Past events

Navigation, the ability to reach a desired goal location, is a complex behavior that occurs in complex environments. It requires the animal to know its own location in the environment, but also be attentive to other things in the environment that could influence its route – such as the navigational goal or other alternative goals, landmarks and obstacles along the route, as well as other conspecifics it may encounter. Despite the complexity and richness of real-world navigation, most studies of the neural basis of navigation were done in small empty setups. During my PhD, I focused on how the hippocampus represents navigation in more naturalistic and dynamic scenarios. In my first PhD project I found a vectorial representation of spatial goals in the bat hippocampus, which could support goal-directed navigation. In my second PhD project I found that during dynamic ‘cross-overs’ between two bats, hippocampal neurons switched from representing the bat’s self-position to a conjunctive representation of position × distance to the other bat – an extremely rapid neuronal switch. Taken together, in my PhD I studied the neural basis of dynamic natural navigation by adding more naturalistic aspects of navigation – such as navigation to goals and collision-avoidance behavior – and this allowed me to reveal interesting and surprising new representations in the hippocampus. 

Aggression and dominance hierarchy are basic social behaviors that are essential for the survival and reproductive success of most mammalian species. Typically, they are displayed whenever conspecifics have to compete for limited resources, such as food, water, territory, or access to mates. As a result, and due to sexual selection, intra-sexual competition is higher in males compared to females as fertile females are a limited resource to males. Thus, males often express a higher level of aggression and are most likely to form a dominance hierarchy in a group. Therefore, most studies of the biological basis of intra-sexual aggression and dominance hierarchy have been focused on males. However, it has long been observed that females also compete with each other and can form dominant hierarchies. In this study, we aimed to investigate the role of OT+ PVN neurons in the aggression of wild-derived female mice by comparing them to males. Wild-derived mice were chosen for their higher levels of aggression compared to the lab mouse strains, which might have lost these behavioral traits due to artificial selection and socially restricted environment while in captivity. To manipulate OT+ PVN neurons, we established a wild OT:Cre mouse line by backcrossing wild-derived mice with transgenic lab mice and validated that its phenotype resembles the wild-derived mice. Using these novel wild-backcrossed OT:Cre (Wild-BX) mice, we found that OT+ PVN neurons of females are activated due to agonistic interaction. Next, we virally ablated, using Casp3, or activated, using DREADD, OT+ PVN neurons in wild-BX males and females, and performed a standard resident-intruder assay (RI) to examine territorial aggression towards same-sex adults and unfamiliar pups. We found that ablation of OT+ PVN neurons in wild-BX females reduces adult and pup-directed aggression and increases sniffing behavior. In contrast, activation of this neuronal population promotes aggressive behavior toward adults and pups and decrees sniffing behavior. In males, similar manipulations did not affect either of these aggressive or sniffing behaviors, except a weak impact on pup-directed aggression. Moreover, by examining group behavior in a semi-natural environment, we found that ablation of OT+ PVN neurons suppresses dominant hierarchy formation in groups of wild-BX females. In contrast, activation strengthened the hierarchy and increased agonistic behavior in the group. In males, in contrast to the RI, the OT+ PVN ablation delayed the formation of the hierarchy and increased the anxiety in the group, whereas activation weakened the hierarchy and increased pro-social behavior. These findings suggest that OT PVN neurons have a sexually-dimorphic effect in aggression and dominance hierarchy behaviors, and they emphasize the importance of investigating both sexes in ethologically-relevant animal models and social contexts, in the study of socially relevant neuromodulators. Zoom link: https://weizmann.zoom.us/j/96648920836?pwd=OXlvV0NPTHIrVHNLYUpvZ2lNTnJZdz09 Meeting ID: 966 4892 0836 Password: 248477

Making decisions, attending to certain items, and manipulating information in working memory are fundamental behaviors that rely on specific neural circuitry. Throughout my research I have contributed to understanding such behaviors in human and in nonhuman primates but found that despite tremendous advances in the field, we still lack a mechanistic understanding of what goes wrong in conditions such as dementia or autism. My long-term research goal is to determine the circuits that support cognitive behavior, in health and disease. In my talk, I present three key contributions I have made towards uncovering neuronal circuits for cognition in the macaque, an animal model whose neural circuitry affords unique insight into human brain function. First, I demonstrate the utility of rigorous psychophysical frameworks in determining the causal contribution of key brain regions to behavior in a perceptual decision-making task. Next, I describe how causal manipulations of brain areas involved in attentional control can be used to identify hitherto unknown areas and reveal new functional circuits in support of selective attention and object recognition. Finally, I show how computational analyses of population data reveal circuits within circuits with distinct roles in supporting working memory. I end the talk by presenting my future research directions and approach: to leverage my experience studying how we select from external information (from sensory signals) to investigate how we select from internal information (from information stored in visual working memory). By blending theory-driven experiments with large-scale electrophysiological recording and circuit-specific causal manipulations in behaving macaques, I aim to uncover how we select relevant information from working memory, and equally important, how we fail to do so when struck by disorders of executive or memory function.

Naturalistic experimental paradigms in neuroimaging arose from a pressure to test the validity of models we derive from highly controlled experiments in real-world contexts. In many cases, however, such efforts led to the realization that models developed under particular experimental manipulations failed to capture much variance outside the context of that manipulation. The critique of non-naturalistic experiments is not a recent development; it echoes a persistent and subversive thread in the history of modern psychology. The brain has evolved to guide behavior in a multidimensional world with many interacting variables. The assumption that artificially decoupling and manipulating these variables will lead to a good understanding of the brain may be untenable. Recent advances in artificial neural networks provide an alternative computational framework to model cognition in natural contexts. In contrast to the simplified and interpretable hypotheses we test in the lab, these models do not learn simple, human-interpretable rules or representations of the world. Instead, they use local computations to interpolate over task-relevant manifolds in high-dimensional parameter space. Counterintuitively, over-parameterized deep neural models are parsimonious and straightforward, as they provide a versatile, robust solution for learning a diverse set of functions in natural contexts. Naturalistic paradigms should not be deployed as an afterthought if we hope to build models of brain and behavior that extend beyond the laboratory into the real world. In my talk, I will discuss the relevance of deep neural models to cognition in the context of natural language and deep language models. Zoom link- https://weizmann.zoom.us/j/95406893197?pwd=REt5L1g3SmprMUhrK3dpUDJVeHlrZz09 Meeting ID: 954 0689 3197 Password: 750421

Depression and anxiety disorders are among the most common childhood psychiatric disorders. Selective serotonin reuptake inhibitors (SSRIs) are generally considered first-line treatment for both depression and anxiety in this age group. However, 30%–40% of all patients who receive a sufficient dose and duration of treatment fail to respond. Moreover, SSRI use is frequently associated with adverse events (AEs), including activation symptoms, manic switch and increased suicidal behavior (SBs). These are particularly relevant in pediatric populations because of concerns about the suicide threat of SSRIs, resulting in a "black-box" warning. There are currently no biomarkers that can predict treatment response or AEs. Identification of such biomarkers could help to maximize the benefit-risk ratio for the use of SSRIs and speed the matching of treatment to patient. Given the fact that depression / anxiety risk is influenced by both genetic and environmental factors and that both state and trait factors will be important in treatment response prediction, a multidimensional biomarker panel covering several levels of biological information would likely be necessary. The main objective of this research thesis is to identify biomarkers that will aid in the prediction of response and suicidal and other AEs of SSRI treatment in children and adolescents treated for depression and/or anxiety disorders. We examined the involvement of specific biomarkers (miRNA’s, DNA methylation, single nucleotide polymorphism [SNP's] and metabolites) in the response to SSRIs treatment in children and adolescents and in the differences observed between individuals exhibiting response or non-response/AEs to treatment with SSRIs. Two hundred and sixty-six children and adolescents with depression and/or anxiety disorders were recruited and treated with fluoxetine. The overall response rate was 55%. Several targets from several biological domains (DNA methylation profile, miRNA’s and metabolites) were identifies as differentially expressed between responders and non-responders at baseline test. Pathway analysis of the predicted targets was carried out to assess their putative biological functions. Interestingly, when combining targets from the four biological domains, the targets were predicted to regulate specific biological pathways associated with immune system pathways and/or developmental pathways. Dysregulation of complex gene networks in the developing brain is thought to underlie depression with childhood or adolescent onset. Thus, the identified molecules might play critical roles in transcriptional networks related to treatment response and AEs. These transcriptional networks are particularly relevant to the developing human brain and to neurodevelopmental disorders with childhood/adolescent onset, such as depression and anxiety disorders. Zoom link: https://weizmann.zoom.us/j/91093085114?pwd=RVBKbEZXbjlsaVZrUVRuNThtVHB1UT09 Meeting ID: 910 9308 5114 Password : 419366

Dopamine regulates multiple brain functions including learning, motivation and movement. Furthermore, the striatum, a major target of dopamine neurons, is parceled into multiple subregions that are associated with different types of behavior, such as Pavlovian, goal-directed, and habitual behaviors. An important question in the field is how dopamine regulates these diverse functions. It has been thought that midbrain dopamine neurons broadcast reward prediction error signals to drive reinforcement learning. However, recent studies have found more diverse dopamine signals than originally thought. How can we reconcile these results? In this talk, I will discuss our recent studies characterizing diverse dopamine signals, and how these findings can be understood in a coherent theoretical framework. Zoom Link: https://weizmann.zoom.us/j/95406893197?pwd=REt5L1g3SmprMUhrK3dpUDJVeHlrZz09 Meeting ID: 954 0689 3197 Password: 750421

Hippocampal place cells fire at a high rate whenever an animal is in a specific location in an environment and are thought to support spatial and episodic memory. When an animal visits different environments, place cells typically ‘remap’ (i.e., change their preferred locations), and when revisiting the same environment, the same spatial code reemerges. In a recent study by our lab, place cells were shown to globally remap, forming multiple distinct representations (maps) of the same environment that stably coexist across time. In that study, switching between different maps of the same environment happened only after the mice were disconnected from the environment.             Here I performed a set of experiments to further understand the mechanism underlying switching between multiple maps. My project established a way to manipulate this mechanism, both through external orientation inputs and by acting directly on the hippocampal network state using optogenetics. My results provide support for the proposed role of head-direction or other orientation signals in the switching between maps. They also support the model of maps as stable attractors, where the specific attractor (map) used depends on the initial conditions of the network. Zoom: https://weizmann.zoom.us/j/92871200575?pwd=WWdZbXVmM1R5RkFZYnpTajloelVTZz09 Meeting ID: 928 7120 0575 Password: 344121

: Drug addiction is a chronically relapsing disorder characterized by compulsive drug use despite catastrophic personal consequences (e.g., loss of family, job) and even when the substance is no longer perceived as pleasurable. In this talk, I will present results of human neuroimaging studies, utilizing a multimodal approach (neuropsychology, functional magnetic resonance imaging, event-related potentials recordings), to explore the neurobiology underlying the core psychological impairments in drug addiction (impulsivity, drive/motivation, insight/awareness) as associated with its clinical symptomatology (intoxication, craving, bingeing, withdrawal). The focus of this talk is on understanding the role of the dopaminergic mesocorticolimbic circuit, and especially the prefrontal cortex, in higher-order executive dysfunction (e.g., disadvantageous decision-making such as trading a car for a couple of cocaine hits) in drug addicted individuals. The theoretical model that guides the presented research is called iRISA (Impaired Response Inhibition and Salience Attribution), postulating that abnormalities in the orbitofrontal cortex and anterior cingulate cortex (and other prefrontal cortical regions underlying higher order executive function), as related to dopaminergic dysfunction, contribute to the core clinical symptoms in drug addiction. Specifically, our multi-modality program of research is guided by the underlying working hypothesis that drug addicted individuals disproportionately attribute reward value to their drug of choice at the expense of other potentially but no-longer-rewarding stimuli, with a concomitant decrease in the ability to inhibit maladaptive drug use. In this talk I will also explore whether treatment (as usual) and 6-month abstinence enhance recovery in these brain-behavior compromises in treatment seeking cocaine addicted individuals. Promising neuroimaging studies, which combine pharmacological (i.e., oral methylphenidate, or RitalinTM) and salient cognitive tasks or functional connectivity during resting-state, will be discussed as examples of using neuroimaging in the empirical guidance for the development of effective neurorehabilitation strategies (including cognitive reappraisal, mindfulness, and transcranial direct current stimulation) in drug addiction. Zoom Lindk-https://weizmann.zoom.us/j/95406893197?pwd=REt5L1g3SmprMUhrK3dpUDJVeHlrZz09 Meeting ID 954 0689 3197 Password 750421