Past events

Cognitive function and emotional homeostasis, and the aspiration to decipher their neuronal basis have stood at the heart of neuroscience since its inception. The complexity of the circuits underlying these processes is immense, and new techniques are necessary to provide novel efficient ways to make a significant progress in brain research. Optogenetic tools enable temporally and spatially precise in-vivo activation or inactivation of genetically defined cell populations, thus enabling deconstruction of systems that were not available for research. An example for that is my work re-examining the role of the hippocampus in remote memory. The prevailing theory suggests that the process of remote memory consolidation requires early involvement of the hippocampus, followed by the neocortex. In the course of this process, an influence of hippocampus on neocortex may enable the hippocampus to facilitate the remote cortical storage of memory, rather than stably store the memory itself. Indeed, contextual fear memories in rodents are completely unaffected by hippocampal lesions or pharmacological inhibition on the remote timescale of weeks after training, but do depend on the hippocampus over the recent timescale of days after training. However, in exploring the contribution of defined cell types to remote memory using optogenetic methods (which are orders of magnitude faster in onset and offset than earlier methods), we found that even weeks after contextual conditioning, the contextual fear memory recall could be abolished by optogenetic inhibition of excitatory neurons in the CA1 region of the hippocampus- at times when all earlier studies had found no detectable influence of hippocampus. We also optogenetically confirmed the remote-timescale importance of anterior cingulate cortex. In exploring mechanisms, we found that loss of hippocampal involvement at remote timepoints depended on the timescale of hippocampal inhibition, since 1) we replicated earlier pharmacological work using longer-lasting drug-mediated inhibition of hippocampus (revealing the recent, but not remote, effects on memory); and 2) extending optogenetic inhibition of hippocampus to match typical pharmacological timescales converted the remote hippocampus-dependence to remote hippocampus-independence. These findings uncover a remarkable dynamism in the mammalian memory retrieval process, in which underlying neural circuitry adaptively shifts the default structures involved in memory—normally depending upon the hippocampus even at remote timepoints, but flexibly moving to alternate mechanisms when the hippocampus is offline on the timescale of minutes. This new model is further supported by the finding that contextual memory was instantaneously suppressed by CA1 inhibition even in the midst of a single freely-moving behavioral session, after the memory was already retrieved. Our findings have broad implications for the interpretation of drug or lesion data in other systems, and may open an exciting therapeutic avenue for PTSD patients, in which a pathology-inducing contextual memory could be stopped as it appears without permanently affecting other memories.

Multiple lines of evidence link numerous diseases to inherited errors in alternative splicing, the process connecting different exon and intron sequences to diversify gene expression. We explore potential involvement of acquired alternative splicing changes in non-familial Alzheimer's and Parkinson's diseases (AD, PD), where synaptic functioning fails and cholinergic or dopaminergic neurons die prematurely. Using whole genome microarrays, we found massive decline in exon exclusion events in the AD entorhinal cortex. In brain-injected mice, blocking exon exclusion caused learning and memory impairments and destruction of cholinergic neurons caused AD-like changes in exon exclusion. Suggesting physiological relevance, blocking exon exclusion in primary neuronal cells was preventable by cholinergic stimulation and caused dendritic and synapse loss. In comparison, blood leukocytes from advanced PD patients showed different alternative splicing changes. These were largely reversed by deep brain stimulation (DBS), which reduces motor symptoms, and were reversed again after disconnecting the stimulus. Measured modifications correlated with neurological treatment efficacy and classified controls from advanced PD patients and pre- from post-surgery patients. In an independent patient cohort, a "molecular signature" (6 out of the modified transcripts) further classified controls from patients with early PD or other neurological diseases. Our findings demonstrate functionally relevant disease-specific alternative splicing changes in the AD brain and PD leukocytes; highlight acquired alternative splicing changes as causally involved in different neurodegenerative diseases and identify new targets for intervention in DBS-treatable neurological diseases.

Neuronal processing has a high energetic cost, all of which is supplied through brain vasculature. What are the design rules for this system? How is flow controlled by neuronal activity? How do neurons respond to failures in the vasculature? Theses questions will be addressed at the level of necortex in rat and mouse. An essential aspect of this work is the use of nonlinear optical tools to measure and perturb vasodynamics and automate the large-scale mapping of brain angioarchitecture.

One main alteration in neural function observed in human cocaine addicts is reduced function in the medial prefrontal cortex (mPFC). However, whether altered function of the mPFC precede, or result from, excessive self-administration of cocaine, and the exact neurochemical changes it consists of, is still unknown. To answer these questions, one needs an appropriate animal model of addiction. As, it is well established that differences in the route of, and control over, cocaine-administration, or in the frequency and size of the daily-dose of cocaine, result in significant differences in cocaine-induced neurochemical effects; then if we are to better understand the neuroadaptations that underlie the development of addiction in humans, we should employ animal models that mimic as closely as possible the human situation. Hence, my lab utilize an animal model that employs intravenous self-administration of cocaine, under conditions (based on Ahmed & Koob, 1998) that distinguish the effects of brief versus extended daily access to cocaine upon both behavior and neural substrates. This permits the investigation of neuroadaptations associated with the transition from the drug-naïve state to controlled drug-use, versus the further adaptations associated with the transition from controlled to compulsive drug-use. Using this model, we measured basal, as well as cocaine-induced, release of glutamate and dopamine within the mPFC during and after various levels of exposure to cocaine. The differences we found between controlled and compulsive drug-states, will be discussed in this talk.

All sensory systems are active to some extent. Echolocating bats, which rely on their own emitted energy to perceive the surroundings, probably employ the most tightly-controlled active sensing system. The sensory degrees of freedom that bats can control are commonly divided into three categories: Timing, Signal design, and Directionality. In this talk, I will address all three categories and will summarize what we already understand and what we would love to understand.

Abstract: The intent of this presentation is to help bridge the gap between the clinical realm and the research laboratory. The clinical literature has a growing mass of evidence showing how disorders such as epilepsy, Alzheimer’s disease, stroke, or surgically-induced injury to peripheral nerve, can have devastating effects on olfactory and gustatory functions. A loss of function might be an early symptom with diagnostic value that helps the clinician identify the disease state. The presentation will introduce the non-clinician to common diagnostic and experimental tests of olfactory and taste functions. Various causes of olfactory loss will be discussed, plus their therapy

Several state-of-the-art computer vision systems for face detection, e.g., Viola-Jones [1], rely on region-based features that compute contrast by adding and subtracting average image intensity within different regions of the face. This is a powerful strategy due to the invariance of these features across changes in illumination (as proposed by Sinha [2]). The computational mechanisms underlying face detection in biological systems, however, remain unclear. We set to investigate the role of region-based features in the macaque middle face patch, an area that consists of face-selective neurons. We found that individual neurons were tuned to subsets of contrast relationships between pairs of face regions. The sign of tuning for these relationships was strikingly consistent across the population (for example, almost all neurons preferred a lower average intensity in the eye region relative to the nose region). Furthermore, the pairs and polarity of tuning were fully consistent with Sinha’s proposed ratio-template model of face detection [2]. Non-face images from the CBCL dataset that contained correct contrast polarities in pre-defined regions (facial parts) did not elicit increased firing in face-selective neurons, suggesting that the neurons are not only computing averaged intensity according to a fixed template, but are also sensitive to the specific shape of features within a region. [1] Robust Real-time Object Detection, Paul Viola and Michael Jones. Second International Workshop on Statistical and Computational Theories of Vision – Modeling, Learning, Computing, and Sampling. Vancouver, Canada, July, 2001. [2] Qualitative Representations for Recognition, Pawan Sinha. Proceedings of the Second International Workshop on Biologically Motivated Computer Vision, Tubingen, November, 2002.

During the first year of life, babies learn skills of movement which serve them not only for their present stage, but are building blocks for future stages. There are special qualities of the learning process in early development stages, which allow the learned experiences to be generalized in later stages. For example the skills that are learned in horizontal locomotion (crawling) are also applied in walking. This learning process is playful and rich with mistakes It is complex in the sense that at each moment there is an overlap of a few functions. For example, keeping the balance while lifting a toy.By observing video clips of a few babies playing, we will see some of the necessary qualities of the learning process. We will also see movement lessons given to disabled children, providing them with the normal ingredients of the learning process, in spite of their disabilities.