לוח שנה משולב

Movement shapes our interactions with the world, providing a means to translate intent into action. Among the wide repertoire of mammalian motor behaviors, the precise coordination of limb muscles to propel arms, hands and digits through space with speed and precision represents one of the more impressive achievements of the motor system. Skilled forelimb movements emerge from interactions between feedforward command pathways that induce muscle contraction and feedback systems that report and refine movement. Two broad classes of feedback modify motor output: one that originates in the periphery, and a second that is generated within the central nervous system itself. Yet the mechanisms by which these feedback pathways influence forelimb movement remain poorly understood.

We take advantage of the genetic tractability of mice to examine the organization of motor circuits and define the ways in which these pathways enable dexterous behaviors. First, I will discuss recent studies that explore the transmission of proprioceptive and cutaneous signals from the forelimb into the spinal cord and brainstem, describing neural circuits that modulate the strength of this peripheral feedback and the implications of this sensory gain control for limb movement. Second, I will describe work exploring a diverse class of spinal interneurons that we hypothesize convey copies of forelimb motor commands as internal feedback to the cerebellum, enabling online predictions of motor outcome and reducing dependence on delayed sensory information. Through a complementary set of molecular, anatomical, electrophysiological and behavioral approaches, these findings are yielding insight into the organizational and functional logic of peripheral and internal feedback, and revealing how the circuits that convey feedback information help to orchestrate skilled behavior.

The magnetic properties of ultrathin magnetic films and multilayers, e.g. magnetic anisotropies and exchange coupling, strongly depend on the surface and interface structure. Chemical composition, crystallinity, grain sizes and their distribution govern the magnetic behaviour. All these structural properties can be modified by particle irradiation. Magnetic patterning without affecting the surface topography becomes feasible, which may be of interest in applications. Homogeneous ion irradiation through masks and focused ion beam and ion projection lithography can be applied for patterning. The creation of magnetic feature sizes down to a few ten nm is possible. The main areas are magnetic data storage applications, such as hard magnetic media with a large perpendicular magnetic anisotropy (PMA) or patterned media with an improved signal-to-noise ratio and magnetic sensor elements.
The PMA is very common at magnetic metal/oxide interfaces. It is thought to be a result of electronic hybridization between the oxygen and the magnetic transition metal orbit across the interface. Interest in this phenomenon appeared in 2010 when it was demonstrated that the PMA at magnetic transition metal/oxide interfaces could be used to build out-of-plane magnetized magnetic tunnel junctions (MTJ) for spin-transfer-torque magnetic random access memory (STT-MRAM) cells. In these systems, the PMA at the CoFeB/MgO interface can be used to simultaneously obtain good memory retention, thanks to the large PMA amplitude, and a low write current, thanks to a relatively weak Gilbert damping.
I’ll give a short overview over the irradiation experiments aiming at a modification of magnetic and magnetoresistive properties of different layered magnetic structures. Then I’ll describe in detail our recent experiments on ion irradiation of double-MgO free layers designed for application in perpendicular MTJ. The samples comprised a MgO / FeCoB / X / FeCoB / MgO layer stack, where X stands for an ultrathin (0.2 nm) Ta or W spacer. In particular, we have induced easy-cone states, with different cone angles, in thin (tFeCoB = 2.6 nm) free layers with a W spacer, initially exhibiting a uniaxial anisotropy. This easy cone only exists if K1 > 0, K2 < 0 and – K2 > 2K1, with K1 and K2 being the first- and second-order anisotropy constants. Easy-cone anisotropy may help reduce the stochasticity of the spin transfer torque switching. Importantly, no increase in the Gilbert damping after irradiation has been observed.

Monoaminergic (noradrenergic, dopaminergic and serotonergic) modulation of hippocampal activity is assumed to play a major role in neuronal plasticity, learning and memory. Understanding the locus of action of these neuromodulators at the cellular level will expand our knowledge of their nature and allow us to identify issues related to their dysfunction. In the present work I study the effects of norepinephrine (NE) and dopamine (DA) on spontaneous and evoked activity in patch-clamped neurons of hippocampal slices. Both DA and NE induced a significant decrease in the amplitude of the evoked PSCs recorded from CA1 pyramidal neurons in response to stimulation of the Schaffer collaterals, accompanied by a small decrease in the cell input resistance, and a small hyperpolarization. While decreasing the evoked PSCs, NE promoted an overall increase in spontaneous synaptic activity. Pharmacological assessment of these results indicated an α1 adrenergic receptor involvement in both the decrease of the amplitude of evoked PSCs as well as the increase in spontaneous activity. Surprisingly, the effect of NE on evoked PSCs was partially antagonized by D1 dopaminergic receptor antagonist SCH23390, which suggests that NE activates dopamine receptors. The effect of DA on evoked PSCs was blocked by α1 adrenergic receptor antagonist prazosin, which suggests that DA, in turn, is activating adrenergic receptors.
Noradrenergic system is highly affected by stress; in particular, the differences between NE effects in dorsal and ventral hippocampus (DH and VH, respectively) have been shown to change in stressed animals.
In this work I used two types of stress protocols – Prenatal Stress (PS) and Acute Stress (AS) – to study the effect of stress on monoamine responses in slices of DH and VH. In non-stressed rats, NE effect on the evoked PSCs is larger in DH than in VH. PS and AS rats increased NE effect in VH, thus abolishing the difference between DH and VH. Pharmacological data suggests that these differences result from differential efficiencies of α1 and D1 receptors between DH and VH of both control and PS rats. Acute stress reversed the difference between PS and control rats; in the AS slices the PSC reduction was significantly different between DH and VH of PS rats, and not in control rats.
I conclude that stress increases the NE modulation in VH, but not in DH, thus increasing the role of emotional processing associated with the VH.

Recent advances in cryo-electron microscopy revolutionized the possibilities and capabilities of structural analysis. This presents an exciting opportunity to explore the architecture of macromolecular-complexes which could not be crystallized, but also opens a window into in situ structural determination. Here, I will discuss the excitement in resolving macromolecular structures at atomic resolution and report on advances and challenges in studying molecular assemblies in individual cells and multicellular organisms at ~1nm of resolution. A special focus will be given to the functional organization of the cell’s cytoskeleton, i.e., the actin cytoskeleton, intermediate filaments and nuclear lamins. Our study indicates that in situ structural biology, at high-resolution, shed light on structural assemblies that can only be studied in their native environment, i.e. the cell.

Drug resistance is a major barrier in medical oncology. Refractoriness to anti-cancer therapies is attributed to autonomous-tumor cell survival signaling (intrinsic mechanisms) or is mediated by growth factors secreted by cells in the tumor microenvironment (extrinsic mechanisms). Here I will describe the transcriptional machineries that regulate the expression of receptor tyrosine kinases following treatments with PI3K and EGFR therapies in squamous cell carcinoma of the head and neck. Specifically, I will show that AP-1 regulates AXL expression in PI3K-resistant cells, and EHF determines HER2/3 expression following EGFR inhibition.