Carlos Lois
Using new genetic technologies that allow for highly controlled manipulation of the development and biophysical properties of neurons, Professor Carlos Lois' lab explores how brain circuits are assembled after birth. Several areas of the vertebrate brain have the surprising ability to grow new brain cells in adulthood and integrate them into existing brain circuits connected to memory and information processing. A long-term goal: to harness this regenerative ability for human beings, to correct neurological deficits caused by injury or disease.
It is generally assumed that neurons store information by modifying their synaptic connections with other neurons. The fact that synapses are so malleable—they can modify their functions in response to environmental or behavioral input--allows neurons to be long-lived, such that their synaptic connections are able to encode information over long periods of time.
Surprisingly, a survey of brain development across the animal kingdom reveals that in most animal species, short-lived or renewable neurons are as common as long-lived, non-renewable neurons. In fact, among vertebrates, only the mammalian brain is comprised of long-lived, non-renewable neurons. This observation is leading neuroscientists to believe that the brain’s remarkable ability to modify its information-processing capacity may occur through two parallel and fundamentally different mechanisms: synaptic changes in long-lived neurons, plus the addition or replacement of entirely adult-generated neurons.
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 investigating the mechanisms that neurons use to adapt their intrinsic and synaptic properties as they integrate into circuits and communicate with other neurons.
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 brain areas involved in olfactory perception and spatial memory. In songbirds, the capacity to learn new songs varies during adult life. 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 certain neurons. Just as a heart cell remains a heart cell, certain brain cells may have a dedicated function for life. 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 single-use. 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 possess to encode and store information.
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 previously difficult to genetically analyze. In addition, this highly efficient 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 new way to identify and manipulate the genes of specific subsets of neurons to study their contribution to brain function. We are currently extending this method to conduct forward genetic screens in mice that will allow us an unprecedented means of exploration of the physiological bases of synapse formation. |
