Past events

Sexually reproducing animals display sex-specific behaviors wired onto dimorphic connectivity patterns in the nervous system. The mechanisms underlying the development of sexually dimorphic nervous systems that consists mainly of shared neuronal types remain largely unknown. Within the nervous system, males and females display a number of anatomical sexual dimorphisms often in the form of neurons that are present exclusively in one, but not the other sex. In this talk I will focus on sex-specific wiring of neurons that are present in both sexes, and demonstrate the sex-specific functions of sex-shared neurons in C. elegans. The key finding that I will present is that sex-specific wiring patterns are the result of sex-specific synaptic pruning events. I will show that many neurons initially form synapses in a non-discriminatory manner in both the male and hermaphrodite pattern before sexual maturation, but sex-specific pruning events result in the sex-specific maintenance of subsets of the connections. I will describe the behavioral tests taken to show that rewiring is indicative of repurposing of the function of sensory and interneuron. I will present the conserved genes I uncovered that function to determine sex-specific connectivity patterns. To summarize I will discuss how the sexual identity of individual neurons, by initiating selective synapse loss, refines the circuitry and defines sex-specific synaptic targets. This allows for diversification of behavioral outputs with a limited set of shared neurons.

Striatal disinhibition leads to spontaneous abnormal action release manifesting as motor tics, resembling those expressed in Tourette syndrome patients. We utilized microstimulation within the motor cortex of freely-behaving rats before and after striatal disinhibition to study the spatial and temporal properties of tic expression. The spatial properties of these tics were dependent on the striatal organization while the temporal properties were dependent on the cortico-striatal activity. A data-driven computational model of cortico-striatal function closely replicated the temporal properties of abnormal action release. These converging experimental and computational findings suggest a clear functional dichotomy within the cortico-striatal network, pointing to disparate temporal (cortical) vs. spatial (striatal) encoding of action release.

Astrocytes play active roles in brain physiology by dynamic interactions with neurons. Connexin 30, one of the two main astroglial gap-junction subunits, is thought to be involved in behavioral and basic cognitive processes. However, the underlying cellular and molecular mechanisms were unknown. We will show here in mice that connexin 30 controls hippocampal excitatory synaptic transmission through modulation of astroglial glutamate transport, which directly alters synaptic glutamate levels. Unexpectedly, we found that connexin 30 regulated cell adhesion and migration and that connexin 30 modulation of glutamate transport, occurring independently of its channel function, was mediated by morphological changes controlling insertion of astroglial processes into synaptic clefts. By setting excitatory synaptic strength, connexin 30 plays an important role in long-term synaptic plasticity and in hippocampus-based contextual memory. Taken together, these results establish connexin 30 as a critical regulator of synaptic strength by controlling the synaptic location of astroglial processes.

Inhibitory neurons are critically important for the adaptation of neural circuits to sensory experience, but the molecular mechanisms by which experience controls the connectivity between different types of inhibitory neurons to regulate cortical plasticity are largely unknown. In this talk, I will present studies demonstrating that sensory experience induces in cortical vasoactive intestinal peptide (VIP)-expressing neurons a gene program that is markedly distinct from that induced in excitatory neurons and other subtypes of inhibitory neuron. I will show that is Igf1 one of several activity-regulated genes that are specific to VIP neurons, that IGF1 functions cell-autonomously in VIP neurons to increase inhibitory synaptic input onto these neurons and that VIP neuron-derived IGF1 regulates visual acuity in an experience-dependent manner, likely by promoting the inhibition of disinhibitory neurons and affecting inhibition onto cortical pyramidal neurons. I will discuss how our findings support a model by which experience-induced transcriptional networks regulate the synaptic connectivity of each type of neuron according to a circuit-wide homeostatic logic and I will propose that the analysis of the genomic mechanisms regulating these transcriptional networks will allow us to evaluate the extent to which cell-type-specific homeostatic mechanisms contribute to the function of cortical circuits.

In all sensory modalities the response of cortical cells to repeated stimulus is highly variable from trial to trial and it is often correlated in nearby cells. Spiking mechanisms are highly reliable, suggesting that correlated variability of cortical response results from fluctuations in shared synaptic inputs, as we showed in our previous studies. However, the origin of correlated synaptic activities in the cortex is under dispute. Whereas some studies suggest that correlated variability originates from thalamic inputs, others claim that it emerges in the cortex due to recurrent local activity. By combining optogenetic silencing and paired intracellular recordings in the barrel cortex of anesthetized mice as well as using paired LFP-intracellular recordings in awake mice, we revealed the origin of synchronized ongoing and sensory evoked cortical activities.

: I will review a set of biologically inspired NeuroImaging methods (i.e. methods that take into consideration the brain topography, neuronal adaptation and population receptive fields, brain functional connectivity and so on), that we developed and/or refined to shed light on maps and computations in the human brain. Starting from retinotopy, we used partial correlations resting-state functional connectivity analysis to show that the large-scale topographical biases in all 3 dimensions of retinotopy are preserved in individuals without any visual experience. I will discuss how this result challenges classical views of retinotopy as the key organizational principle for computations in the visual system, and further suggest plasticity principles beyond classical Hebbian learning. Next, we use virtual environments to show that key retinotopic regions (mainly in the dorsal visual stream) are recruited not only during vision-based navigation but even when early-blind and sighted-blindfolded learn to navigate these same environments using audition. I will then show how such approaches can be applied to study the whole-body somatosensory-motor system, and demonstrate that topographical gradients are far more widespread than previously known. These findings help to bridge gaps between animal and human studies, and have clinical relevance to improve and refine deep-brain-stimulation and imaging-based diagnostics. Finally, I will briefly present the development of crossmodal adaptation and multiphase spectral analysis to study topographical binding and crossmodal integration. Based on all of these results I will discuss the intriguing hypothesis that our brain is topographically organized for high-order cognitive functions as well, and discuss our plans to combine the aforementioned approaches with the use of the high-field imaging (7T) that is required to test it. I will conclude by summarizing the wide set of tools that enable us to investigate and gain novel insights into the nature of the Topographical Multisensory Human Brain mind. (Most relevant papers for the talk: Striem-Amit et al. Neuron 2012; Cerbral Cortex 2012; Curr Biol 2014; Brain 2015; Zeharia et al. PNAS 2012; J Neurosci 2015; Saadon-Grosman et al. PNAS 2015; Murray, et al. Trends Neurosci 2016 (cond. accepted); Maidenbaum et al. (in preparation)); Siuda-Krzywicka et al. Elife 2016; Sabbah et al. NeuroImage 2016 (accepted).