Ofer Yizhar

Weizmann Institute of Science | weizmann · Department of Neurobiology

Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to...

We investigated the efficacy of optogenetic inhibition at presynaptic terminals using halorhodopsin, archaerhodopsin and chloride-conducting channelrhodopsins. Precisely timed activation of both archaerhodopsin and halorhodpsin at presynaptic terminals attenuated evoked release. However, sustained archaerhodopsin activation was paradoxically associ...

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 t...

The prefrontal cortex (PFC) plays an important role in regulating social functions in mammals, and its dysfunction has been linked to social deficits in neurodevelopmental disorders. Yet little is known of how the PFC encodes social information and how social representations may be altered in such disorders. Here, we show that neurons in the medial...

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 involvemen...

Oxytocin is essential in shaping social behavior across the lifespan. While the role of oxytocin signaling in parental care has been widely investigated, little is known about its function in social behavior during early life. This is partly due to the lack of precise technologies for studying the developing brain. Here, we studied the role of oxyt...

In the classical model of the basal ganglia, direct pathway striatal projection neurons (dSPNs) send projections to the substantia nigra (SNr) and entopeduncular nucleus to regulate motor function. Recent studies have re-established that dSPNs also possess axon collaterals within the globus pallidus (GPe) (bridging collaterals), yet the significanc...

Information is transmitted between brain regions through the release of neurotransmitters from long-range projecting axons. Understanding how the activity of such long-range connections contributes to behavior requires efficient methods for reversibly manipulating their function. Chemogenetic and optogenetic tools, acting through endogenous G-prote...

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 st...

Physical exercise is known to augment brain functioning, improving memory and cognition. However, while some of the physiological effects of physical activity on the brain are known, little is known about its effects on the neural code. Using calcium imaging in freely behaving mice, we study how voluntary exercise affects the quality and long-term...

Focal cortical epilepsies are frequently refractory to available anticonvulsant drug therapies. One key factor contributing to this state is the limited availability of animal models that allow to reliably study focal cortical seizures and how they recruit surrounding brain areas in vivo. In this study, we selectively expressed the inhibitory chemo...

Optogenetic actuators enable highly precise spatiotemporal interrogation of biological processes at levels ranging from the subcellular to cells, circuits and behaving organisms. Although their application in neuroscience has traditionally focused on the control of spiking activity at the somatodendritic level, the scope of optogenetic modulators f...

Optogenetic techniques have been developed to allow control over the activity of selected cells within a highly heterogeneous tissue, using a combination of genetic engineering and light. Optogenetics employs natural and engineered photoreceptors, mostly of microbial origin, to be genetically introduced into the cells of interest. As a result, cell...

Many organisms sense light using rhodopsins, photoreceptive proteins containing a retinal chromophore. Here we report the discovery, structure and biophysical characterization of bestrhodopsins, a microbial rhodopsin subfamily from marine unicellular algae, in which one rhodopsin domain of eight transmembrane helices or, more often, two such domain...

Neurophotonics was launched in 2014 coinciding with the launch of the BRAIN Initiative focused on development of technologies for advancement of neuroscience. For the last seven years, Neurophotonics’ agenda has been well aligned with this focus on neurotechnologies featuring new optical methods and tools applicable to brain studies. While the BRAI...

Neurons are brain cells that can represent and store information, and they help our bodies to respond to events happening around us. How is information represented, processed and stored by neurons? Which neurons are activated while we perform a specific behavior? These are fundamental scientific questions. One important experimental approach to ans...

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 st...

Mammalian social interactions are orchestrated by a wide array of neural circuits. While some aspects of social behaviors are driven by subcortical circuits, and are considered to be highly conserved and hard-wired, others require dynamic and context-dependent modulation that integrates current state, past experience and goal-driven action selectio...

Working memory is an essential human trait required for all cognitive activities. Our previous model from \citet{mongillo_2008,mi_2017} uses synaptic facilitation to store traces of working memory. Thus memories can be maintained without persistent neural activity. A critical component of this model is a central inhibition which prevents multiple i...

All-optical methods for imaging and manipulating brain networks with high spatial resolution are fundamental to study how neuronal ensembles drive behavior. Stimulation of neuronal ensembles using holographic techniques requires high-sensitivity actuators to avoid photodamage and heating. Moreover, two-photon-excitable opsins should be insensitive...

Information is carried between brain regions through neurotransmitter release from axonal presynaptic terminals. Understanding the functional roles of defined neuronal projection pathways in cognitive and behavioral processes requires temporally precise manipulation of their activity in vivo. However, existing optogenetic tools have low efficacy an...

Focal cortical epilepsies are frequently refractory to available anticonvulsant drug therapies. One key factor contributing to this state is the limited availability of animal models that allow to reliably study focal cortical seizures and how they recruit surrounding brain areas in-vivo . In this study, we selectively expressed the inhibitory chem...

Understanding the function of nitric oxide, a lipophilic messenger in physiological processes across nervous, cardiovascular and immune systems, is currently impeded by the dearth of tools to deliver this gaseous molecule in situ to specific cells. To address this need, we have developed iron sulfide nanoclusters that catalyse nitric oxide generati...

Subdivisions of mouse whisker somatosensory thalamus project to cortex in a region-specific and layer-specific manner. However, a clear anatomical dissection of these pathways and their functional properties during whisker sensation is lacking. Here, we use anterograde trans-synaptic viral vectors to identify three specific thalamic subpopulations...

Complex behavioral phenotyping techniques are becoming more prevalent in the field of behavioral neuroscience, and thus methods for manipulating neuronal activity must be adapted to fit into such paradigms. Here, we present a head-mounted, magnetically activated device for wireless optogenetic manipulation that is compact, simple to construct, and...

Decades of research support the idea that associations between a conditioned stimulus (CS) and an unconditioned stimulus (US) are encoded in the lateral amygdala (LA) during fear learning. However, direct proof for the sources of CS and US information is lacking. Definitive evidence of the LA as the primary site for cue association is also missing....

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Neurons in neocortical layer 1 (L1) are thought to regulate attentional processes through integration of long-range inputs and disinhibitory effects on the underlying cortex. A new study combines genetically targeted voltage imaging and optogenetics to elucidate the input-output transformations of the L1 network in the mouse somatosensory cortex, r...

A defining feature of sleep is reduced responsiveness to external stimuli, but the mechanisms mediating sensory-evoked arousal remain unclear. We hypothesized that reduced locus coeruleus (LC) norepinephrine (NE) activity during sleep mediates unresponsiveness, and its action promotes sensory-evoked awakenings. We tested this using electrophysiolog...

The prefrontal cortex (PFC) is implicated in processing of the affective state of others through non-verbal communication. This social cognitive function is thought to rely on an intact cortical neuronal excitatory and inhibitory balance. Here combining in vivo electrophysiology with a behavioral task for affective state discrimination in mice, we...

Mouse primary somatosensory barrel cortex (wS1) processes whisker sensory information, receiving input from two distinct thalamic nuclei. The first-order ventral posterior medial (VPM) somatosensory thalamic nucleus most densely innervates layer 4 (L4) barrels, whereas the higher-order posterior thalamic nucleus (medial part, POm) most densely inne...

Motor neuron–specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor n...

Chemogenetic techniques allow selective manipulation of neurons by activating engineered actuator proteins with otherwise inert effector molecules. A recent study (Magnus et al. Science 2019;364:eaav5282) describes the coevolution of highly potent actuator–effector pairs based on a clinically approved antismoking drug. These tools allow selective e...

A defining feature of sleep is reduced responsiveness to external stimuli, but the mechanisms gating sensory-evoked arousal remain unclear. We hypothesized that reduced locus-coeruleus norepinephrine (LC-NE) activity during sleep mediates unresponsiveness, and its action promotes sensory-evoked awakenings. We tested this using electrophysiological,...

We performed two-photon holographic stimulation of blue light-sensitive excitatory opsins using high- and low-repetition rate lasers and we demonstrate high-efficiency neural stimulation with few mW average power per cell in the intact mouse cortex.

Optogenetic silencing allows time-resolved functional interrogation of defined neuronal populations. However, the limitations of inhibitory optogenetic tools impose stringent constraints on experimental paradigms. The high light power requirement of light-driven ion pumps and their effects on intracellular ion homeostasis pose unique challenges, pa...

Animals constantly evaluate their environment in order to avoid potential threats and obtain reward in the form of food, shelter and social interactions. In order to appropriately respond to sensory cues from the environment, the brain needs to form and store multiple cue-outcome associations. These can then be used to form predictions of the valen...

The prefrontal cortex (PFC) plays an important role in regulating social functions in mammals, and impairments in this region have been linked with social dysfunction in psychiatric disorders. Yet little is known of how the PFC encodes social information and of how social representations may be altered in such disorders. Here, we show that neurons...

Document S1. Supplemental Experimental Procedures, Figures S1–S7, and Tables S1–S3

Sensory information is encoded within the brain in distributed spatiotemporal patterns of neuronal activity. Understanding how these patterns influence behavior requires a method to measure and to bidirectionally perturb with high spatial resolution the activity of the multiple neuronal cell types engaged in sensory processing. Here, we combined tw...

Humans and animals can react to the affective state of others in distress. However, exposure to a stressed partner can trigger stress-related adaptations. Two studies shed light on the mechanisms underlying the behavioral responses toward stressed individuals and on the synaptic changes associated with social transmission of stress.

Optogenetic techniques allow versatile, cell type-specific light-based control of cellular activity in diverse set of cells, circuits, and brain structures. Optogenetic actuators are genetically encoded light-sensitive membrane proteins that can be selectively introduced into cellular circuits in the living brain using a variety of genetic approach...

We combined two-photon holographic stimulation of blue light-sensitive opsins with two-photon imaging of red-shifted fluorescence indicators in the intact mouse neocortex to perform cellular-resolution control of neural excitability with minimal crosstalk between imaging and stimulation.

Optogenetic silencing allows time-resolved functional interrogation of defined neuronal populations. However, the limitations of inhibitory optogenetic tools impose stringent constraints on experimental paradigms. The high light power requirement of light-driven ion pumps and their effects on intracellular ion homeostasis pose unique challenges, pa...

Science is ideally suited to connect people from different cultures and thereby foster mutual understanding. To promote international life science collaboration, we have launched ‘‘The Science Bridge’’ initiative. Our current project focuses on partnership between Western and Middle Eastern neuroscience communities.

Despite decades of research on neurobiological mechanisms of psychostimulant addiction, the only effective treatment for many addicts is contingency management, a behavioral treatment that uses alternative non-drug reward to maintain abstinence. However, when contingency management is discontinued, most addicts relapse to drug use. The brain mechan...

Reversible silencing of neuronal activity is a powerful approach for isolating the roles of specific neuronal populations in circuit dynamics and behavior. In contrast with neuronal excitation, for which the majority of studies have used a limited number of optogenetic and chemogenetic tools, the number of genetically encoded tools used for inhibit...

Sodium pumping rhodopsins (NaRs) are a unique member of the microbial-type I rhodopsin family which actively transport Na⁺ and H⁺ depending on ionic condition. In this study, we surveyed 12 different NaRs from various sources of eubacteria for their electrophysiological as well as spectroscopic properties. In mammalian cells several of these NaRs e...

Sodium pumping rhodopsins (NaRs) are a unique member of the microbial-type I rhodopsin family which actively transport Na + and H + depending on ionic condition. In this study, we surveyed 12 different NaRs from various sources of eubacteria for their electrophysiological as well as spectroscopic properties. In mammalian cells several of these NaRs...

Significance Mitochondrial functions depend on the steep H ⁺ electrochemical gradient (ΔμH ⁺ ) across their inner membrane. The available tools for controlling this gradient are essentially limited to inhibitors of the respiratory chain or of the H ⁺ ATPase or to uncouplers, poisons plagued by important side effects and that lack both cell and spat...

Tracking the coordinated activity of cellular events through volumes of intact tissue is a major challenge in biology that has inspired significant technological innovation. Yet scanless measurement of the high-speed activity of individual neurons across three dimensions in scattering mammalian tissue remains an open problem. Here we develop and va...

Fear-related disorders are thought to reflect strong and persistent fear memories. The basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) form strong reciprocal synaptic connections that play a key role in acquisition and extinction of fear memories. While synaptic contacts of BLA cells onto mPFC neurons are likely to play a crucial...

The ability to plan and execute appropriately timed responses to external stimuli is based on a well-orchestrated balance between movement initiation and inhibition. In impulse control disorders involving the prefrontal cortex (PFC) [1], this balance is disturbed, emphasizing the critical role that PFC plays in appropriately timing actions [2-4]. H...

Major resources are now available to develop tools and technologies aimed at dissecting the circuitry and computations underlying behavior, unraveling the underpinnings of brain disorders, and understanding the neural substrates of cognition. Scientists from around the world shared their views around new tools and technologies to drive advances in...

Major resources are now available to develop tools and technologies aimed at dissecting the circuitry and computations underlying behavior, unraveling the underpinnings of brain disorders, and understanding the neural substrates of cognition. Scientists from around the world shared their views around new tools and technologies to drive advances in...

The bed nucleus of the stria terminalis (BNST) is critical in mediating states of anxiety, and its dysfunction has been linked to stress-related mental disease. Although the anxiety-related role of distinct subregions of the anterior BNST was recently reported, little is known about the contribution of the posterior BNST (pBNST) to the behavioral a...

Social encounters are associated with varying degrees of emotional arousal and stress. The mechanisms underlying adequate socioemotional balance are unknown. The medial amygdala (MeA) is a brain region associated with social behavior in mice. Corticotropin-releasing factor receptor type-2 (CRF-R2) and its specific ligand urocortin-3 (Ucn3), known c...

It is commonly assumed, but has rarely been demonstrated, that sex differences in behaviour arise from sexual dimorphism in the underlying neural circuits. Parental care is a complex stereotypic behaviour towards offspring that is shared by numerous species. Mice display profound sex differences in offspring-directed behaviours. At their first enco...

In vivo experimental evidence indicates that acute neuronal activation increases Aβ release from presynaptic terminals, whereas long-term effects of chronic synaptic activation on Aβ pathology remain unclear. To address this issue, we adopted optogenetics and transduced stabilized step-function opsin, a channelrhodopsin engineered to elicit a long-...

Patients with psychiatric disease are diagnosed by psychiatrists based on the information of non-quantitative objective parameters, including behavioral phenotypes. However, how any neural mechanism affects such behavioral phenotypes in patients is still unclear. Recent functional studies suggested the alteration in brain neural/network activity re...

Optogenetics is a technical methodology that allows direct light-based manipulation of genetically specified cells. Optogenetic methods have provided novel insights into the role of defined neuronal populations in brain function and animal behavior. An expanding palette of single-component optogenetic tools provides powerful interventional strategi...