Past events

Williams syndrome (WS) is a neurodevelopmental disorder caused by a heterozygous microdeletion of about 26 genes from chromosomal region 7q11.23, characterized by hypersociability and unique neurocognitive abnormalities. Of those deleted, general transcription factor II-i (Gtf2i), has been shown to affect hypersociability in WS, although the cell type and neural circuitry critical for the hypersociability are poorly understood. To dissect neural circuitry related to hypersociability in WS and to characterize the neuron-autonomous role of Gtf2i we conditionally knockedout Gtf2i in forebrain excitatory neurons and found this recapitulate WS features, including increased sociability and anxiety and neuroanatomical defects. Unexpectedly, we found that in the mutant mouse cortex 70% of the significantly downregulated genes were involved in myelination, together with a reduction in mature oligodendrocyte cells number, disrupted myelin ultrastructure and fine motor deficits. Analyzing the transcriptome in human frontal cortex, we found similar downregulation of myelination-related genes, suggesting a novel pathophysiological mechanism in WS, based on neuron-oligodendrocytes signaling deficits. Overall, our data detail the cellular processes that may lead to the WS typical phenotype and developmental abnormalities, and suggest new paths to explore and treat WS, as well as social and cognitive abnormalities.

We assess the neural mechanisms of learned associations in operant-learned behaviors. These learned associations or memories involve complex sets of highly specific information that must be stored with a high degree of resolution. In contrast, most studies to date examined low resolution neural mechanisms in whole brain areas, cell types or randomly selected neurons regardless of whether they were activated and participated in the behavior. Instead, high resolution memories are thought to be stored by alterations induced selectively within sparsely distributed patterns of neurons, called neuronal ensembles, that are selectively activated by cues relevant to the memory. We developed the Daun02 inactivation procedure with transgenic FosLacZ rats to demonstrate that different patterns of strongly activated Fos-expressing ensembles mediate different memories. Since these ensembles encode the memory, we developed methods that use (1) FACS to discover multiple molecular alterations and (2) FosGFP transgenic rats to discover multiple electrophysiological alterations that are induced only within Fos-expressing neurons. We have since developed a Fos-Tet-Cre transgenic rat system that allows us to selectively manipulate these alterations within Fos-expressing ensembles to assess whether they play a causal role in operant learned behaviors. It is our hope that a focus on the behaviorally activated ensembles that store the memories will permit more focused novel treatments of behavioral disorders.

Mammalian brains store and update quantitative internal variables. Primates and rodents, for example, have an internal sense of whether they are 1 or 10 meters away from a landmark and whether a ripe fruit is twice or four times as appetizing as a less ripe counterpart. Such quantitative internal signals are the basis of cognitive function, however, our understanding of how the brain stores and updates these variables remains fragmentary. In this talk, I will discuss imaging and perturbation experiments in tethered, walking Drosophila. The goal of these experiments is to determine how internal variables are calculated by the tiny Drosophila brain and how these variables influence behavior. Specifically, in the Drosophila central complex a set of heading neurons have been described, whose activity tracks the fly’s orientation, similar to head direction cells in rodents. However, the circuit architecture that gives rise to these orientation tracking properties remains largely unknown in any species. I will describe a set of clockwise- and counterclockwise-shifting neurons whose wiring and calcium dynamics provide a means to rotate the heading system’s angular estimate over time. Shifting neurons are required for the heading system to properly track the fly's movements in the dark, and, their stimulation induces a rotation of the heading signal in the expected direction and by the expected amount. The central features of this circuit are analogous to models proposed for head-direction cells in rodents and may thus inform how neural systems, in general, perform addition.

Williams syndrome (WS) is a neurodevelopmental disorder caused by a heterozygous microdeletion of about 26 genes from chromosomal region 7q11.23, characterized by hypersociability and unique neurocognitive abnormalities. Of those deleted, general transcription factor II-i (Gtf2i), has been shown to affect hypersociability in WS, although the cell type and neural circuitry critical for the hypersociability are poorly understood. To dissect neural circuitry related to hypersociability in WS and to characterize the neuron-autonomous role of Gtf2i we conditionally knockedout Gtf2i in forebrain excitatory neurons and found this recapitulate WS features, including increased sociability and anxiety and neuroanatomical defects. Unexpectedly, we found that in the mutant mouse cortex 70% of the significantly downregulated genes were involved in myelination, together with a reduction in mature oligodendrocyte cells number, disrupted myelin ultrastructure and fine motor deficits. Analyzing the transcriptome in human frontal cortex, we found similar downregulation of myelination-related genes, suggesting a novel pathophysiological mechanism in WS, based on neuron-oligodendrocytes signaling deficits. Overall, our data detail the cellular processes that may lead to the WS typical phenotype and developmental abnormalities, and suggest new paths to explore and treat WS, as well as social and cognitive abnormalities.

We assess the neural mechanisms of learned associations in operant-learned behaviors. These learned associations or memories involve complex sets of highly specific information that must be stored with a high degree of resolution. In contrast, most studies to date examined low resolution neural mechanisms in whole brain areas, cell types or randomly selected neurons regardless of whether they were activated and participated in the behavior. Instead, high resolution memories are thought to be stored by alterations induced selectively within sparsely distributed patterns of neurons, called neuronal ensembles, that are selectively activated by cues relevant to the memory. We developed the Daun02 inactivation procedure with transgenic FosLacZ rats to demonstrate that different patterns of strongly activated Fos-expressing ensembles mediate different memories. Since these ensembles encode the memory, we developed methods that use (1) FACS to discover multiple molecular alterations and (2) FosGFP transgenic rats to discover multiple electrophysiological alterations that are induced only within Fos-expressing neurons. We have since developed a Fos-Tet-Cre transgenic rat system that allows us to selectively manipulate these alterations within Fos-expressing ensembles to assess whether they play a causal role in operant learned behaviors. It is our hope that a focus on the behaviorally activated ensembles that store the memories will permit more focused novel treatments of behavioral disorders.

Mammalian brains store and update quantitative internal variables. Primates and rodents, for example, have an internal sense of whether they are 1 or 10 meters away from a landmark and whether a ripe fruit is twice or four times as appetizing as a less ripe counterpart. Such quantitative internal signals are the basis of cognitive function, however, our understanding of how the brain stores and updates these variables remains fragmentary. In this talk, I will discuss imaging and perturbation experiments in tethered, walking Drosophila. The goal of these experiments is to determine how internal variables are calculated by the tiny Drosophila brain and how these variables influence behavior. Specifically, in the Drosophila central complex a set of heading neurons have been described, whose activity tracks the fly’s orientation, similar to head direction cells in rodents. However, the circuit architecture that gives rise to these orientation tracking properties remains largely unknown in any species. I will describe a set of clockwise- and counterclockwise-shifting neurons whose wiring and calcium dynamics provide a means to rotate the heading system’s angular estimate over time. Shifting neurons are required for the heading system to properly track the fly's movements in the dark, and, their stimulation induces a rotation of the heading signal in the expected direction and by the expected amount. The central features of this circuit are analogous to models proposed for head-direction cells in rodents and may thus inform how neural systems, in general, perform addition.