Carlos Lois MD, PhD
|Institution||University of Massachusetts Medical School|
|Address||University of Massachusetts Medical School|
364 Plantation Street, LRB
Worcester MA 01605
|Institution||UMMS - Graduate School of Biomedical Sciences|
ASSEMBLY OF BRAIN CIRCUITS AND THE CELLULAR MECHANISMS OF BEHAVIOR
Our laboratory is interested in the assembly of neuronal circuits and the mechanisms by which brain circuits give rise to behavior. We focus on the process of neuron addition into 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. To investigate how behavior arises from the activity of neurons in brain circuits, we are generating transgenic songbirds to manipulate key genes involved in the assembly of circuits that mediate vocal learning behavior.
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. 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.
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, differentiate into neurons, and establish synaptic contacts with other neurons in the circuit. We are interested in understanding the cellular and molecular mechanisms that control the integration of these neurons into neuronal circuits. We are currently testing the hypothesis that synaptic input into newly born adult neurons guides the integration of these cells into existing circuits. In addition, 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. To study the role of electrical and synaptic activity on neuronal integration we have developed new tools to manipulate the biophysical properties of neurons by genetically modifying the activity of ion channels and neurotransmitter receptors.
Genetic control of the assembly of circuits involved in vocal learning.
Vocal learning depends on the ability of brain circuits to perceive and imitate sound sequences and use these sequences for communication. Songbirds such as canaries and zebra finches have been a favorite experimental system for the study of vocal learning in animals for decades. These animals exhibit a robust and spontaneous vocal learning behavior, and they have dedicated brain circuits, known as the song system, that participate in the learning and production of song. Zebra finches listen to the songs that their fathers produce, and imitate these sounds until they acquire a stable adult-like song. In this respect, the time course and strategy of vocal learning in zebra finches is very similar to the manner in which human infants learn to speak. These observations suggest that the zebra finch could be an ideal system where to start investigating the genetic and biological basis of vocal learning. Recently, my laboratory has succeeded in the development of a series of techniques that allow us to genetically modify the brain of songbirds. These technical advances open new opportunities for the study of the relationship between genes and learning in an animal species with a robust behavioral repertoire. We are currently generating transgenic songbirds to manipulate key genes involved in the assembly of circuits involved in vocal learning behavior.
Figure 1: Genetic manipulation of the electrical properties of neurons.
Newly-generated neurons (green) in the hippocampus of adult mice are rendered hyperexcitable by delivering into them Nachbac, a voltage-gated sodium channel, via recombinant retroviruses. Genetically-enhanced excitability increases the number of inhibitory synapses (arrows) on the genetically modified neurons (green). By genetically controlling the electrical properties of neurons we investigate how neuronal activity regulates the integration of cells into brain circuits, and the connections between neurons.
Figure 2: Stem cells are committed to the production of neurons with defined connectivity.
Stem cells located in the subventricular zone (SVZ) are committed to generate the same neuronal type (granule cells in the olfactory bulb) with defined connectivity. Stem cells located in the anterior regions of the SVZ (labeled in red) produce neurons whose dendrites reach the upper layers of the olfactory bulb. In contrast, stem cells located in the posterior SVZ (labeled in green) produce neurons whose dendrites branch in the lower layers of the OB. Our laboratory is currently investigating the molecules that regulate the patterns of connectivity of neurons in this brain region.
Figure 3: Genetically modified songbirds to investigate the molecular bases of vocal learning anc complex behavior.
Our lab has developed several techniques to genetically manipulate the development and function of neurons during the assembly of neuronal circuits. We have recently developed new genetic methods that have allowed us to generate transgenic songbirds to investigate the genetic basis of the assembly of brain circuits involved in vocal communication. We are using these transgenic songbirds to investigate the rules by which neurons migrate, choose their final locations, establish connections with each other, and give rise to behavior.
Our laboratory uses tools of molecular biology, cell biology and electrophysiology to investigate the assembly of brain circuits. Two rotation projects are available:
1) to explore the role of neuronal activity on the migration and formation of synapses
2) to design a transsynaptic genetic system to elucidate the wiring diagram of brain circuits.
Postdoctoral position in electrophysiology
We are seeking a highly motivated individual to work on a research project focused on the assembly and wiring of brain circuits. The research combines techniques in electrophysiology, molecular biology, neuroanatomy, virology, and transgenesis in rodents. Applicants with experience in electrophysiology who are motivated for developing careers as independent investigators, are especially encouraged.
A Ph.D. in neuroscience or a related field is required and candidates should have a record of research excellence demonstrated by publication. Experience with electrophysiological recordings in vivo or in slices is required.
Postdoctoral position in developmental neuroscience
We are seeking a highly motivated individual to work on a research project focused on the assembly and wiring of brain circuits. The research combines techniques in electrophysiology, molecular biology, neuroanatomy, virology, and transgenesis in rodents. Applicants with experience in molecular or cell biology who are motivated for developing careers as independent investigators, are especially encouraged.
A Ph.D. in neuroscience or a related field is required and candidates should have a record of research excellence demonstrated by publication. Expertise in molecular biology, cell biology and/or neuroscience is required.
Two postdoctoral positions are available to study in this laboratory.
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