All events, 2010

The Optimism Bias: A tour of the positively irrational brain

Lecture
Date:
Thursday, December 30, 2010
Hour: 15:00
Location:
Gerhard M.J. Schmidt Lecture Hall
Dr. Tali Sharot
|
University College London

New Developments in the Genetics of Eating Disorders

Lecture
Date:
Wednesday, December 29, 2010
Hour: 15:00
Location:
Nella and Leon Benoziyo Building for Brain Research
Allan Kaplan
|
Professor of Psychiatry, University of Toronto

The eating disorders anorexia nervosa (AN) and bulimia nervosa (BN) are serious psychiatric disorders characterized by disturbed eating behavior and characteristic psychopathology, and in the case of AN, very low weight. The mortality of AN is the highest of any psychiatric disorder. The etiology of AN and BN are multidetermined; there are factors biologically, psychologically and socioculturallly that predispose an individual to an eating disorder. Biologically, genes contribute significantly to the risk for eating disorders. Studies have shown that the risk of anorexia nervosa in first degree relatives if one parent has AN is between 8-10%.compraed to the general population risk of 1%. The concordance rate for MZ twins in AN is close to 70%. Approximately 70% of the variance in AN is attributable to genetic effects whereas about 30% is attributable to unique environmental effects. For BN, approximately 60% of the variance in BN is attributable to genetic effects whereas about 40% is attributable to unique environmental effects. Eating disorders do not map on to one chromosome Instead there are dimensions that are genetic, such as risk of obesity, anxiety, and temperament such as perfectionism and obssessionality that are inherited and place an individual at risk for an eating disorder Gender is also a genetic risk factor for an eating disorder. Being female is a risk factor for an eating disorder, not just because females are more sensitive to cultural pressure than males. Females are more commonly affected by eating disorders because female brains are much more sensitive to dietary manipulation than male brains related to the effects of estrogen and progesterone on serotonin metabolism. Tryptophan depletion does not significantly affect levels of brain serotonin in males but dramatically reduces levels of serotonin produced in females’ brains. Dieting, especially restricting carbohydrates lowers the level of blood tryptophan available to cross the blood brain and be available to be synthesized to serotonin. Patients are at risk for an eating disorder will reduce the levels of serotonin produced in their brains by dieting and restricting carbohydrates, leading to changes in satiety and mood and increasing the likelihood of an eating disorder developing . There are those who believe that binge eating develops in response to a hyposerotonergic state in an attempt to restore tryptophan available for brain serotonin synthesis I have been involved in several large multi site genetic studies of eating disorders over the past 15 years. In a linkage analysis of affected relative AN pairs, when only restricting anorexics were included in the analyses, a significant signal was found on the long arm of chromosome 1. Candidate genes that have been found in that area of chromosome 1 include the serotonin 1D receptor gene, the opiod delta gene, and the dopamine D2 receptor gene. In a linkage analyses on a sample of affected relative pairs with BN, a significant signal was found on chromosome 10 when the sample included only subjects who vomited. I am currently involved in a whole genome wide association study ( GWAS) of 4000 AN cases and 4000 female controls which will hopefully elucidate which specific genes contribute to the risk for AN. Future genetic studies we are involved in will focus on why patients with AN are able to drop their weight to dangerously low levels, whereas patients with bulimia nervosa (BN) with similar psychopathology and dysfunctional eating behaviors are protected from extreme weight loss and do not develop AN. So far, research on genes that are important for appetite and weight regulation, such as the leptin receptor (LEPR), ghrelin (GHRL), melanocortin 4 receptor (MC4R), and brain derived neurotrophic factor (BDNF), has yielded conflicting findings in AN and BN, while related genes with potential in the same genetic systems have not been sufficiently studied. Considering that AN in adults tends to follow a chronic course and currently does not have any evidence-based treatments, determining the role of genetic factors in the vulnerability to achieve low weight in AN patients could be an important first step toward improved treatment.

On Informational Principles of Embodied Cognition

Lecture
Date:
Wednesday, December 29, 2010
Hour: 12:00
Location:
Gerhard M.J. Schmidt Lecture Hall
Dr. Daniel Polani
|
School of Computer Science, University of Hertfordshire, UK

For many decades, Artificial Intelligence adopted a platonic view that intelligent behaviour is produced in the "brain" only and any body is only an incidental translator between thought and action. In the last two decades, in view of the successes of the subsumption architecture and embodied robotics, this perspective has changed to acknowledge the central importance of the body and the perception-action loop as whole in helping an organisms' brain to carry out useful ("intelligent") behaviours. A central keyword for this phenomenon is, of course, "environmental/morphological computation" (Paul 2006; Pfeifer and Bongard 2007). The question arises, how/why exactly does this work? What are the principles that make environmental computation work so successfully and how can the contribution that the body provides to cognition be characterized objectively? In the last years, Information Theory has been identified as providing a natural language to characterize cognitive processing, cognitive invariants as well as the contribution of the embodiment to the cognitive process. The talk will review some highlights of the current state-of-the-art in the field and provide some - sometimes quite surprising - illustrations of the power of the informational view of cognition.

Visual Inference Amid Fixational Eye Movements

Lecture
Date:
Tuesday, December 28, 2010
Hour: 12:30
Location:
Jacob Ziskind Building
Dr. Yoram Burak
|
Center for Brain Science, Harvard University

Our visual system is capable of inferring the structure of 2-d images at a resolution comparable (or, in some tasks, greatly exceeding) the receptive field size of individual retinal ganglion cells (RGCs). Our capability to do so becomes all the more surprising once we consider that, while performing such tasks, the image projected on the retina is in constant jitter due to eye and head motion. For example, the motion between two subsequent discharges of a foveal RGC typically exceeds the receptive field size, so the two subsequent spikes report on different regions of the visual scene. This suggests that, to achieve high-acuity perception, the brain must take the image jitter into account. I will discuss two theoretical investigations of this theme. I will first ask how the visual system might infer the structure of images drawn from a large, relatively unconstrained ensemble. Due to the combinatorially large number of possible images, it is impossible for the brain to act as an ideal observer that performs optimal Bayesian inference based on the retinal spikes. However, I will propose an approximate scheme derived from such an approach, which is based on a factorial representation of the multi-dimensional probability distribution, similar to a mean-field approximation. The decoding scheme that emerges from this approximation suggests a neural implementation that involves two neural populations, one that represents an estimate for the position of the eye, and another that represents an estimate of the stabilized image. I will discuss the performance of this decoding strategy under simplified assumptions on retinal coding. I will also compare it to other schemes, and discuss possible implications for neural visual processing in the foveal region. In the second part of the talk I will focus on the Vernier task, in which human subjects achieve hyper-acuity, greatly exceeding the receptive field size of a single RGC. The optimal decoder for this task can be formalized and analyzed mathematically in detail. I will show that a linear, perceptron-type decoder cannot achieve hyper-acuity. On the other hand a quadratic decoder, which is sensitive to coincident spiking in pairs of neurons, constitutes an effective and structurally simple solution to the problem. Furthermore, the performance achieved by such a decoder is close to the limit imposed by the ideal Bayesian decoder. Therefore, spike coincidence detectors in the early visual system may facilitate hyper-acuity vision in the presence of fixational eye-motion.

Connectivity and activity of C. elegans locomotion

Lecture
Date:
Monday, December 27, 2010
Hour: 15:00
Location:
Nella and Leon Benoziyo Building for Brain Research
Dr. Gal Haspel
|
National Institute of Neurological Disorders and Stroke, NIH

I study the neuronal basis of locomotion in the nematode C elegans. With only 302 neurons in its nervous system, 75 of which are locomotion motorneurons, C. elegans offers a tractable network to study locomotion. In this talk I will describe my research, which uses a neuroethological approach to study both the behavior and the underlying connectivity and activity of neurons and muscle cells.

Genetic dissection of rheumatoid arthritis – the end of the beginning

Lecture
Date:
Monday, December 27, 2010
Hour: 12:00
Location:
Arthur and Rochelle Belfer Building for Biomedical Research
Dr. Katherine Siminovitch
|
Mount Sinai Hospital Toronto, Ontario

In this talk I will review the rationale for searching for autoimmune disease susceptibility genes and in particular for genes conferring risk for rheumatoid arthritis(RA). I will then review the current state of knowledge on RA genes and will then focus on one of the few newly-discovered genes (PTPN22) for which we know the disease causal gene variant. This gene encodes a tyrosine phosphatase ,LYP, and I will present recent data from my lab in which we use an animal model to show how the RA-associated PTPN22/LYP variant causes T cell dysfunction that could predispose to autoimmunity.

Optogenetic deconstruction of the neuronal circuits underlying dynamic retrieval strategies for long-term memories

Lecture
Date:
Tuesday, December 21, 2010
Hour: 12:30
Location:
Jacob Ziskind Building
Dr. Inbal Goshen
|
Dept of Bioengineering, Stanford University, Stanford CA

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.

Anesthesia: a window to the neuronal activity underlying consciousness

Lecture
Date:
Tuesday, December 7, 2010
Hour: 12:30
Location:
Jacob Ziskind Building
Dr. Aeyal Raz
|
Dept of Anesthesia Rabin Medical Center

The neural mechanisms underlying consciousness have been one of the most intriguing yet elusive questions facing science. We will discuss how the activity of the neuronal population changes during loss of consciousness following administration of general anesthesia drugs. We measured the changes of Sub-thalamic nucleus neurons activity during administration of propofol (GABAA agonists) and Remifentanil (opiate agonist). This was done during implantation of deep brain stimulation electrodes for the treatment of Parkinson&#8217;s disease in humans. Administration of both Propofol and remifentanil leads to a similar reduction of STN multi-unit neuronal spiking activity. Remifentanil seems to interfere with the oscillatory pattern of STN activity whereas propofol does not. In order to broaden our understanding of the effect of anesthetic drugs, we performed extra-cellular recordings of neuronal activity from the cortex and globus pallidus of vervet monkeys using multiple electrodes. The recordings were performed during sedation with Ketamine (NMDA antagonist). Our results demonstrate the appearance of synchronous oscillatory activity of the LFP at slow (<1 Hz) delta (3-4Hz) and gamma (35-50Hz) in the motor cortex and globus pallidus following ketamine injection and loss of consciousness. These oscillations are synchronized between regions as well, and are correlated to the spiking activity of neurons in these regions. We propose that loss of consciousness following anesthesia is due to the appearance of synchronized oscillatory activity in different regions of the brain, preventing the normal processing and passage of information.

Acquired alternative splicing changes in Alzheimer's and Parkinson's diseases

Lecture
Date:
Tuesday, November 30, 2010
Hour: 12:30
Location:
Jacob Ziskind Building
Prof. Hermona Soreq
|
Safra Center of Neuroscience The Hebrew University of Jerusalem

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.

Visualizing Circuits in the Visual System

Lecture
Date:
Thursday, November 25, 2010
Hour: 12:00
Location:
Arthur and Rochelle Belfer Building for Biomedical Research
Prof. Josh Sanes
|
Center for Brain Science Harvard University

Formation of neural circuits requires that axons recognize appropriate cells, and even appropriate parts of cells, upon which to synapse. In the retina, amacrine and bipolar cells form synapses on retinal ganglion cells (RGCs) in the inner plexiform layer (IPL). The visual features to which different RGC subtypes respond depend on what input they receive, prime determinants of which are the IPL sublaminae in which their dendrites make synapses. We have therefore sought molecules that mark RGC subtyoes and mediate lamina-specific connectivity. Candidates include members of the immunoglobulin superfamily, such as Sidekicks, Dscams and JAMs, and members of the cadherin superfamily, such as Class II and protocadherins. I will discuss our progress toward identifying and testing such candidates. I will also discuss methods for tracing connections of retinal neurons in wild-type and mutant mice, so that we can assess the consequences of perturbing target recognition systems.

Pages

All events, 2010

The Optimism Bias: A tour of the positively irrational brain

Lecture
Date:
Thursday, December 30, 2010
Hour: 15:00
Location:
Gerhard M.J. Schmidt Lecture Hall
Dr. Tali Sharot
|
University College London

New Developments in the Genetics of Eating Disorders

Lecture
Date:
Wednesday, December 29, 2010
Hour: 15:00
Location:
Nella and Leon Benoziyo Building for Brain Research
Allan Kaplan
|
Professor of Psychiatry, University of Toronto

The eating disorders anorexia nervosa (AN) and bulimia nervosa (BN) are serious psychiatric disorders characterized by disturbed eating behavior and characteristic psychopathology, and in the case of AN, very low weight. The mortality of AN is the highest of any psychiatric disorder. The etiology of AN and BN are multidetermined; there are factors biologically, psychologically and socioculturallly that predispose an individual to an eating disorder. Biologically, genes contribute significantly to the risk for eating disorders. Studies have shown that the risk of anorexia nervosa in first degree relatives if one parent has AN is between 8-10%.compraed to the general population risk of 1%. The concordance rate for MZ twins in AN is close to 70%. Approximately 70% of the variance in AN is attributable to genetic effects whereas about 30% is attributable to unique environmental effects. For BN, approximately 60% of the variance in BN is attributable to genetic effects whereas about 40% is attributable to unique environmental effects. Eating disorders do not map on to one chromosome Instead there are dimensions that are genetic, such as risk of obesity, anxiety, and temperament such as perfectionism and obssessionality that are inherited and place an individual at risk for an eating disorder Gender is also a genetic risk factor for an eating disorder. Being female is a risk factor for an eating disorder, not just because females are more sensitive to cultural pressure than males. Females are more commonly affected by eating disorders because female brains are much more sensitive to dietary manipulation than male brains related to the effects of estrogen and progesterone on serotonin metabolism. Tryptophan depletion does not significantly affect levels of brain serotonin in males but dramatically reduces levels of serotonin produced in females&#8217; brains. Dieting, especially restricting carbohydrates lowers the level of blood tryptophan available to cross the blood brain and be available to be synthesized to serotonin. Patients are at risk for an eating disorder will reduce the levels of serotonin produced in their brains by dieting and restricting carbohydrates, leading to changes in satiety and mood and increasing the likelihood of an eating disorder developing . There are those who believe that binge eating develops in response to a hyposerotonergic state in an attempt to restore tryptophan available for brain serotonin synthesis I have been involved in several large multi site genetic studies of eating disorders over the past 15 years. In a linkage analysis of affected relative AN pairs, when only restricting anorexics were included in the analyses, a significant signal was found on the long arm of chromosome 1. Candidate genes that have been found in that area of chromosome 1 include the serotonin 1D receptor gene, the opiod delta gene, and the dopamine D2 receptor gene. In a linkage analyses on a sample of affected relative pairs with BN, a significant signal was found on chromosome 10 when the sample included only subjects who vomited. I am currently involved in a whole genome wide association study ( GWAS) of 4000 AN cases and 4000 female controls which will hopefully elucidate which specific genes contribute to the risk for AN. Future genetic studies we are involved in will focus on why patients with AN are able to drop their weight to dangerously low levels, whereas patients with bulimia nervosa (BN) with similar psychopathology and dysfunctional eating behaviors are protected from extreme weight loss and do not develop AN. So far, research on genes that are important for appetite and weight regulation, such as the leptin receptor (LEPR), ghrelin (GHRL), melanocortin 4 receptor (MC4R), and brain derived neurotrophic factor (BDNF), has yielded conflicting findings in AN and BN, while related genes with potential in the same genetic systems have not been sufficiently studied. Considering that AN in adults tends to follow a chronic course and currently does not have any evidence-based treatments, determining the role of genetic factors in the vulnerability to achieve low weight in AN patients could be an important first step toward improved treatment.

On Informational Principles of Embodied Cognition

Lecture
Date:
Wednesday, December 29, 2010
Hour: 12:00
Location:
Gerhard M.J. Schmidt Lecture Hall
Dr. Daniel Polani
|
School of Computer Science, University of Hertfordshire, UK

For many decades, Artificial Intelligence adopted a platonic view that intelligent behaviour is produced in the "brain" only and any body is only an incidental translator between thought and action. In the last two decades, in view of the successes of the subsumption architecture and embodied robotics, this perspective has changed to acknowledge the central importance of the body and the perception-action loop as whole in helping an organisms' brain to carry out useful ("intelligent") behaviours. A central keyword for this phenomenon is, of course, "environmental/morphological computation" (Paul 2006; Pfeifer and Bongard 2007). The question arises, how/why exactly does this work? What are the principles that make environmental computation work so successfully and how can the contribution that the body provides to cognition be characterized objectively? In the last years, Information Theory has been identified as providing a natural language to characterize cognitive processing, cognitive invariants as well as the contribution of the embodiment to the cognitive process. The talk will review some highlights of the current state-of-the-art in the field and provide some - sometimes quite surprising - illustrations of the power of the informational view of cognition.

Visual Inference Amid Fixational Eye Movements

Lecture
Date:
Tuesday, December 28, 2010
Hour: 12:30
Location:
Jacob Ziskind Building
Dr. Yoram Burak
|
Center for Brain Science, Harvard University

Our visual system is capable of inferring the structure of 2-d images at a resolution comparable (or, in some tasks, greatly exceeding) the receptive field size of individual retinal ganglion cells (RGCs). Our capability to do so becomes all the more surprising once we consider that, while performing such tasks, the image projected on the retina is in constant jitter due to eye and head motion. For example, the motion between two subsequent discharges of a foveal RGC typically exceeds the receptive field size, so the two subsequent spikes report on different regions of the visual scene. This suggests that, to achieve high-acuity perception, the brain must take the image jitter into account. I will discuss two theoretical investigations of this theme. I will first ask how the visual system might infer the structure of images drawn from a large, relatively unconstrained ensemble. Due to the combinatorially large number of possible images, it is impossible for the brain to act as an ideal observer that performs optimal Bayesian inference based on the retinal spikes. However, I will propose an approximate scheme derived from such an approach, which is based on a factorial representation of the multi-dimensional probability distribution, similar to a mean-field approximation. The decoding scheme that emerges from this approximation suggests a neural implementation that involves two neural populations, one that represents an estimate for the position of the eye, and another that represents an estimate of the stabilized image. I will discuss the performance of this decoding strategy under simplified assumptions on retinal coding. I will also compare it to other schemes, and discuss possible implications for neural visual processing in the foveal region. In the second part of the talk I will focus on the Vernier task, in which human subjects achieve hyper-acuity, greatly exceeding the receptive field size of a single RGC. The optimal decoder for this task can be formalized and analyzed mathematically in detail. I will show that a linear, perceptron-type decoder cannot achieve hyper-acuity. On the other hand a quadratic decoder, which is sensitive to coincident spiking in pairs of neurons, constitutes an effective and structurally simple solution to the problem. Furthermore, the performance achieved by such a decoder is close to the limit imposed by the ideal Bayesian decoder. Therefore, spike coincidence detectors in the early visual system may facilitate hyper-acuity vision in the presence of fixational eye-motion.

Connectivity and activity of C. elegans locomotion

Lecture
Date:
Monday, December 27, 2010
Hour: 15:00
Location:
Nella and Leon Benoziyo Building for Brain Research
Dr. Gal Haspel
|
National Institute of Neurological Disorders and Stroke, NIH

I study the neuronal basis of locomotion in the nematode C elegans. With only 302 neurons in its nervous system, 75 of which are locomotion motorneurons, C. elegans offers a tractable network to study locomotion. In this talk I will describe my research, which uses a neuroethological approach to study both the behavior and the underlying connectivity and activity of neurons and muscle cells.

Genetic dissection of rheumatoid arthritis – the end of the beginning

Lecture
Date:
Monday, December 27, 2010
Hour: 12:00
Location:
Arthur and Rochelle Belfer Building for Biomedical Research
Dr. Katherine Siminovitch
|
Mount Sinai Hospital Toronto, Ontario

In this talk I will review the rationale for searching for autoimmune disease susceptibility genes and in particular for genes conferring risk for rheumatoid arthritis(RA). I will then review the current state of knowledge on RA genes and will then focus on one of the few newly-discovered genes (PTPN22) for which we know the disease causal gene variant. This gene encodes a tyrosine phosphatase ,LYP, and I will present recent data from my lab in which we use an animal model to show how the RA-associated PTPN22/LYP variant causes T cell dysfunction that could predispose to autoimmunity.

Optogenetic deconstruction of the neuronal circuits underlying dynamic retrieval strategies for long-term memories

Lecture
Date:
Tuesday, December 21, 2010
Hour: 12:30
Location:
Jacob Ziskind Building
Dr. Inbal Goshen
|
Dept of Bioengineering, Stanford University, Stanford CA

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&#8212;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.

Anesthesia: a window to the neuronal activity underlying consciousness

Lecture
Date:
Tuesday, December 7, 2010
Hour: 12:30
Location:
Jacob Ziskind Building
Dr. Aeyal Raz
|
Dept of Anesthesia Rabin Medical Center

The neural mechanisms underlying consciousness have been one of the most intriguing yet elusive questions facing science. We will discuss how the activity of the neuronal population changes during loss of consciousness following administration of general anesthesia drugs. We measured the changes of Sub-thalamic nucleus neurons activity during administration of propofol (GABAA agonists) and Remifentanil (opiate agonist). This was done during implantation of deep brain stimulation electrodes for the treatment of Parkinson&#8217;s disease in humans. Administration of both Propofol and remifentanil leads to a similar reduction of STN multi-unit neuronal spiking activity. Remifentanil seems to interfere with the oscillatory pattern of STN activity whereas propofol does not. In order to broaden our understanding of the effect of anesthetic drugs, we performed extra-cellular recordings of neuronal activity from the cortex and globus pallidus of vervet monkeys using multiple electrodes. The recordings were performed during sedation with Ketamine (NMDA antagonist). Our results demonstrate the appearance of synchronous oscillatory activity of the LFP at slow (<1 Hz) delta (3-4Hz) and gamma (35-50Hz) in the motor cortex and globus pallidus following ketamine injection and loss of consciousness. These oscillations are synchronized between regions as well, and are correlated to the spiking activity of neurons in these regions. We propose that loss of consciousness following anesthesia is due to the appearance of synchronized oscillatory activity in different regions of the brain, preventing the normal processing and passage of information.

Acquired alternative splicing changes in Alzheimer's and Parkinson's diseases

Lecture
Date:
Tuesday, November 30, 2010
Hour: 12:30
Location:
Jacob Ziskind Building
Prof. Hermona Soreq
|
Safra Center of Neuroscience The Hebrew University of Jerusalem

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.

Visualizing Circuits in the Visual System

Lecture
Date:
Thursday, November 25, 2010
Hour: 12:00
Location:
Arthur and Rochelle Belfer Building for Biomedical Research
Prof. Josh Sanes
|
Center for Brain Science Harvard University

Formation of neural circuits requires that axons recognize appropriate cells, and even appropriate parts of cells, upon which to synapse. In the retina, amacrine and bipolar cells form synapses on retinal ganglion cells (RGCs) in the inner plexiform layer (IPL). The visual features to which different RGC subtypes respond depend on what input they receive, prime determinants of which are the IPL sublaminae in which their dendrites make synapses. We have therefore sought molecules that mark RGC subtyoes and mediate lamina-specific connectivity. Candidates include members of the immunoglobulin superfamily, such as Sidekicks, Dscams and JAMs, and members of the cadherin superfamily, such as Class II and protocadherins. I will discuss our progress toward identifying and testing such candidates. I will also discuss methods for tracing connections of retinal neurons in wild-type and mutant mice, so that we can assess the consequences of perturbing target recognition systems.

Pages

All events, 2010

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All events, 2010

A Conference on Neurodegenerative Diseases in Memory of Late Prof. Irith Ginzburg (1943-2008)

Conference
Date:
Wednesday, January 13, 2010
Hour:
Location:

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