Past events

Angelman syndrome (AS) is a human neuropsychiatric disorder associated with autism, mental retardation, motor dysfunction, and epilepsy. In most cases, AS is caused by the deletion of small portions of chromosome 15, which includes the UBE3A gene. The UBE3A gene encodes an enzyme termed ubiquitin ligase E3A. A mouse model of AS has been generated and these mice exhibit abnormalities that correlate with neurological alterations observed in humans with AS. One of the prominent affected brain regions in AS is the hippocampus. We characterized the CA1 pyramidal neurons in the AS mice, and observed alterations in the intrinsic membrane properties of these cells between AS mice and their wild-type littermates. These alterations were correlated with increased expression of specific proteins, mainly related to the axon initial segment (AIS). Furthermore, the AIS morphology of these neurons in the AS mice was also found to be altered. By determining the temporal sequence for the increased expression of these proteins we have discovered the precipitating event for the observed AIS alterations which coincides with the homeostatic model of the neuron. Finally, we rescued the hippocampal pathology via a genetic manipulation based on this understanding. Taken together, our findings are the first to suggest that AIS plasticity alterations exist in mammalian brain in-vivo and could be involved in neuropsychiatric disorders such as AS. They also offer a novel conceptualization of neuropsychiatric disorders and propose the option for an innovative therapeutic strategy.

Uncertainty is inherent to any situation we encounter. Our individual attitudes towards uncertainty strongly affect our evaluation of different available options and our behavior based on these evaluations. In the talk I will describe a series of studies in which we combine experimental economics and other behavioral methods with functional MRI to study the behavioral and neural characteristics of attitudes towards uncertainty and learning under uncertainty.

In Huntington’s disease (HD) – a devastating autosomal-dominant neurodegenerative disease – the striatum displays reduced cholinergic markers, despite the resiliency of cholinergic interneurons (ChIs) – the source of striatal acetylcholine – to the neurodegeneration that decimates striatal projection neurons. Autonomous spiking of ChIs is unchanged in transgenic HD mice, suggesting a functional deficit in extrinsically driven activity. Using two transgenic mouse models of HD, we show that ChI responses to cortical input are boosted by a post-synaptic up-regulation of the persistent sodium current. This boosting is replicated by in wild-type mice by diminished activation of group I metabotropic glutamate receptors (mGluRs). Activation of group I mGluRs in HD mice counters the boosting. We propose that the recently described loss of thalamic synapses in striatum, reduces group I mGluR activation in ChIs which promotes boosting of cortical inputs. The augmentation of cortical inputs may function to compensate for the lost thalamic glutamatergic drive.

Most neurons involved in perceptual judgments are at least two synapses removed from sensory receptors. Psychophysical models that link perception to the physical qualities of external stimuli are thus black boxes. Opening these black boxes is challenging and requires comprehensive estimates of activity in many neurons carrying perceptually relevant signals. Because sensory representations are distributed over large numbers of neurons, such estimates have generally remained elusive. Here, we take advantage of the well-characterized olfactory system of fruit flies to relate knowledge of the neuronal population representations of odors to behavioral measures of odor discrimination. Flies detect odors using ~50 types of olfactory receptor neurons (ORNs). ORN axons segregate anatomically by receptor type and transmit signals via separate synaptic relays, to discrete classes of excitatory projection neurons (ePNs). Previously, ORN responses to odors and a transformation estimating PN spike rates from measured ORN spike rates were presented. ePNs project to the mushroom body, and the lateral horn (LH). The LH, thought to be responsible of naïve behavior, also receives input from a functionally uncharacterized group of GABAergic inhibitory PNs (iPNs). The fact that iPNs target exclusively the LH hints at a possible function of these inhibitory neurons in naïve behavior. We formulate and test a simple model of innate odor discrimination that takes as its input the estimated PN signals projected onto the LH and generates as its output a prediction of whether two odors can be distinguished. We show that the main determinant of discriminability is the distance between the PN activity patterns evoked by two odors. Experimental manipulations of this distance have graded predictable perceptual consequences. We further show that, inhibition by iPNs makes closely related odors easier to distinguish, in all likelihood by imposing a high-pass filter on ePN output that stretches the distances between partially overlapping odor representations.

Understanding the neural circuitry underlying addictive behavior is essential as a first step towards treating addiction. The nucleus accumbens and the ventral pallidum are two interconnected regions known to mediate reward-related behavior. Using a multidisciplinary approach I describe synaptic changes in both regions following exposure to cocaine. However, the connectivity patterns between these regions and how specific projections are affected by drugs of abuse remain elusive. In an attempt to elucidate the nature of these connections I will show preliminary results calling for a re-examination of the current thinking about accumbal inputs to the ventral pallidum. Future work will engage in describing how these pathways are differentially changed in drug addiction.

Chronic stress is widely regarded as key risk factor for a variety of diseases, including depression. Yet, while some individuals are vulnerable to stress, others are remarkably resilient. It seems clear that genetic predispositions interact with environmental demands such as chronic stress and modulate its long-term outcome. In addition, there is abundant evidence that environmental circumstances early in life are capable of shaping the adult phenotype. In the last years two seemingly opposing views on early life stress have emerged, the two-hit model and the mismatch model. While the first hypothesis states that aversive experiences early in life predispose individuals to be more vulnerable to aversive challenges later in life, the second hypothesis argues that aversive experiences early in life result in individuals that are better adapted to aversive challenges later in life. There are published data that support either hypotheses, but the interaction with genetic predispositions has rarely been addressed. In my presentation I will propose that both views may be accurate and that the outcome of an early-life stress exposure depend on the genetic background of the individual. In addition, even within the same individual certain phenotypes may be progressively affected by multiple stress exposures (two-hit model), while other phenotypes would be most affected under mismatched conditions. I will illustrate the potential of genetic variations to modulate the outcome of early life adversity and discuss research strategies necessary to address the issue of genetic*development*environment interaction.

The human race has been reading and writing for only 5,000 years, suggesting that the mechanisms for these processes involve both cultural evolution and biological exaptation. Brain mechanisms of reading are hard to discern because skilled reading is so fast and efficient. Use of ambiguous words allows us to slow down some of these processes and explore the interactions of orthographic, phonological, and semantic processes. We took advantage of the characteristics of Hebrew to explore the relative effects of phonological and semantic ambiguity on access to meaning. Twenty-three participants performed a semantic decision talk on pairs of words. Half the pairs were constituted of two unambiguous words, and in half, the first word was either a homophonic homograph (like bank), or a heterophonic homograph (like tear). Our procedure allowed us to separately examine two stages of the access to meaning: the activation of multiple meanings, and then the selection of the appropriate meaning. Previous imaging studies of ambiguity resolution have not made this distinction. In the first stage, we show that different regions of the left hemisphere respond differentially to homophones and to heterophones in both whole brain analysis and in ROI comparisons of sub-regions of both anterior and posterior regions of the left hemisphere. In the second stage, in meaning selection, we again see different effects that are dependent of the phonological status of the ambiguous word, and also similar effects of the interaction between frequency effects and contextual effects in the two hemispheres. We interpret these findings in the context of a brain model of reading.