Kabitzke P.A.,Columbia University |
Kabitzke P.A.,New York State Psychiatric Institute |
Simpson E.H.,Columbia University |
Simpson E.H.,New York State Psychiatric Institute |
And 6 more authors.
Genes, Brain and Behavior | Year: 2015
Impairments in social behavior characterize many neurodevelopmental psychiatric disorders. In fact, the temporal emergence and trajectory of these deficits can define the disorder, specify their treatment and signal their prognosis. The sophistication of mouse models with neurobiological endophenotypes of many aspects of psychiatric diseases has increased in recent years, with the necessity to evaluate social behavior in these models. We adapted an assay for the multimodal characterization of social behavior at different development time points (juvenile, adolescent and adult) in control mice in different social contexts (specifically, different sex pairings). Although social context did not affect social behavior in juvenile mice, it did have an effect on the quantity and type of social interaction as well as ultrasonic vocalizations in both adolescence and adulthood. We compared social development in control mice to a transgenic mouse model of the increase in postsynaptic striatal D2R activity observed in patients with schizophrenia (D2R-OE mice). Genotypic differences in social interactions emerged in adolescence and appeared to become more pronounced in adulthood. That vocalizations emitted from dyads with a D2R-OE subject were negatively correlated with active social behavior while vocalizations from control dyads were positively correlated with both active and passive social behavior also suggest social deficits. These data show that striatal dopamine dysfunction plays an important role in the development of social behavior and mouse models such as the one studied here provide an opportunity for screening potential therapeutics at different developmental time points. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.
Bailey C.H.,Columbia University |
Bailey C.H.,New York State Psychiatric Institute |
Bailey C.H.,Kavli Institute for Brain science |
Kandel E.R.,Columbia University |
And 4 more authors.
Cold Spring Harbor Perspectives in Medicine | Year: 2015
Consolidation of implicit memory in the invertebrate Aplysia and explicit memory in the mammalian hippocampus are associated with remodeling and growth of preexisting synapses and the formation of new synapses. Here, we compare and contrast structural components of the synaptic plasticity that underlies these two distinct forms of memory. In both cases, the structural changes involve time-dependent processes. Thus, some modifications are transient and may contribute to early formative stages of long-term memory, whereas others are more stable, longer lasting, and likely to confer persistence to memory storage. In addition, we explore the possibility that trans-synaptic signaling mechanisms governing de novo synapse formation during development can be reused in the adult for the purposes of structural synaptic plasticity and memory storage. Finally,we discuss howthese mechanisms set in motion structural rearrangements that prepare a synapse to strengthen the same memory and, perhaps, to allow it to take part in other memories as a basis for understanding how their anatomical representation results in the enhanced expression and storage of memories in the brain. © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
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.
Si K.,Stowers Institute for Medical Research |
Si K.,University of Kansas Medical Center |
Kandel E.R.,Howard Hughes Medical Institute |
Kandel E.R.,Columbia University |
And 2 more authors.
Cold Spring Harbor Perspectives in Biology | Year: 2016
Prions are a self-templating amyloidogenic state of normal cellular proteins, such as prion protein (PrP). They have been identified as the pathogenic agents, contributing to a number of diseases of the nervous system. However, the discovery that the neuronal RNA-binding protein, cytoplasmic polyadenylation element-binding protein (CPEB), has a prion-like state that is involved in the stabilization of memory raised the possibility that prion-like proteins can serve normal physiological functions in the nervous system. Here, we review recent experimental evidence of prion-like properties of neuronal CPEB in various organisms and propose a model of how the prion-like state may stabilize memory. © 2016 Cold Spring Harbor Laboratory Press; All rights reserved.
News Article | November 20, 2015
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.