Past events

My long term interest lies in the mechanistic understanding of sensory processes underlying behavioral responses in laboratory as well as natural wild environments. External sensory cues control complex behaviors such as mating, predator avoidance or orientation in space that are essential for the animal survival and the propagation of the species. In rodents, pheromones play a major role in controlling innate social and sexual responses including mating, nursing and aggression. However, although these behaviors display striking sexual dimorphisms, surprisingly few anatomical and molecular features have been identified that differentiate the male from the female brain. Using genetic and behavioral tools, I have shown that the vomeronasal organ (VNO), an olfactory sensory organ in the nasal cavity of many mammals which detects pheromones, is responsible for the control of male- and female-specific social and sexual behaviors. Amazingly, female mice in which the VNO has been genetically or surgically inactivated engage in male-typical courtship and sexual behaviors including mounting, pelvic thrusting and courtship vocalization, that are indistinguishable from that of normal male mice. These findings suggest a model in which male and female circuits that regulate innate reproductive behaviors exist in the brain of both sexes, while a sex-specific chemosensory network enables pheromonal cues to control the sex-specificity of behavior. To gain a deeper understanding of the molecular and neuronal processes underling sex-specific innate behaviors my lab will combine molecular and genetic tools, together with unique behavioral approaches, to study animal behavioral responses under natural ethologically relevant conditions. Furthermore, to uncover novel VNO-mediated pheromone responses that might have degenerated or been suppressed in inbred laboratory mouse lines, wild-caught mouse strains will be studied in wide range of behavioral, genetically and physiological assays.

Memory scientists have been inspired and directed for decades in their search for brain mechanisms mediating learning and memory by the postulates of D.O. Hebb. Two of Hebb's most influential postulates include that co-incident activation of pre-and post-synaptic cells could be a mechanism for learning (Hebbian/associative long term potentiation). In addition once a memory is aquired, it initially exists in a fragile, labile state, after which it becomes stabilized/consolidated in the brain. While these postulates have been incredibly influential and largely correct, the data suggests it is may be time to move beyond these postulates. Data will be presented to demonstrate that synapses may not be sensitive to co-incidence of pre- and post-synaptic activation, rather they may be sensitive to probability of their co-activation. Second, we demonstrate that even old consolidated memories return to a labile state when they are remember, and must be reconsolidated in order to persist. This suggests that the traditional Consolidation Hypotheses, including Hebb's postulates, are no longer sufficient to explain the data.

TRP channels constitute a large and diverse family of proteins that are expressed in many tissues and cell types. The TRP superfamily is conserved throughout evolution from nematodes to humans. The name TRP is derived from a spontaneously occurring Drosophila mutant lacking TRP that responded to a continuous light with a Transient Receptor Potential (therefore, it was designated TRP by Minke). The Drosophila TRP and TRP-like (TRPL) channels, which are activated by the inositol lipid signaling cascade, were used later on to isolate the first mammalian TRP homologues. TRP channels mediate responses to light, nerve growth factors, pheromones, olfaction, taste, mechanical, temperature, pH, osmolarity, vasorelaxation of blood vessels, metabolic stress and pain. Furthermore, mutations in members of the TRP family are responsible for several diseases. Although a great deal is known today about members of the mammalian TRP channels, the exact physiological function and gating mechanisms of most channels are still elusive. Removal of divalent open channel block by depolarization plays a critical role in learning and memory, which is mediated by the N-methyl-D-aspartate (NMDA) channel. TRP channels also exhibit open channel block, but the physiological mechanism of its removal is still unknown. We found that lipids produced by phospholipase C (PLC) and hypoosmotic solutions remove divalent open channel block from the Drosophila TRPL channels without depolarization. Application of lipids increased single channel current and caused impermeable cation influx. The tarantula peptide GsMTx-4 specifically blocks a range of stretch-activated channels, but not by specific interaction with the channel proteins themselves but rather by modification of the channel-lipid boundary. The GsMTx-4 toxin blocked the lipids effect on TRPL channels. We found remarkable commonality between the effects of lipids on the Drosophila TRPL and the mammalian NMDA channels. We suggest a new lipid-dependent mechanism to alleviate open channel block, which operates under physiological conditions, in synergism with depolarization. The profound effect of lipids modulation allows cross talk between channel activity and lipid-producing pathways. Joint work with Moshe Parnas, Ben Katz & Shaya Lev

Glucose is the major source of energy utilized by the brain and is transported by the blood. However, it has been proposed that neurons obtain most of their energy from extracellular lactate, a glucose metabolite produced by astrocytes. Interestingly, astrocytes provide a physical link to the vasculature by their perivascular endfoot processes and are organized in network thanks to extensive intercellular communication through gap junctions. The aim of this work was to determine whether the connectivity of local astrocyte networks contributes to their metabolic supportive function to neurons. The expression of connexins 43 and 30 (Cx43, Cx30), the two main gap junction proteins in astrocytes, was particularly enriched in perivascular endfeet of astrocytes and delineated blood vessel walls in mouse hippocampal slices. Glucose trafficking dynamics was examined at the single-cell level using the fluorescent glucose derivative 2-NBDG (2- ([N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2 deoxyglucose). When injected for 20 minutes by whole cell recordings in single astrocytes lining blood vessels, 2-NBDG diffused through the astrocyte gap junction-mediated network, with a preferential pathway along interconnected astrocyte endfeet around blood vessels. This traffic was activity dependent, being reduced in the presence of TTX and increased during repetitive synaptic stimulation or epileptic conditions, and involved the activation of glutamatergic AMPA receptors. Interestingly, the permeability of Cx43, but not Cx30, was selectively regulated by glutamatergic neuronal activity. In contrast 2-NBDG, dialysed in CA1 pyramidal cells or interneurons, did not diffuse to other cells. Exogenous glucose deprivation induces a slow depression of synaptic transmission in hippocampal slices, suggesting that intrinsic energy reserves sustain neurotransmission. To test whether glucose from astrocytic networks can sustain synaptic activity, fEPSPs were recorded during exogenous glucose deprivation, while dialysing intracellularly glucose in a single astrocyte via a patch pipette. Depression of fEPSP during exogenous glucose deprivation was inhibited when glucose was administered to the astrocytic network. This effect was not caused by leakage of glucose in the extracellular space, as it was not observed in the double knockout mice for Cx30 and Cx43, devoid of gap-junction coupling. Altogether these results indicate that gap junctions play a role in the metabolic supportive function of astrocytes by providing an activity-dependent intercellular route for glucose delivery from blood vessels to distal neurons.