@article {1684, title = {Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.}, journal = {Proc Natl Acad Sci U S A}, volume = {114}, year = {2017}, month = {2017 01 24}, pages = {E610-E618}, abstract = {

The signaling mechanisms that choreograph the assembly of the highly asymmetric pre- and postsynaptic structures are still poorly defined. Using synaptosome fractionation, immunostaining, and coimmunoprecipitation, we found that Celsr3 and Vangl2, core components of the planar cell polarity (PCP) pathway, are localized at developing glutamatergic synapses and interact with key synaptic proteins. Pyramidal neurons from the hippocampus of Celsr3 knockout mice exhibit loss of \~{}50\% of glutamatergic synapses, but not inhibitory synapses, in culture. Wnts are known regulators of synapse formation, and our data reveal that Wnt5a inhibits glutamatergic synapses formed via Celsr3. To avoid affecting earlier developmental processes, such as axon guidance, we conditionally knocked out Celsr3 in the hippocampus 1 week after birth. The CA1 neurons that lost Celsr3 also showed a loss of \~{}50\% of glutamatergic synapses in vivo without affecting the inhibitory synapses assessed by miniature excitatory postsynaptic current (mEPSC) and electron microscopy. These animals displayed deficits in hippocampus-dependent behaviors in adulthood, including spatial learning and memory and fear conditioning. In contrast to Celsr3 conditional knockouts, we found that the conditional knockout of Vangl2 in the hippocampus 1 week after birth led to a large increase in synaptic density, as evaluated by mEPSC frequency and spine density. PCP signaling is mediated by multiple core components with antagonizing functions. Our results document the opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.

}, keywords = {Animals, Behavior, Animal, Cadherins, Cell Polarity, Cells, Cultured, Excitatory Postsynaptic Potentials, Glutamic Acid, Hippocampus, Locomotion, Male, Maze Learning, Mice, Knockout, Nerve Tissue Proteins, Pyramidal Cells, Receptors, Cell Surface, Synapses, Wnt-5a Protein}, issn = {1091-6490}, doi = {10.1073/pnas.1612062114}, author = {Thakar, Sonal and Wang, Liqing and Yu, Ting and Ye, Mao and Onishi, Keisuke and Scott, John and Qi, Jiaxuan and Fernandes, Catarina and Han, Xuemei and Yates, John R and Berg, Darwin K and Zou, Yimin} } @article {1688, title = {Subiculum neurons map the current axis of travel.}, journal = {Nat Neurosci}, volume = {20}, year = {2017}, month = {2017 02}, pages = {170-172}, abstract = {

Flexible navigation demands knowledge of boundaries, routes and their relationships. Within a multi-path environment, a subpopulation of subiculum neurons robustly encoded the axis of travel. The firing of axis-tuned neurons peaked bimodally, at head orientations 180{\textdegree} apart. Environmental manipulations showed these neurons to be anchored to environmental boundaries but to lack axis tuning in an open arena. Axis-tuned neurons thus provide a powerful mechanism for mapping relationships between routes and the larger environmental context.

}, keywords = {Action Potentials, Animals, Brain Mapping, Hippocampus, Male, Neurons, Orientation, Rats, Sprague-Dawley, Space Perception}, issn = {1546-1726}, doi = {10.1038/nn.4464}, author = {Olson, Jacob M and Tongprasearth, Kanyanat and Nitz, Douglas A} } @article {126, title = {REST Regulates Non-Cell-Autonomous Neuronal Differentiation and Maturation of Neural Progenitor Cells via Secretogranin II.}, journal = {J Neurosci}, volume = {35}, year = {2015}, month = {2015 Nov 4}, pages = {14872-84}, abstract = {

UNLABELLED: RE-1 silencing transcription factor (REST), a master negative regulator of neuronal differentiation, controls neurogenesis by preventing the differentiation of neural stem cells. Here we focused on the role of REST in the early steps of differentiation and maturation of adult hippocampal progenitors (AHPs). REST knockdown promoted differentiation and affected the maturation of rat AHPs. Surprisingly, REST knockdown cells enhanced the differentiation of neighboring wild-type AHPs, suggesting that REST may play a non-cell-autonomous role. Gene expression analysis identified Secretogranin II (Scg2) as the major secreted REST target responsible for the non-cell-autonomous phenotype. Loss-of-function of Scg2 inhibited differentiation in vitro, and exogenous SCG2 partially rescued this phenotype. Knockdown of REST in neural progenitors in mice led to precocious maturation into neurons at the expense of mushroom spines in vivo. In summary, we found that, in addition to its cell-autonomous function, REST regulates differentiation and maturation of AHPs non-cell-autonomously via SCG2.

SIGNIFICANCE STATEMENT: Our results reveal that REST regulates differentiation and maturation of neural progenitor cells in vitro by orchestrating both cell-intrinsic and non-cell-autonomous factors and that Scg2 is a major secretory target of REST with a differentiation-enhancing activity in a paracrine manner. In vivo, REST depletion causes accelerated differentiation of newborn neurons at the expense of spine defects, suggesting a potential role for REST in the timing of the maturation of granule neurons.

}, keywords = {Animals, Cell Differentiation, Cells, Cultured, Female, Hippocampus, Mice, Mice, Inbred C57BL, Neural Stem Cells, Neurogenesis, Neurons, Rats, Wistar, Repressor Proteins, Secretogranin II}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.4286-14.2015}, author = {Kim, Hyung Joon and Denli, Ahmet M and Wright, Rebecca and Baul, Tithi D and Clemenson, Gregory D and Morcos, Ari S and Zhao, Chunmei and Schafer, Simon T and Gage, Fred H and Kagalwala, Mohamedi N} } @article {213, title = {Sparse and distributed coding of episodic memory in neurons of the human hippocampus.}, journal = {Proc Natl Acad Sci U S A}, volume = {111}, year = {2014}, month = {2014 Jul 1}, pages = {9621-6}, abstract = {

Neurocomputational models hold that sparse distributed coding is the most efficient way for hippocampal neurons to encode episodic memories rapidly. We investigated the representation of episodic memory in hippocampal neurons of nine epilepsy patients undergoing intracranial monitoring as they discriminated between recently studied words (targets) and new words (foils) on a recognition test. On average, single units and multiunits exhibited higher spike counts in response to targets relative to foils, and the size of this effect correlated with behavioral performance. Further analyses of the spike-count distributions revealed that (i) a small percentage of recorded neurons responded to any one target and (ii) a small percentage of targets elicited a strong response in any one neuron. These findings are consistent with the idea that in the human hippocampus episodic memory is supported by a sparse distributed neural code.

}, keywords = {Epilepsy, Hippocampus, Humans, Memory, Episodic, Models, Neurological, Neurophysiological Monitoring, Neuropsychological Tests}, issn = {1091-6490}, doi = {10.1073/pnas.1408365111}, author = {Wixted, John T and Squire, Larry R and Jang, Yoonhee and Papesh, Megan H and Goldinger, Stephen D and Kuhn, Joel R and Smith, Kris A and Treiman, David M and Steinmetz, Peter N} } @article {158, title = {Neuroscience. The brain activity map.}, journal = {Science}, volume = {339}, year = {2013}, month = {2013 Mar 15}, pages = {1284-5}, keywords = {Brain Diseases, Brain Mapping, Hippocampus, Humans, Neural Pathways, Neurons}, issn = {1095-9203}, doi = {10.1126/science.1236939}, author = {Alivisatos, A Paul and Chun, Miyoung and Church, George M and Deisseroth, Karl and Donoghue, John P and Greenspan, Ralph J and McEuen, Paul L and Roukes, Michael L and Sejnowski, Terrence J and Weiss, Paul S and Yuste, Rafael} } @article {207, title = {Hippocampal signals for strong memory when associative memory is available and when it is not.}, journal = {Hippocampus}, volume = {21}, year = {2011}, month = {2011 Jan}, pages = {9-21}, abstract = {

The paired-associate task has been used with functional magnetic resonance imaging (fMRI) in studies that assessed the role of the medial temporal lobe (MTL) subserving recollection and familiarity.Some researchers have interpreted their results to mean that the hippocampus selectively subserves recollection and not familiarity[cf., Eichenbaum et al., (2007) Annu Rev Neurosci 30:123{\textendash}152]. Yet many of these results confound recollection and familiarity with strong and weak memories, and it is not clear whether the conclusions represent differences between memory processes or memory strength. In the current study, participants were scanned with fMRI during retrieval in a paired-associate task, and a new approach separated the analysis of memory strength from the analysis of memory processes. The data were sorted by confidence level in an old/new task, and the high-confidence responses were compared in categories when associative memory was highly accurate and when it was not available. The results show that high-confidence memory produced increased activity in the hippocampus,relative to the level for forgotten pairs, both when associative memory was available and when it was not. Two interpretations are discussed for the behavioral results for when associative memory was not available: one account based on familiarity and the other account based on noncriterial recollection. The conclusion is that recognition of the word-pairs was based on familiarity when associative memory was not available. Together with the fMRI results that activity in two regions associated with cognitive control (left ventrolateral prefrontal cortex and left inferior parietal lobule) was greater when responses were based on associative memory than when based on familiarity, the findings suggest that the hippocampus supports strong memory and that cortical regions make an additional contribution to recollection.

}, keywords = {Brain Mapping, Female, Hippocampus, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Memory}, issn = {1098-1063}, doi = {10.1002/hipo.20716}, author = {Wais, Peter E} } @article {174, title = {Adult neurogenesis: integrating theories and separating functions.}, journal = {Trends Cogn Sci}, volume = {14}, year = {2010}, month = {2010 Jul}, pages = {325-37}, abstract = {

The continuous incorporation of new neurons in the dentate gyrus of the adult hippocampus raises exciting questions about memory and learning, and has inspired new computational models to understand the function of adult neurogenesis. These theoretical approaches suggest distinct roles for new neurons as they slowly integrate into the existing dentate gyrus network: immature adult-born neurons seem to function as pattern integrators of temporally adjacent events, thereby enhancing pattern separation for events separated in time; whereas maturing adult-born neurons possibly contribute to pattern separation by being more amenable to learning new information, leading to dedicated groups of granule cells that respond to experienced environments. We review these hypothesized functions and supporting empirical research and point to new directions for future theoretical efforts.

}, keywords = {Adult, Adult Stem Cells, Animals, Cell Proliferation, Hippocampus, Humans, Models, Biological, Neurogenesis, Neurons}, issn = {1879-307X}, doi = {10.1016/j.tics.2010.04.003}, author = {Aimone, James B and Deng, Wei and Gage, Fred H} } @article {182, title = {New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?}, journal = {Nat Rev Neurosci}, volume = {11}, year = {2010}, month = {2010 May}, pages = {339-50}, abstract = {

The integration of adult-born neurons into the circuitry of the adult hippocampus suggests an important role for adult hippocampal neurogenesis in learning and memory, but its specific function in these processes has remained elusive. In this article, we summarize recent progress in this area, including advances based on behavioural studies and insights provided by computational modelling. Increasingly, evidence suggests that newborn neurons might be involved in hippocampal functions that are particularly dependent on the dentate gyrus, such as pattern separation. Furthermore, newborn neurons at different maturation stages may make distinct contributions to learning and memory. In particular, computational studies suggest that, before newborn neurons are fully mature, they might function as a pattern integrator by introducing a degree of similarity to the encoding of events that occur closely in time.

}, keywords = {Adult Stem Cells, Animals, Hippocampus, Humans, Learning, Memory, Models, Neurological, Neurogenesis, Neurons}, issn = {1471-0048}, doi = {10.1038/nrn2822}, author = {Deng, Wei and Aimone, James B and Gage, Fred H} } @article {177, title = {Sustained dorsal hippocampal activity is not obligatory for either the maintenance or retrieval of long-term spatial memory.}, journal = {Hippocampus}, volume = {20}, year = {2010}, month = {2010 Dec}, pages = {1366-75}, abstract = {

Memories are initially stored in a labile state and are subject to modification by a variety of treatments, including disruption of hippocampal function. We infused a sodium channel blocker (or CNQX) to inactivate the rat dorsal hippocampus reversibly for 1 week following training on a task of spatial memory (the water maze). Previous work with conventional lesions has established that the dorsal hippocampus is essential for both the acquisition and expression of memory in this task. The question in the present study was whether chronic disruption of neuronal activity in the dorsal hippocampus after training would abolish memory or whether memory would survive extended disruption of hippocampal activity. As expected from earlier work, we found that performance was impaired during the infusion period. The critical test occurred 1 week after the lesion was reversed. We found that retention of the water maze recovered to control levels. Accordingly, sustained hippocampal activity following training is not obligatory for either the maintenance of long-term spatial memory or its subsequent retrieval.

}, keywords = {6-Cyano-7-nitroquinoxaline-2,3-dione, Animals, Excitatory Amino Acid Antagonists, Hippocampus, Male, Maze Learning, Memory, Rats, Rats, Long-Evans, Space Perception, Spatial Behavior}, issn = {1098-1063}, doi = {10.1002/hipo.20722}, author = {Broadbent, Nicola J and Squire, Larry R and Clark, Robert E} }