Salk Institute

GageLab

Research

Our laboratory focuses on the following areas:

Neurogenesis

The continuous incorporation of new neurons into the dentate gyrus of the adult hippocampus – a process also known as neurogenesis - raises exciting questions about brain plasticity during memory acquisition and learning in adulthood. We are currently investigating the functional significance of adult-born neurons using a combination of techniques including live imaging of active neurons in the hippocampus and single cell sequencing during memory acquisition. Our goal is to understand the molecular basis of memory encoding during adult neurogenesis. The results of our studies could impact our understanding of the basic components of learning and provide insight into memory decline during aging and disorders that impair normal cognitive processes, such as Alzheimer Disease.

Modeling neurodegenerative and neuropsychiatric disorders using induced pluripotent stem cells (iPSCs) and directly reprogrammed neurons (iN)

The use of patient-derived induced pluripotent stem cells (iPSCs) offers a unique possibility to model neuropsychiatric and neurodegenerative disorders with complex genetic etiologies. Previously the investigation of the candidate genes’ biological functions was hindered by limited access to neural tissue. By investigating iPSC-derived neurons, we are able to capture the genetic architecture of patients and healthy, matched neurotypical individuals. Our lab uses reprogramming technology to study various aspects of neuronal development in neurological diseases such as Schizophrenia, Autism Spectrum Disorders, Bipolar Disease, Parkinson’s Disease, and Multiple Sclerosis. We are now able to compare specific cellular phenotypes, such as neuronal connectivity, neuronal firing properties and gene expression profiles. This methodology represents a strategy for understanding the basic biological aspects underlying complex neuropsychiatric and neurodevelopmental disease and could potentially have important clinical outcomes such as development of diagnostic tools and new therapies.

Neuronal mosaicism and diversity

Mostly undervalued for its biological function, mobile element-derived DNA comprises nearly half of the human genome. Challenging the dogma that neuronal genomes are invariable, recent studies have demonstrated that mobile elements such as LINE-1 (L1) and Alu retrotransposons actively retrotranspose during neurogenesis, thereby creating neuron-to-neuron genomic diversity. In addition, mounting data demonstrates that mobile elements are misregulated in certain neurological disorders, including Rett Syndrome and Schizophrenia. In our lab we are investigating the potential consequences of mobile element-derived genomic diversity and the possible contribution of mobile elements to disease. We are using a combination of state-of-the-art techniques, including single cell genome isolation and next generation sequencing, to reveal new somatic DNA insertions derived from mobile element activity

Human evolution

Identifying cellular and molecular differences between human and non-human primates (NHPs) is essential to understanding the evolution and diversity of our own species. Until now, preserved tissues have been the main tools for most comparative studies between humans and our closest living relatives (chimpanzees and bonobos). However, these tissue samples do not fairly represent the distinctive traits of live cell behavior and are not amenable to genetic manipulation. Using reprogramming technology, we have generated and characterized iPSCs and have derived neurons from NHPs (chimpanzees, bonobos, gorillas). These cells consist on a unique biological material to elucidate relevant phenotypical differences between humans and NHPs, and those differences could have potential adaptation value and contribute to the understanding of great ape evolution.

 

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