OVERVIEW
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 addition in the brain of vertebrates, and seek to understand how new neurons integrate into the circuits of the 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.

RESEARCH SUMMARY
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.

a) 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. In addition, we are using two-photon microscopy to image the addition of genetically labeled newly generated neurons into the brain of live animals in real time. With these tools we are currently investigating the mechanisms that neurons use to integrate into circuits and establish connections with other neurons.

b) 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.

Selected Publications

Sequential development of synapses in dendritic domains during adult neurogenesis. Kelsch W, Lin CW, Lois C. Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16803-8.

Distinct mammalian precursors are committed to generate neurons with defined dendritic projection patterns.  Kelsch W, Mosley CP, Lin CW, Lois C. PLoS Biol. 2007 Nov;5(11):e300.

Generation of tissue-specific transgenic birds with lentiviral vectors. Scott BB and Lois C. Proc Natl Acad Sci USA. Nov 8;102(45):16443-7. (2005)

Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors. Lois, C., Hong, E.J., Pease, S.S., Brown, E.J. and Baltimore, D. Science 295:868-871. (2002).

Search PubMed for Lois lab publications.