During early life, most sensory systems are still largely immature. As a notable exception, the olfactory system is functional at birth, controlling mother–offspring interactions and neonatal survival. Here, we elucidate the structural and functional principles underlying the communication between olfactory bulb (OB) and lateral entorhinal cortex (LEC)—the gatekeeper of limbic circuitry—during neonatal development. Combining optogenetics, pharmacology, and electrophysiology in vivo with axonal tracing, we show that mitral cell–dependent discontinuous theta bursts in OB drive network oscillations and time the firing in LEC of anesthetized mice via axonal projections confined to upper cortical layers. Acute pharmacological silencing of OB activity diminishes entorhinal oscillations, whereas odor exposure boosts OB–entorhinal coupling at fast frequencies. Chronic impairment of olfactory sensory neurons disrupts OB–entorhinal activity. Thus, OB activity shapes the maturation of entorhinal circuits. [ABSTRACT FROM AUTHOR]