Our laboratory is interested in the assembly of neuronal circuits, and the genetic control of brain development and function. We focus on the process of neuron replacement in the brain of vertebrates, and seek to understand how new neurons integrate into the circuits of the adult brain, and their role in information processing and storage. To address these questions our laboratory develops new technologies to genetically manipulate the development and biophysical properties of neurons.
One of the basic assumptions of neuroscience is that neurons store information by modifying their synaptic connections with other neurons. According to this view, the malleability of synapses allows neurons to be very long-lived cells because they can modify their functions in response to environmental or behavioral demands. Interestingly, a survey of brain development across the animal kingdom reveals the surprising observation that in most animal species short- lived or renewable neurons are as common as long-lived, non-renewable neurons. In fact, among vertebrate nervous systems, only the mammalian brain is mostly comprised of long-lived non-renewable neurons. These observations suggest that the ability of the brain to modify its information processing capacity may occur through two parallel and fundamentally different mechanisms, one based on synaptic changes in long-lived neurons and another based on the cellular addition or replacement of entire adult-generated neurons.
Regulation of neuronal integration into brain circuits.
The brain of adult vertebrates harbors a population of neuronal stem cells that continues to proliferate throughout the life of the animal, and whose progeny migrate through the brain and differentiate into neurons. We are interested in understanding the cellular and molecular mechanisms that control the integration of these neurons into neuronal circuits. To study the role of electrical activity on neuronal integration we have developed new tools to alter the biophysical properties of neurons by genetically modifying the activity of ion channels and neurotransmitter receptors. With these tools we are currently investigating the mechanisms that neurons use to adapt their intrinsic and synaptic properties as they integrate into circuits and communicate with other neurons.
Neuronal replacement and the cellular mechanisms of memory.
Most neurons in the brain are born before birth and are never replaced. In contrast, certain populations of neurons are continuously replaced throughout the life of the animal. Do neurons acquired in adult life participate in a special form of memory storage that requires the replacement of old neurons? In mammals, neuronal replacement occurs at high levels in two brain areas be involved in olfactory perception and spatial memory. In songbirds, the capacity to learn their songs varies during adult life, and this variation is correlated to radical structural changes in the brain nuclei controlling song, which include massive neuronal replacement.
Several observations have led to the hypothesis that learning may involve irreversible changes in the molecular properties of the relevant neurons, analogous to the terminal differentiation of some cell types. According to this hypothesis, neurons that encode the traces for a particular memory cannot be used again to encode a different memory; in other words, memory-related neurons are for single-use, or disposable. Recently we have developed several new tools that allow us to genetically control the function of neurons. By using these techniques we are manipulating the birth, death, and electrical function of newly generated neurons in the brain of behaving animals, both in the olfactory system of mice, and in the song system of songbirds. The long-term goal of these experiments is to understand the different mechanisms that neurons posses to encode and store information.
Genetic technologies for the study of neuronal function.
Our laboratory has developed a new transgenic technology based on the delivery of recombinant lentiviruses into embryos. This technique has allowed us to generate transgenic animals in species of neurobiological interest such as birds, that had been until now refractory to genetic analysis. In addition the high efficiency of this technology allows us to undertake novel strategies for gene discovery in the brain. In order to achieve gene expression in selective tissues or cell types we have developed a novel method based on enhancer trapping in which a viral vector integrates into the cell's genome and it recapitulates the expression pattern of the endogenous gene that is nearby its integration site. This method allows for the identification and genetic manipulation of specific subsets of neurons to study their contribution to brain function. We are currently extending this method to achieve insertional mutagenesis in mice to perform forward genetic screens in order to investigate the physiological bases of synapse formation, maintenance and elimination.
Kelsch W, Mosley CP, Lin CW, Lois C. Distinct mammalian precursors are committed to generate neurons with defined dendritic projection patterns. PLoS Biol. 2007 Nov;5(11):e300.
Scott BB, Lois C. Developmental origin and identity of song system neurons born during vocal learning in songbirds. J Comp Neurol. 2007 May 10;502(2):202-14.
Scott BB and Lois C. Generation of tissue-specific transgenic birds with lentiviral vectors. Proc Natl Acad Sci USA. Nov 8;102(45): 16443-7. (2005)
Lois, C., Hong, E.J., Pease, S.S., Brown, E.J. and Baltimore, D.Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors. Science 295:868-871. (2002).
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