“I want to be a ballet dancer,” said Billy Elliot in the movie of the same name. His father had other ideas: “Lads do football…or boxing…or wrestling!” Perhaps Billy just wanted to protect his brain from contact sports? And what about the father? Had he, perhaps, read MIT’s Joseph Altman in the 1960s, or Boston University’s Michael Kaplan and James Hinds, in the 1970s, identifying radio-labeled neuroblasts in the adult hippocampus and olfactory bulb? If those pioneers reassured Billy’s father that neurogenesis protected the brain, then the older Elliott was before his time, and well ahead of the first Keystone Symposium on the topic. It is ironic, then, that the symposium concluded with a nod to Billy—limbo dancing on a packed floor and mambo lines snaking through the Sagebrush Inn Conference Center.
Two hundred scientists and physicians ascended to Taos, New Mexico, for the inaugural Keystone Symposium on Adult Neurogenesis, held 9-14 January 2011. In 41 talks, leaders in the field addressed everything from the original discovery of adult neurogenesis and the regulation of neural stem cells (NSC) in the central nervous system, to the functional implications of NSCs in neurological disorders, as well as the latest pharmaceutical developments in the field. Sponsored by Abbott Laboratories, the meeting was organized by Jenny Hsieh, University of Texas Southwestern Medical Center at Dallas; Fred Gage, The Salk Institute for Biological Studies, La Jolla, California; Alejandro Schinder, Fundacion Instituto Leloir, Buenos Aires, Argentina; and Pierre-Marie Lledo, Pasteur Institute, Paris, France.
In his keynote address, Gage chronicled advances in adult neurogenesis since Altman’s pioneering work on rodents in the 1960s. It took nearly 30 more years for the scientific community to put to sleep the “no new neurons” dogma that dominated at the time (see Rakic, 1985). Though the functional and therapeutic relevance of newborn neurons remains inconclusive, several thousand publications over the past decade collectively attest that this new subfield in neurobiology has become firmly established. Gage attributed this exponential progress to methodological and technological advances. He emphasized the importance of technology in the future if scientists wish to fully understand what controls adult neurogenesis. “Adult neurogenesis has emerged as a dynamic and broadly relevant field in neuroscience. The challenge for the future will be to reveal the mechanisms underlying the process,” said Gage.
Gage and his group are developing high-throughput models, driven by cloud computing, of the murine dentate gyrus (DG) circuitry that describes 300,000 cells and one billion synapses. By comparison, the human DG comprises 20 million cells, indicating that more technological advances are needed before the human dentate gyrus can be modeled.
Regulatory Mechanisms in Adult Hippocampal Neurogenesis (AHN)
In the mammalian brain, adult neurogenesis occurs in the dentate gyrus of the hippocampus and in the subventricular zone. The first session focused on how signals within these neurogenic niches control proliferation and differentiation of neural stem cells (NSCs), which are capable of both self-renewal and multipotent differentiation into various types of mature and functional neurons. The work of Arturo Alvarez-Buylla, University of California, San Francisco, implicated the Gli1/Sonic hedgehog pathway, as well as the location of NSCs within the SVZ as regulators of neuron specificity in mice. Jonas Frisén, Karolinska Institute, Sweden, captivated the audience with his studies that pioneered carbon dating to retrospectively determine the age of neural cells and thereby identify neurogenic regions within the human brain. A presentation by Dieter Chichung Lie, Helmholtz Zentrum Munich, Germany, implicated Notch signaling as a regulatory mechanism of Sox2 expression in murine NSCs, controlling stem cell maintenance and differentiation for proper hippocampal function.
Jenny Hsieh chaired a session that surveyed the molecular pathways important in adult neurogenesis. Her talk emphasized cell-intrinsic regulators. Hsieh focused on the transcription repressor REST/NRSF, which she demonstrated is required for timely progression of adult neurogenesis as well as maintenance of the adult NSC pool. In their talks, Yanhong Shi, Beckman Research Institute, Duarte, California, and Chun-Li Zhang, University of Texas Southwestern Medical Center, implicated the transcription factor TLX in NSC regulation. They showed that TLX can be manipulated with various miRNAs to regulate self-renewal, fate-determination, and neuronal maturation. Gerd Kempermann, Biotechnologisches Zentrum, Dresden, Germany, who authored the new textbook Adult Neurogenesis 2, called regulation and function of neurogenesis “inseparable.” Kempermann presented modifications of classic behavioral tests such as the Morris water maze that implicated adult neurogenesis in complex learning situations in which novel information has to become integrated into the older representation of the world.
A strong understanding of how newborn neurons functionally integrate into existing circuitry will be critical to ultimately manipulating adult neurogenesis for clinical therapy. Alejandro Schinder described his recent findings suggesting that newborn neurons in adult mice exhibit enhanced synaptic plasticity before they reach maturity. His work indicates that neurons mature at variable rates based on localization within the DG. These rates have functional implications for the encoding of episodic memory and can be accelerated by exercise; these include increased excitability and long-term potentiation, as well as preferential recruitment of new neurons for special learning.
Hongjun Song, Johns Hopkins University, Baltimore, Maryland, is interested in parsing sequential regulation during adult hippocampal neurogenesis. He presented new analytical methods including an in vivo photo excitation technique. Additionally, his group is developing what could be the first 3D-computer projection of the murine DG. This technology holds potential for analyzing fate specification, morphogenesis, migration, axon and dendritic development, synapse formation, and plasticity of newborn neurons in the brain. Amelia Eisch, University of Texas Southwestern Medical Center at Dallas, showed that the small molecule isoxazole-9 increases both neurogenesis and memory in mice. She noted neurogenic differences in the anterior versus posterior DG following self-administration of cocaine as a model for addiction. Interestingly, decreased neurogenesis leads to vulnerability to cocaine addiction but no altered behavior toward food reward.
More than half of all newborn hippocampal neurons die within two weeks of their birth. Nora Abrous, INSERM, Bordeaux, France, suggested that this death is both selective and homeostatic. Her group has demonstrated that spatial learning regulates the number and dendritic arbor shape of newborn hippocampal neurons. As the excitatory neurotransmitter glutamate is implicated in development and maturation of new neurons, Abrous has implicated the NMDA glutamate receptor as a regulator of dendrite development. Her work indicates that spatial memory formation shapes new networks. Paul Frankland, University of Toronto, Ontario, developed a diphtheria toxin-based transgenic system to ablate neurogenesis in mice. He demonstrated that doing so after, but not before, training induces retrograde amnesia; this reinforces an important role of neurogenesis in memory. Janet Wiles, University of Queensland, Brisbane, concluded the session with a presentation of her robotic organism iRat, which is being developed as a computational model of the DG to analyze spatial cognition and memory.—Lansdale Henderson.
Lansdale Henderson is an undergraduate student working in Jonathan Kipnis’s lab at the University of Virginia.
This is Part 1 of a two-part series. See also Part 2.