Yizhar Lab

Organization, function & plasticity
of prefrontal circuits

Research

Our lab is interested in the neural circuit substrates of complex behaviors, including social behavior, decision making, learning and memory. Work in the lab is focused on how specific neural circuits regulate these functions, on disease-related changes and their electrophysiological and behavioral correlates.

The lab also develops and applies advanced optogenetic technologies for modulating brain functions. Optogenetic technology uses a combination of gene therapy and optical techniques to directly regulate the function of neurons in the living brain. We have developed numerous optogenetic tools for refined control of neural activity, focusing specifically on optogenetic suppression of synaptic transmission, a key technique that allows researchers to ask how the activity in specific brain pathways contributes to behavior.

The prefrontal cortex is a brain region that plays important roles in goal-directed behaviors. Problems in prefrontal function are associated with various psychiatric disorders, including major depression, schizophrenia, autism and obsessive-compulsive disorders. Our goal is to understand how this complex circuit operates and to gain a basic understanding of the mechasnisms for its malfunction in disease states. We have developed methods to study the connectivity of prefrontal cortical neurons at single-cell resolution, and are now applying this technique to further understand how this complex circuit is organized, and how its connectivity changes during learning.

Research page

Optogenetic tool development

Organization of cortical synaptic connectivity

Functional dissection of prefrontal circuits

Cortical modulation of social behavior

Early-life social behavior

Selected Publications

Determinants of functional synaptic connectivity among amygdala-projecting prefrontal cortical neurons in male mice

Printz Y., Patil P., Mahn M., Benjamin A., Litvin A., Levy R., Bringmann M. & Yizhar O. (2023) Nature Communications. 14, 1667.

Submitted version

The medial prefrontal cortex (mPFC) mediates a variety of complex cognitive functions via its vast and diverse connections with cortical and subcortical structures. Understanding the patterns of synaptic connectivity that comprise the mPFC local network is crucial for deciphering how this circuit processes information and relays it to downstream structures. To elucidate the synaptic organization of the mPFC, we developed a high-throughput optogenetic method for mapping large-scale functional synaptic connectivity in acute brain slices. We show that in male mice, mPFC neurons that project to the basolateral amygdala (BLA) display unique spatial patterns of local-circuit synaptic connectivity, which distinguish them from the general mPFC cell population. When considering synaptic connections between pairs of mPFC neurons, the intrinsic properties of the postsynaptic cell and the anatomical positions of both cells jointly account for ~7.5% of the variation in the probability of connection. Moreover, anatomical distance and laminar position explain most of this fraction in variation. Our findings reveal the factors determining connectivity in the mPFC and delineate the architecture of synaptic connections in the BLA-projecting subnetwork.

Efficient optogenetic silencing of neurotransmitter release with a mosquito rhodopsin

Mahn M., Saraf-Sinik I., Patil P., Pulin M., Bitton E., Karalis N., Bruentgens F., Palgi S., Gat A., Dine J., Wietek J., Davidi I., Levy R., Litvin A., Zhou F., Sauter K., Soba P., Schmitz D., Lüthi A., Rost B. R., Wiegert J. S. & Yizhar O. (2021) Neuron. 109, 10, p. 1621-1635.e8

Accepted version

Information is carried between brain regions through neurotransmitter release from axonal presynaptic terminals. Understanding the functional roles of defined neuronal projection pathways requires temporally precise manipulation of their activity. However, existing inhibitory optogenetic tools have low efficacy and off-target effects when applied to presynaptic terminals, while chemogenetic tools are difficult to control in space and time. Here, we show that a targeting-enhanced mosquito homolog of the vertebrate encephalopsin (eOPN3) can effectively suppress synaptic transmission through the G_i/o signaling pathway. Brief illumination of presynaptic terminals expressing eOPN3 triggers a lasting suppression of synaptic output that recovers spontaneously within minutes in vitro and in vivo. In freely moving mice, eOPN3-mediated suppression of dopaminergic nigrostriatal afferents induces a reversible ipsiversive rotational bias. We conclude that eOPN3 can be used to selectively suppress neurotransmitter release at presynaptic terminals with high spatiotemporal precision, opening new avenues for functional interrogation of long-range neuronal circuits in vivo.

Co-coding of head and whisker movements by both VPM and POm thalamic neurons

Oram T. B., Tenzer A., Saraf-Sinik I., Yizhar O. & Ahissar E. (2024) Nature Communications. 15, 5883.

Rodents continuously move their heads and whiskers in a coordinated manner while perceiving objects through whisker-touch. Studies in head-fixed rodents showed that the ventroposterior medial (VPM) and posterior medial (POm) thalamic nuclei code for whisker kinematics, with POm involvement reduced in awake animals. To examine VPM and POm involvement in coding head and whisker kinematics in awake, head-free conditions, we recorded thalamic neuronal activity and tracked head and whisker movements in male mice exploring an open arena. Using optogenetic tagging, we found that in freely moving mice, both nuclei equally coded whisker kinematics and robustly coded head kinematics. The fraction of neurons coding head kinematics increased after whisker trimming, ruling out whisker-mediated coding. Optogenetic activation of thalamic neurons evoked overt kinematic changes and increased the fraction of neurons leading changes in head kinematics. Our data suggest that VPM and POm integrate head and whisker information and can influence head kinematics during tactile perception.

All Publications