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, 1, 1667.

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 (Cambridge, Mass.). 109, 10, p. 1621-1635

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 Gi/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.

Neural basis for fasting activation of the hypothalamic–pituitary–adrenal axis

Douglass A. M., Resch J. M., Madara J. C., Kucukdereli H., Yizhar O., Grama A., Yamagata M., Yang Z. & Lowell B. B. (2023) Nature. 620, 7972, p. 154-162

Fasting initiates a multitude of adaptations to allow survival. Activation of the hypothalamic–pituitary–adrenal (HPA) axis and subsequent release of glucocorticoid hormones is a key response that mobilizes fuel stores to meet energy demands 1–5. Despite the importance of the HPA axis response, the neural mechanisms that drive its activation during energy deficit are unknown. Here, we show that fasting-activated hypothalamic agouti-related peptide (AgRP)-expressing neurons trigger and are essential for fasting-induced HPA axis activation. AgRP neurons do so through projections to the paraventricular hypothalamus (PVH), where, in a mechanism not previously described for AgRP neurons, they presynaptically inhibit the terminals of tonically active GABAergic afferents from the bed nucleus of the stria terminalis (BNST) that otherwise restrain activity of corticotrophin-releasing hormone (CRH)-expressing neurons. This disinhibition of PVH Crh neurons requires γ-aminobutyric acid (GABA)/GABA-B receptor signalling and potently activates the HPA axis. Notably, stimulation of the HPA axis by AgRP neurons is independent of their induction of hunger, showing that these canonical ‘hunger neurons’ drive many distinctly different adaptations to the fasted state. Together, our findings identify the neural basis for fasting-induced HPA axis activation and uncover a unique means by which AgRP neurons activate downstream neurons: through presynaptic inhibition of GABAergic afferents. Given the potency of this disinhibition of tonically active BNST afferents, other activators of the HPA axis, such as psychological stress, may also work by reducing BNST inhibitory tone onto PVH Crh neurons.

All Publications