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.

  Commitment of stem cells to the production of neurons with defined connectivity.    Stem cells located in the subventricular zone (SVZ) of adult mice 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 investigating the molecules that regulate the patterns of connectivity of neurons in this brain region.

Commitment of stem cells to the production of neurons with defined connectivity.

Stem cells located in the subventricular zone (SVZ) of adult mice 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 investigating the molecules that regulate the patterns of connectivity of neurons in this brain region.

 

  Regulation of synaptic connections by intrinsic electrical activity.    Newly-generated neurons (green) in adult mice are rendered hyperexcitable by delivering into them Nachbac, a voltage-gated sodium channel, via recombinant retroviruses. (Bottom) 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.

Regulation of synaptic connections by intrinsic electrical activity.

Newly-generated neurons (green) in adult mice are rendered hyperexcitable by delivering into them Nachbac, a voltage-gated sodium channel, via recombinant retroviruses. (Bottom) 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.

 

  Subcellular distribution of synaptic inputs and integration of neurons into circuits (left) Granule cells in the olfactory bulb have neurotransmitter receptors in the apical (top) and basal (bottom) dendrites.    Recent evidence suggests that the inputs directed to the apical dendrites favors the survival and integration of new neurons into the bulb. In contrast, the input directed towards the basal dendrites impairs the integration of new neurons. We are currently investigating the molecular basis for this differential effect of these 2 subcellular compartments on the neuron’s survival.

Subcellular distribution of synaptic inputs and integration of neurons into circuits (left) Granule cells in the olfactory bulb have neurotransmitter receptors in the apical (top) and basal (bottom) dendrites.

Recent evidence suggests that the inputs directed to the apical dendrites favors the survival and integration of new neurons into the bulb. In contrast, the input directed towards the basal dendrites impairs the integration of new neurons. We are currently investigating the molecular basis for this differential effect of these 2 subcellular compartments on the neuron’s survival.

 

  Action potentials regulate the maturation of synaptic inputs.    We have recently generated reagents that allow us to genetically block action potentials in individual neurons. We have observed that neurons without action potentials (left bottom) survive and integrate into the brain, but they fail to receive synaptic input (right bottom). We are investigating the mechanisms by which intrinsic neuronal activity regulates the formation and functional maturation of synapses.

Action potentials regulate the maturation of synaptic inputs.

We have recently generated reagents that allow us to genetically block action potentials in individual neurons. We have observed that neurons without action potentials (left bottom) survive and integrate into the brain, but they fail to receive synaptic input (right bottom). We are investigating the mechanisms by which intrinsic neuronal activity regulates the formation and functional maturation of synapses.