Kavli Institute for Brain Science

New York City, NY, United States

Kavli Institute for Brain Science

New York City, NY, United States
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Zhang W.,Riverside Research Institute | Schneider D.M.,Riverside Research Institute | Belova M.A.,Riverside Research Institute | Morrison S.E.,Riverside Research Institute | And 7 more authors.
Journal of Neuroscience | Year: 2013

Recent electrophysiological studies on the primate amygdala have advanced our understanding of how individual neurons encode information relevant to emotional processes, but it remains unclear how these neurons are functionally and anatomically organized. To address this, we analyzed cross-correlograms of amygdala spike trains recorded during a task in which monkeys learned to associate novel images with rewarding and aversive outcomes. Using this task, we have recently described two populations of amygdala neurons: one that responds more strongly to images predicting reward (positive value-coding), and another that responds more strongly to images predicting an aversive stimulus (negative value-coding). Here, we report that these neural populations are organized into distinct, but anatomically intermingled, appetitive and aversive functional circuits, which are dynamically modulated as animals used the images to predict outcomes. Furthermore, we report that responses to sensory stimuli are prevalent in the lateral amygdala, and are also prevalent in the medial amygdala for sensory stimuli that are emotionally significant. The circuits identified here could potentially mediate valence-specific emotional behaviors thought to involve the amygdala. © 2013 the authors.


de Nooij J.C.,Biochemistry and Molecular Biophysics | Simon A.,University of Aberdeen | Doobar S.,Biochemistry and Molecular Biophysics | Steel K.P.,Wellcome Trust Sanger Institute | And 6 more authors.
Journal of Neuroscience | Year: 2015

Mechanoreception is an essential feature of many sensory modalities. Nevertheless, the mechanisms that govern the conversion of a mechanical force to distinct patterns of action potentials remain poorly understood. Proprioceptive mechanoreceptors reside in skeletal muscle and inform the nervous system of the position of body and limbs in space. We show here that Whirlin/Deafness autosomal recessive 31 (DFNB31), a PDZ-scaffold protein involved in vestibular and auditory hair cell transduction, is also expressed by proprioceptive sensory neurons (pSNs) in dorsal root ganglia in mice. Whirlin localizes to the peripheral sensory endings of pSNs and facilitates pSN afferent firing in response to muscle stretch. The requirement of Whirlin in both proprioceptors and hair cells suggests that accessory mechanosensory signaling molecules define common features of mechanoreceptive processing across sensory systems. © 2015 de Nooij et al.


Baranes A.F.,Columbia University | Oudeyer P.-Y.,French Institute for Research in Computer Science and Automation | Oudeyer P.-Y.,ENSTA ParisTech | Gottlieb J.,Columbia University | Gottlieb J.,Kavli Institute for Brain Science
Frontiers in Neuroscience | Year: 2014

Devising efficient strategies for exploration in large open-ended spaces is one of the most difficult computational problems of intelligent organisms. Because the available rewards are ambiguous or unknown during the exploratory phase, subjects must act in intrinsically motivated fashion. However, a vast majority of behavioral and neural studies to date have focused on decision making in reward-based tasks, and the rules guiding intrinsically motivated exploration remain largely unknown. To examine this question we developed a paradigm for systematically testing the choices of human observers in a free play context. Adult subjects played a series of short computer games of variable difficulty, and freely choose which game they wished to sample without external guidance or physical rewards. Subjects performed the task in three distinct conditions where they sampled from a small or a large choice set (7 vs 64 possible levels of difficulty), and where they did or did not have the possibility to sample new games at a constant level of difficulty. We show that despite the absence of external constraints, the subjects spontaneously adopted a structured exploration strategy whereby they (1) started with easier games and progressed to more difficult games, (2) sampled the entire choice set including extremely difficult games that could not be learnt, (3) repeated moderately and high difficulty games much more frequently than was predicted by chance, and (4) had higher repetition rates and chose higher speeds if they could generate new sequences at a constant level of difficulty. The results suggest that intrinsically motivated exploration is shaped by several factors including task difficulty, novelty and the size of the choice set, and these come into play to serve two internal goals - maximize the subjects' knowledge of the available tasks (exploring the limits of the task set), and maximize their competence (performance and skills) across the task set. © 2014 Baranes, Oudeyer and Gottlieb.


Jin I.,Columbia University | Udo H.,Kyushu University | Rayman J.B.,Columbia University | Puthanveettil S.,Columbia University | And 6 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2012

Whereas short-term (minutes) facilitation at Aplysia sensory-motor neuron synapses is presynaptic, long-term (days) facilitation involves synaptic growth, which requires both presynaptic and postsynaptic mechanisms. How are the postsynaptic mechanisms recruited, and when does that process begin? We have been investigating the possible role of spontaneous transmitter release from the presynaptic neuron. In the previous paper, we found that spontaneous release is critical for the induction of long-term facilitation, and this process begins during an intermediate-term stage of facilitation that is the first stage to involve postsynaptic as well as presynaptic mechanisms. We now report that increased spontaneous release during the short-term stage acts as an orthograde signal to recruit postsynaptic mechanisms of intermediate-term facilitation including increased IP3, Ca2+, and membrane insertion and recruitment of clusters of AMPA-like receptors, which may be first steps in synaptic growth during long-term facilitation. These results suggest that the different stages of facilitation involve a cascade of pre- and postsynaptic mechanisms, which is initiated by spontaneous release and may culminate in synaptic growth.


Avlar B.,Columbia University | Kahn J.B.,Columbia University | Kahn J.B.,University of Pennsylvania | Jensen G.,Columbia University | And 7 more authors.
Behavioral Neuroscience | Year: 2015

Increasing motivation can positively impact cognitive performance. Here we employed a cognitive timing task that allows us to detect changes in cognitive performance that are not influenced by general activity or arousal factors such as the speed or persistence of responding. This approach allowed us to manipulate motivation using three different methods; molecular/genetic, behavioral and pharmacological. Increased striatal D2Rs resulted in deficits in temporal discrimination. Switching off the transgene improved motivation in earlier studies, and here partially rescued the temporal discrimination deficit. To manipulate motivation behaviorally, we altered reward magnitude and found that increasing reward magnitude improved timing in control mice and partially rescued timing in the transgenic mice. Lastly, we manipulated motivation pharmacologically using a functionally selective 5-HT2C receptor ligand, SB242084, which we previously found to increase incentive motivation. SB242084 improved temporal discrimination in both control and transgenic mice. Thus, while there is a general intuitive belief that motivation can affect cognition, we here provide a direct demonstration that enhancing motivation, in a variety of ways, can be an effective strategy for enhancing temporal cognition. Understanding the interaction of motivation and cognition is of clinical significance since many psychiatric disorders are characterized by deficits in both domains. © 2015 American Psychological Association.


Jin I.,Columbia University | Kandel E.R.,Columbia University | Kandel E.R.,New York State Psychiatric Institute | Kandel E.R.,Kavli Institute for Brain Science | And 3 more authors.
Learning and Memory | Year: 2011

Whereas short-term plasticity involves covalent modifications that are generally restricted to either presynaptic or postsynaptic structures, long-term plasticity involves the growth of new synapses, which by its nature involves both pre- and postsynaptic alterations. In addition, an intermediate-term stage of plasticity has been identified that might form a bridge between short- and long-term plasticity. Consistent with that idea, although short-term term behavioral sensitization in Aplysia involves presynaptic mechanisms, intermediate-term sensitization involves both pre- and postsynaptic mechanisms. However, it has not been known whether that is also true of facilitation in vitro, where a more detailed analysis of the mechanisms involved in the different stages and their interrelations is feasible. To address those questions, we have examined preand postsynaptic mechanisms of short- and intermediate-term facilitation at Aplysia sensory-motor neuron synapses in isolated cell culture. Whereas short-term facilitation by 1-min 5-HT involves presynaptic PKA and CamKII, intermediate-term facilitation by 10-min 5-HT involves presynaptic PKC and postsynaptic Ca2+ and CamKII, as well as both pre- and postsynaptic protein synthesis. These results support the idea that the intermediate-term stage is the first to involve both pre- and postsynaptic molecular mechanisms, which could in turn serve as some of the initial steps in a cascade leading to synaptic growth during long-term plasticity. © 2011 Cold Spring Harbor Laboratory Press.


Simpson E.H.,Columbia University | Simpson E.H.,New York State Psychiatric Institute | Kellendonk C.,Columbia University | Ward R.D.,Columbia University | And 12 more authors.
Biological Psychiatry | Year: 2011

Background: Deficits in incentive motivation, the energizing of behavior in pursuit of a goal, occur in many psychiatric disorders including schizophrenia. We previously reported deficits in both cognition and incentive motivation in a transgenic mouse model of increased striatal-specific dopamine D2 receptor (D2R) density (D2R-OE mice). This molecular alteration is observed in patients with schizophrenia, making D2R-OE mice a suitable system to study the cellular and molecular mechanisms of motivation and avolition, as well as a tool for testing potential therapies against motivational deficits. Methods: Behavioral studies using operant conditioning methods were performed both to further characterize the incentive motivation deficit in D2R-OE mice and test a novel pharmacological treatment target that arose from an unbiased expression study performed using gene chips and was validated by quantitative reverse transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry. Results: The reluctance of D2R-OE mice to work is due neither to intolerance for low rates of reward, decreased reactivity to reward, nor increased sensitivity to satiety or fatigue but to a difference in willingness to work for reward. As in patients with schizophrenia, this deficit was not ameliorated by D2R blockade, suggesting that reversal of the motivational deficit by switching off the transgene results from molecular changes downstream of D2R overexpression. We observed a reversible increase in serotonin subtype 2C (5-HT2C) receptor expression in D2R-OE mice. Systemic injection of a 5-HT2C receptor antagonist increased incentive motivation in D2R-OE and control mice. Conclusions: We propose that targeting 5-HT2C receptors may be a useful approach to modulate incentive motivation in psychiatric illness. © 2011 Society of Biological Psychiatry.


Alberini C.M.,New York University | Kandel E.R.,Zuckerman Mind Brain Behavior Institute | Kandel E.R.,New York State Psychiatric Institute | Kandel E.R.,Kavli Institute for Brain Science | And 2 more authors.
Cold Spring Harbor Perspectives in Biology | Year: 2015

De novo transcription of DNA is a fundamental requirement for the formation of long-term memory. It is required during both consolidation and reconsolidation, the posttraining and postreactivation phases that change the state of the memory from a fragile into a stable and long-lasting form. Transcription generates both mRNAs that are translated into proteins, which are necessary for the growth of new synaptic connections, as well as noncoding RNA transcripts that have regulatory or effector roles in gene expression. The result is a cascade of events that ultimately leads to structural changes in the neurons that mediate long-term memory storage. The de novo transcription, critical for synaptic plasticity and memory formation, is orchestrated by chromatin and epigenetic modifications. The complexity of transcription regulation, its temporal progression, and the effectors produced all contribute to the flexibility and persistence of long-term memory formation. In this article, we provide an overview of the mechanisms contributing to this transcriptional regulation underlying long-term memory formation. © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.


Fioriti L.,Columbia University | Myers C.,Columbia University | Huang Y.-Y.,Columbia University | Li X.,Columbia University | And 12 more authors.
Neuron | Year: 2015

Consolidation of long-term memories depends on de novo protein synthesis. Several translational regulators have been identified, and their contribution to the formation of memory has been assessed in the mouse hippocampus. None of them, however, has been implicated in the persistence of memory. Although persistence is a key feature of long-term memory, how this occurs, despite the rapid turnover of its molecular substrates, is poorly understood. Here we find that both memory storage and its underlying synaptic plasticity are mediated by the increase in level and in the aggregation of the prion-like translational regulator CPEB3 (cytoplasmic polyadenylation element-binding protein). Genetic ablation of CPEB3 impairs the maintenance of both hippocampal long-term potentiation and hippocampus-dependent spatial memory. We propose a model whereby persistence of long-term memory results from the assembly of CPEB3 into aggregates. These aggregates serve as functional prions and regulate local protein synthesis necessary for the maintenance of long-term memory. Fioriti et al. found that the translational regulator CPEB3 is a prion-like molecule that aggregates to form an amyloid-like structure in the brain of mice. CPEB3 aggregates mediate the maintenance of hippocampal-based long-term memories. © 2015 Elsevier Inc.


News Article | November 20, 2015
Site: www.biosciencetechnology.com

Most people probably think that we perceive the five basic tastes—sweet, sour, salty, bitter and umami (savory)—with our tongue, which then sends signals to our brain “telling” us what we’ve tasted. However, scientists have turned this idea on its head, demonstrating in mice the ability to change the way something tastes by manipulating groups of cells in the brain. The findings were published in the online edition of Nature. “Taste, the way you and I think of it, is ultimately in the brain,” said study leader Charles S. Zuker, Ph.D., professor of biochemistry and molecular biophysics and of neuroscience, a member of the Kavli Institute for Brain Science and the Mortimer B. Zuckerman Mind Brain Behavior Institute, and a Howard Hughes Medical Institute Investigator at Columbia University Medical Center (CUMC). “Dedicated taste receptors in the tongue detect sweet or bitter and so on, but it’s the brain that affords meaning to these chemicals.” The primary aim of Dr. Zuker’s lab is to understand how the brain transforms detection of chemical stimuli into perception. Over the past decade or so, Dr. Zuker and his colleagues proved that there are dedicated receptors for each taste on the tongue, and that each class of receptor sends a specific signal to the brain. More recently, they demonstrated that each taste is sensed by unique sets of brain cells, located in separate locations in the brain’s cortex – generating a map of taste qualities in the brain. The scientists used optogenetics, which allowed them to directly activate specific neurons with laser light. Yueqing Peng, a postdoctoral associate in Dr. Zuker’s lab, examined whether manipulating the neurons in these brain regions could evoke the perception of sweet or bitter, without the mouse actually tasting either. (Sweet and bitter tastes were chosen because they are most critical and recognizable tastes for humans and other animals. Sweet taste permits the identification of energy-rich nutrients, while bitter warns against the intake of potentially noxious chemicals.) “In this study, we wanted to know if specific regions in the brain really represent sweet and bitter. If they do, silencing these regions would prevent the animal from tasting sweet or bitter, no matter how much we gave them,” he said. “And if we activate these fields, they should taste bitter or sweet, even though they’re only getting plain water.” This is exactly what the researchers observed. When scientists injected a substance into the mice to silence the sweet neurons, the animals could not reliably identify sweet. They could, however, still detect bitter. The animals regained their ability to taste sweet when the drug was flushed from the brain. Conversely, silencing the bitter neurons prevented the mice from recognizing bitter, but they could still taste sweet. Remarkably, the researchers were also able to make the animals think they were tasting bitter or sweet even when the animal was only drinking water. When the researchers activated the sweet neurons during drinking, they observed behavioral responses in the mice associated with sweet, such as impressively increased licking. In contrast, stimulating bitter neurons dramatically suppressed licking, and elicited classic taste-rejection responses, including the activation of gagging behavior.  These results showed that by manipulating the brain centers representing sweet and bitter taste they could directly control an animal’s sensory perception and behavioral actions, said Peng. The researchers also performed optogenetic tests on animals that had never tasted sweet or bitter chemicals, and showed that activation of the corresponding neurons triggered the appropriate behavioral response. “These experiments formally prove that the sense of taste is completely hardwired, independent of learning or experience,” said Dr. Zuker, “which is different from the olfactory system. Odors don’t carry innate meaning until you associate them with experiences. One smell could be great for you and horrible to me.” (As humans, of course, we can eventually learn to enjoy bitters and dislike sugar.) In a final set of experiments, animals were trained to report the identity of an orally applied sweet and bitter stimulus by performing a novel behavioral task, allowing the researchers to test what the animal is tasting.  In the experiments, the mice tasted real bitter, sweet, and salty chemicals at times, but at other times the researchers used the laser to activate the animals’ sweet or bitter cortical fields. The behavior of the mice did not differ between the real and virtual tastes, demonstrating that the light is mimicking the perception of bitter and sweet. “In other words, taste is all in the brain,” said Zuker.

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