The main goal of this proposal is to investigate transcriptional programs that govern functional maturation of adult-born neurons. Our lab aims to uncover new regulatory pathways that control activity-dependent survival and integration of neural precursors in the adult brain, which may be useful towards development of neuro- regenerative therapies. The rodent olfactory system features robust and lifelong neurogenesis and thereby serves as a well-characterized model to examine the mechanisms of synaptogenesis and circuit rewiring in the adult brain. Adult-born neurons arise in the subventricular zone of the lateral ventricles and migrate anteriorly in the rostral migratory stream. On migration into the olfactory bulb, adult-born neurons that receive activation cues from pre-existing circuitry differentially execute transcriptional programs that sustain survival and functional maturation. We recently reported that survival and integration is critically linked o signaling by local interneurons that secrete the neuropeptide corticotropin-releasing hormone (CRH). Local CRH signaling induces transcriptional activation in adult-born neurons, downregulates apoptotic signaling, and drives the development of synaptic infrastructure. It remains unknown, however, how downstream effectors transduce this extrinsic signal into transcriptional programs that underwrite synaptic assembly, morphological development, and synaptic maturation. Using gain- and loss-of-function animal models of local CRH signaling, we discovered that CRH signaling dynamically regulates expression of the brain-specific Homeobox-containing transcription factor Brain-5 (BRN5). More specifically, overactive CRH signaling upregulates transcription of BRN5, and decreased CRH signaling downregulates transcription of BRN5. BRN5 is described as a pro-neural differentiation factor in embryonic neural precursors, and its expression remains high in the olfactory areas of the adult brain. Littl is known about the function of BRN5 in adult-born neuron development. Understanding the molecular links between extrinsic cues and pro-neural transcriptional programs that support normal brain cell development in the adult brain may help guide tissue repair or regeneration strategies in neurodevelopmental or degenerative disease. Therefore, to elucidate the role of BRN5 in neuronal development in the adult brain, I will use biochemical, genetic, and electrophysiological techniques to test the hypothesis that: BRN5 influences synaptic maturation in adult-born neurons.
The overarching goal of this proposal is to examine the transcriptional programs that underlie activity- dependent survival, maturation, and circuit integration of adult-born neurons. We recently discovered that the putative pro-neural transcription factor, Brain-5, is dynamically expressed in the regenerating olfactory circuit and herein propose to test the hypothesis that Brain-5 influences synaptic maturation in adult-born neurons. Understanding the mechanisms of neuronal development and circuit plasticity in the adult brain may help guide therapeutic cell renewal and repair approaches in neurodevelopmental or degenerative disease.
| Liu, Gary; Patel, Jay M; Tepe, Burak et al. (2018) An Objective and Reproducible Test of Olfactory Learning and Discrimination in Mice. J Vis Exp : |
| McClard, Cynthia K; Kochukov, Mikhail Y; Herman, Isabella et al. (2018) POU6f1 Mediates Neuropeptide-Dependent Plasticity in the Adult Brain. J Neurosci 38:1443-1461 |
