It turns out you are not born with all the neurons you’ll ever need; adult neurogenesis is alive and kicking in the mammalian brain. Most notably for Alzheimer’s disease researchers, this happens in the dentate gyrus of the hippocampus, an area of the brain intimately involved in learning and memory, and one that is vulnerable in AD. As evident from the first Keystone Symposium on Adult Neurogenesis, which took place in Taos, New Mexico, 9-14 January 2011, scientists are only just beginning to understand how the phenomenon relates to normal and abnormal processes in the aging brain. Landsale Henderson, an undergraduate student at the University of Virginia with a definite knack for writing, attended the meeting and brings you this report, edited by Tom Fagan.
Taos: New Neurons in New Mexico—Highlights from Keystone
“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.
Taos: Disease, Drug Development, and Adult Neurogenesis
It is now firmly established that neurogenesis takes place in two small regions of the mammalian adult brain: the subventricular zone just underneath the brain ventricles and the subgranular zone of the dentate gyrus in the hippocampus. Research suggests that neurons born to those regions in adult brains are functional and integrate into neural networks in some circumstances. But does adult neurogenesis have any relevance to neurological/neurodegenerative disorders, such as depression or Alzheimer’s disease, and could neurogenesis represent a novel target for therapeutics? These ideas were discussed at the inaugural Keystone Symposium on Adult Neurogenesis, held 9-14 January 2011, in Taos, New Mexico. While this branch of neuroscience is still in its infancy, there were hints that neurogenesis may play an important role in adult diseases.
Steven Goldman, University of Rochester Medical Center, New York, is known for his studies of the songbird model of adult neurogenesis. Goldman described a BDNF/noggin treatment that induced neurogenesis and delayed disease onset and extended survival in a mouse model of Huntington’s disease. Hans-Peter Lipp, University of Zurich, Switzerland, challenged some widely accepted assumptions. He noted that adult hippocampal neurogenesis has been demonstrated in only six out of the 26 mammalian orders. Contrary to the axiom that running increases neurogenesis in lab mice, he found no neurogenesis in wild wood mice. Lipp is currently investigating whether age-related reduction of hippocampal neurogenesis might represent a stabilizing effect during habituation, and whether a temporary increase in the birth of hippocampal neurons may reflect habit breaking and the learning of new routines.
Günther Zupanc, Northeastern University, Boston, Massachusetts, and Tatyana Dias, Edinburgh University, United Kingdom, presented zebrafish as a model for adult neurogenesis research. Dias, a graduate student, addressed spinal cord neurogenesis and excited the audience with a video clip that showed adult zebrafish that recovered their ability to swim several weeks after the scientists had completely transected their spinal cord. Dias suggested that Notch signaling, which reduced motor neuron numbers during spinal cord neurogenesis in the fish, may account for some limited regenerative potential in mammalian spinal injury as well.
Many neurological disorders have been associated with diminished adult neurogenesis. This correlation has left researchers wondering if that diminution contributes to disease pathology and etiology, and also, if enhancing neurogenesis could be a viable therapeutic strategy.
It has been known for many years that ischemic stroke increases adult neurogenesis (Jin et al., 2001). Furthermore, the brain’s natural neurogenic repair mechanisms induce production, migration, and functional integration of neuroblasts into damaged tissue, explained Olle Lindvall, University of Lund, Sweden. Stroke recovery, however, requires not only an adequate supply and survival of neuroblasts in the damaged tissue, but also functional synaptic connectivity of new neurons. Lindvall’s data demonstrated that an inflammatory response following stroke regulates such synaptic development in adult-born neurons.
Unlike stroke, there is no evidence of reactive neurogenesis in Parkinson’s disease (PD). No new neurons have been reported in the adult substantia nigra—the primary site of dopaminergic neuronal loss in PD. Rather, decreased neurogenesis was observed in autopsy PD tissue (Höglinger et al., 2004). Could the reduced generation of newborn neurons in neurogenic regions contribute to the development of some non-motor symptoms in PD? Jürgen Winkler, Universitätsklinikum, Erlangen, Germany, demonstrated that downregulating α-synuclein (the pathological protein typically found in Lewy bodies) restores neurogenesis in the hippocampus and olfactory bulb of mice. This implies that impaired hippocampal and olfactory bulb neurogenesis may be associated with non-motor symptoms in PD, such as anxiety, depression, and hyposmia (poor ability to smell). His data implicate the Notch signaling pathway as impairing the survival of adult-born neurons in transgenic PD models. Winkler also demonstrated that the administration of certain growth factors could promote migration of newly generated neurons to lesioned tissue. This work hints that newly generated neuroblasts may help to restore dysfunctional striatal circuitry and impaired motor function.
Though the hippocampus is best known for its role in learning and memory, it is also active in stress and emotion, mood, and anxiety. For example, patients with chronic major depression have smaller hippocampi. Rene Hen and Amar Sahay, Columbia University, New York, presented work supporting the notion that impaired adult neurogenesis can explain aspects of depression. These studies demonstrated that genetic expansion of adult neurogenesis in mice decreased anxiety-like behavior, under certain conditions, raising the question of whether stimulation of neurogenesis could provide a future therapy for anxiety disorder. Mi-Hyeon Jang, Johns Hopkins University, Baltimore, Maryland, then suggested that secreted frizzled-related protein-3 (sFRP3), a Wnt inhibitor, is a potential therapeutic target for depression treatment. Jang observed that electroconvulsive stimulation of the hippocampal neuronal circuitry downregulates sFRP3 expression and accelerates AHN. He noted that chronic antidepressant treatment suppresses sFRP3 expression in the DG.
The final session looked toward the future of neuronal repair, covering the latest approaches and technologies for translating neural progenitor proliferation to clinical applications. Vanderhaeghen, University of Brussels, Belgium, discussed embryonic stem (ES) cells and other pluripotent stem cells as tools for modeling and treating human disease. He presented striking in vitro data that demonstrated the sequential generation of a diverse population of neurons from stem cells, including those that seemed to be bona fide cortical neurons. Grafting these neurons into the cerebral cortex led to proper axonal projections. Carrolee Barlow, Brain Cells Inc., San Diego, California, demonstrated how drugs that can promote neurogenesis have been identified by in vitro and in vivo screening of neurogenesis and behavioral impacts in animals. From such screens, she selected drug candidates including, Buspar (buspirone) and melatonin. She reported that Buspirone alone, an agonist for the 5HT-1 serotonin receptor, upregulates both gliogenesis and neurogenesis, whereas the combination of buspirone and melatonin resulted in upregulation of neurogenesis without the increase in glia. Based on the preclinical findings, the investigators studied if the combination of buspirone and melatonin could be used to treat patients with major depressive disorder. She showed the positive clinical data from a double-blind placebo-controlled study demonstrating that the combination of Buspar and melatonin can help ameliorate depression symptoms in patients. Anders Haegerstrand, NeuroNova AB, Stockholm, Sweden, is researching neurogenic and neuroprotective drugs for treatment of a wide range of neurodegenerative diseases. He found that PDGF-BB promotes proliferation of progenitors in SVZ as well as improves symptoms in animal models of PD. Haegerstrand also presented a drug-delivery system which is currently used to deliver PDGF to patients with PD. It features a pump running directly into one of the lateral ventricles in the brain. The drug evenly disperses throughout all ventricles by virtue of cerebrospinal fluid flow. Haegerstrand also showed that Exendin-4, a glucagon-like peptide 1 agonist, dose-dependently increases neuron proliferation in the SVZ and hippocampus. Exendin-4 is currently in clinical trials for AD and PD (see ARF related news story).
Neural Stem Cells in Alzheimer’s Disease Frank LaFerla, University of California, Irvine, delivered a rapid-fire talk on the translation of science to medicine, mouse to (wo)man, and disease to therapy. LaFerla addressed one of the fundamental motives behind the investigation of adult neurogenesis—the therapeutic potential. Likening the AD hallmarks of β amyloid (Aβ) plaques and tau-laden neurofibrillary tangles to “toothpaste squeezed from a tube,” LaFerla said that once they are established, it seems nearly impossible to reverse the process by means of stem cell therapy. Consequently, LaFerla described a prophylactic approach using NSC-derived BDNF that exploits the benefits of NSCs without requiring cell transplantation. Results demonstrated enhanced hippocampal synaptic plasticity and ameliorated cognitive function without altering Aβ or tau pathology.
LaFerla reminded the audience that Alzheimer’s disease destroys up to 50 percent of the 100 billion human brain cells and the 100 trillion synapses they form. He believes that a more promising direction of stem cell research lies in identifying a range of cell lines derived from different ethnic groups that could be used universally among diseased patients. LaFerla surmised that the medical objective of cell replacement is at odds with the realities of adult neurogenesis. “Neural stem cell therapies likely won’t work to combat Alzheimer’s, ” LaFerla said, “but we owe it to our patients to leave no stone unturned.”
In summary, adult neurogenesis is a complex process whose medical relevance is speculative at present and will only be revealed with a greater understanding of how the brain works. In the meantime, NSCs present a unique opportunity to understand neural plasticity and the anomalous phenomenon of adult neurogenesis.—Lansdale Henderson.
Lansdale Henderson is an undergraduate student working in Jonathan Kipnis’s lab at the University of Virginia.
This is Part 2 of a two-part series. See also Part 1.
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