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Carlos Lois
Using new genetic technologies that allow
for highly controlled manipulations of animal brains, Professor
Carlos Lois' lab explores the phenomenon of "neurogenesis,"
the surprising ability of certain species to grow new brain
cells in adulthood and integrate them into existing brain
circuits connected to memory. A long-term goal: to harness
this regenerative ability for human beings, to correct neurological
deficits from injury or disease.
It is generally assumed that the generation of neurons ceases before or soon after birth, and consequently, that neurons are not replaced in the brain of adult animals. According to this view, neurons are long-lived, such that their synaptic connections are able to encode information over long periods of time. Acquisition of information in learning and memory is thought to rely on the strengthening and weakening of pre-existing synaptic connections. In the last several years, however, this traditional view has been challenged by increasing numbers of reports of adult neurogenesis in the brains of birds, fish, mice, rats and primates, including humans. Furthermore, newly generated neurons have been observed to functionally integrate into existing neuronal circuits in adult animals. Our lab is interested in manipulating the birth, death and function of newly generated neurons by genetic methods in the adult animal to gain a better understanding of their concerted roles in memory storage. These experiments will allow us to probe the mechanisms and behavioral consequences of adult neurogenesis and its role in plasticity of the adult brain. In addition, our laboratory is interested in understanding the mechanisms that allow newly-generated neurons to integrate in the functioning circuits of the adult brain. To answer these questions we are investigating the phenomenon of adult neurogenesis in mammals and songbirds.
Many neurological disorders, such as epilepsy or Parkinson's disease, are caused by distortions in the structure and connectivity of neuronal circuits due to genetic lesions or physical insults. Unfortunately, the human brain has a very limited ability for repair, and disorders of the nervous system are usually permanent and irreversible. However, the discovery that new neurons are continuously incorporated into the brains of postnatal animals, including humans, immediately suggested that this phenomenon could be exploited to replace neurons in the brain and spinal cord lost to disease or injury.
Unfortunately, naturally occurring adult neurogenesis in mammals is not a useful mechanism for the repair of the nervous system, because it is restricted to the production of a single class of neurons in just two regions of the brain. Furthermore, when these newly generated neurons are grafted into other brain areas, they fail to differentiate into other neuronal types and do not integrate into functioning neuronal circuits. One of the goals of our laboratory is to understand the mechanisms that restrict the migration and differentiation of newly generated neurons in the brain of adult mammals. To answer this question we are investigating two interrelated aspects of the problem: first, we are characterizing the cellular and molecular factors in the adult mammalian brain that restrict the migration of neurons; second, we are characterizing the genes that determine the fate of the adult-generated neurons.
The most robust demonstration of neurogenesis in the adult brain has been characterized in songbirds. In many species of songbirds, the capacity to learn song varies during adult life, and this variation is correlated to neuroanatomical changes in brain regions controlling song, which include radical variations in neuronal number. For instance, adult male canaries develop new songs seasonally. In the winter before the spring breeding season, they develop a new song pattern and add neurons to song control regions in the brain. During the summer, neurons are discarded from these areas, song patterns degrade, and neuronal production decreases. These observations have led to the hypothesis that song learning in birds 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 memory traces for a particular song cannot be used again to encode a different song; in other words, song-related neurons are for single-use, or disposable. To address these questions and others concerning the function of the newly generated neurons in the brains of adult songbirds, we plan to apply the techniques of molecular genetics to mark and manipulate the birth, death, and function of adult-born neurons in the song-control centers of the adult songbird brain.
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