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156. Neuronal Allocation to a Hippocampal Engram

Author

Park, Sungmo, primary, Kramer, Emily E, additional, Mercaldo, Valentina, additional, Rashid, Asim J, additional, Insel, Nathan, additional, Frankland, Paul W, additional, and Josselyn, Sheena A, additional

Published
2016
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159. Structural foundations of optogenetics: Determinants of channelrhodopsin ion selectivity

Author

Berndt, Andre, primary, Lee, Soo Yeun, additional, Wietek, Jonas, additional, Ramakrishnan, Charu, additional, Steinberg, Elizabeth E., additional, Rashid, Asim J., additional, Kim, Hoseok, additional, Park, Sungmo, additional, Santoro, Adam, additional, Frankland, Paul W., additional, Iyer, Shrivats M., additional, Pak, Sally, additional, Ährlund-Richter, Sofie, additional, Delp, Scott L., additional, Malenka, Robert C., additional, Josselyn, Sheena A., additional, Carlén, Marie, additional, Hegemann, Peter, additional, and Deisseroth, Karl, additional

Published
2015
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161. Impaired Recent, but Preserved Remote, Autobiographical Memory in Pediatric Brain Tumor Patients.

Author

Riggs, Lily, Decker, Alexandra, de Medeiros, Cynthia B., Skocic, Jovanka, Szulc-Lerch, Kamila, Bouffet, Eric, Mabbott, Donald J., Sekeres, Melanie J., Josselyn, Sheena A., Frankland, Paul W., Levine, Brian, Grady, Cheryl L., and Bacopulos, Agnes

Subjects
BRAIN tumors, COGNITION disorder risk factors, AUTOBIOGRAPHICAL memory, HIPPOCAMPUS (Brain), MEDULLOBLASTOMA, PEDIATRICS, PSYCHOLOGY, DISEASE risk factors
Abstract

Medulloblastomas, the most common malignant brain tumor in children, are typically treated with radiotherapy. Refinement of this treatment has greatly improved survival rates in this patient population. However, radiotherapy also profoundly affects the developing brain and is associated with reduced hippocampal volume and blunted hippocampal neurogenesis. Such hippocampal (as well as extrahippocampal) abnormalities likely contribute to cognitive impairments in this population. While several aspects of memory have been examined in this population, the impact of radiotherapy on autobiographical memory has not previously been evaluated. Here we evaluated autobiographical memory in male and female patients who received radiotherapy for posterior fossa tumors (PFTs), including medulloblastoma, during childhood. Using the Children's Autobiographical Interview, we retrospectively assessed episodic and nonepisodic details for events that either preceded (i.e., remote) or followed (i.e., recent) treatment. For post-treatment events, PFT patients reported fewer episodic details compared with control subjects. For pretreatment events, PFT patients reported equivalent episodic details compared with control subjects. In a range of conditions associated with reduced hippocampal volume (including medial temporal lobe amnesia, mild cognitive impairment, Alzheimer's disease, temporal lobe epilepsy, transient epileptic amnesia, frontal temporal dementia, traumatic brain injury, encephalitis, and aging), loss of episodic details (even in remote memories) accompanies hippocampal volume loss. It is therefore surprising that pretreatment episodic memories in PFT patients with reduced hippocampal volume are retained. We discuss these findings in light of the anterograde and retrograde impact on memory of experimentally suppressing hippocampal neurogenesis in rodents. [ABSTRACT FROM AUTHOR]

Published
2018
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162. Elevation of Hippocampal Neurogenesis Induces a Temporally Graded Pattern of Forgetting of Contextual Fear Memories.

Author

Aijing Gao, Xia, Frances, Guskjolen, Axel J., Ramsaran, Adam I., Santoro, Adam, Josselyn, Sheena A., and Frankland, Paul W.

Subjects
HIPPOCAMPUS (Brain), NEURONS, DEVELOPMENTAL neurobiology, HIPPOCAMPUS physiology, FEAR
Abstract

Throughout life neurons are continuously generated in the subgranular zone of the hippocampus. The subsequent integration of newly generated neurons alters patterns of dentate gyrus input and output connectivity, potentially rendering memories already stored in those circuits harder to access. Consistent with this prediction, we previously showed that increasing hippocampal neurogenesis after training induces forgetting of hippocampus-dependent memories, including contextual fear memory. However, the brain regions supporting contextual fear memories change with time, and this time-dependent memory reorganization might regulate the sensitivity of contextual fear memories to fluctuations in hippocampal neurogenesis. By virally expressing the inhibitory designer receptor exclusively activated by designer drugs, hM4Di, we first confirmed that chemogenetic inhibition of dorsal hippocampal neurons impairs retrieval of recent (day-old) but not remote (month-old) contextual fear memories in male mice. We then contrasted the effects of increasing hippocampal neurogenesis at recent versus remote time points after contextual fear conditioning in male and female mice. Increasing hippocampal neurogenesis immediately following training reduced conditioned freezing when mice were replaced in the context 1 month later. In contrast, when hippocampal neurogenesis was increased time points remote to training, conditioned freezing levels were unaltered when mice were subsequently tested. These temporally graded forgetting effects were observed using both environmental and genetic interventions to increase hippocampal neurogenesis. Our experiments identify memory age as a boundary condition for neurogenesis-mediated forgetting and suggest that, as contextual fear memories mature, they become less sensitive to changes in hippocampal neurogenesis levels because they no longer depend on the hippocampus for their expression. [ABSTRACT FROM AUTHOR]

Published
2018
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172. Neurons Are Recruited to a Memory Trace Based on Relative Neuronal Excitability Immediately before Training

Author

Yiu, Adelaide P., primary, Mercaldo, Valentina, additional, Yan, Chen, additional, Richards, Blake, additional, Rashid, Asim J., additional, Hsiang, Hwa-Lin Liz, additional, Pressey, Jessica, additional, Mahadevan, Vivek, additional, Tran, Matthew M., additional, Kushner, Steven A., additional, Woodin, Melanie A., additional, Frankland, Paul W., additional, and Josselyn, Sheena A., additional

Published
2014
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174. Whole-brain mapping of behaviourally induced neural activation in mice

Author

Vousden, Dulcie A., primary, Epp, Jonathan, additional, Okuno, Hiroyuki, additional, Nieman, Brian J., additional, van Eede, Matthijs, additional, Dazai, Jun, additional, Ragan, Timothy, additional, Bito, Haruhiko, additional, Frankland, Paul W., additional, Lerch, Jason P., additional, and Henkelman, R. Mark, additional

Published
2014
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176. Deficiency of a Glycogen Synthase-associated Protein, Epm2aip1, Causes Decreased Glycogen Synthesis and Hepatic Insulin Resistance

Author

Turnbull, Julie, primary, Tiberia, Erica, additional, Pereira, Sandra, additional, Zhao, Xiaochu, additional, Pencea, Nela, additional, Wheeler, Anne L., additional, Yu, Wen Qin, additional, Ivovic, Alexander, additional, Naranian, Taline, additional, Israelian, Nyrie, additional, Draginov, Arman, additional, Piliguian, Mark, additional, Frankland, Paul W., additional, Wang, Peixiang, additional, Ackerley, Cameron A., additional, Giacca, Adria, additional, and Minassian, Berge A., additional

Published
2013
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184. Structural foundations of optogenetics: Determinants of channelrhodopsin ion selectivity.

Author

Berndt, Andre, Soo Yeun Lee, Wietek, Jonas, Ramakrishnan, Charu, Steinberg, Elizabeth E., Rashid, Asim J., Hoseok Kim, Sungmo Park, Santoro, Adam, Frankland, Paul W., Iyer, Shrivats M., Pak, Sally, Ährlund-Richter, Sofie, Delp, Scott L., Malenka, Robert C., Josselyn, Sheena A., Carlén, Marie, Hegemann, Peter, and Deisseroth, Karl

Subjects
OPTOGENETICS, CHLORIDE channels, AMINO acids, BINDING sites, CATIONS, PHOTOCURRENTS
Abstract

The structure-guided design of chloride-conducting channelrhodopsins has illuminated mechanisms underlying ion selectivity of this remarkable family of light-activated ion channels. The first generation of chloride-conducting channelrhodopsins, guided in part by development of a structure-informed electrostatic model for pore selectivity, included both the introduction of amino acids with positively charged side chains into the ion conduction pathway and the removal of residues hypothesized to support negatively charged binding sites for cations. Engineered channels indeed became chloride selective, reversing near -65 mV and enabling a new kind of optogenetic inhibition; however, these first-generation chloride-conducting channels displayed small photocurrents and were not tested for optogenetic inhibition of behavior. Here we report the validation and further development of the channelrhodopsin pore model via crystal structure-guided engineering of next-generation light-activated chloride channels (iC++) and a bistable variant (SwiChR++) with net photocurrents increased more than 15-fold under physiological conditions, reversal potential further decreased by another ~15 mV, inhibition of spiking faithfully tracking chloride gradients and intrinsic cell properties, strong expression in vivo, and the initial microbial opsin channel-inhibitor-based control of freely moving behavior. We further show that inhibition by light-gated chloride channels is mediated mainly by shunting effects, which exert optogenetic control much more efficiently than the hyperpolarization induced by light-activated chloride pumps. The design and functional features of these next-generation chloride-conducting channelrhodopsins provide both chronic and acute timescale tools for reversible optogenetic inhibition, confirm fundamental predictions of the ion selectivity model, and further elucidate electrostatic and steric structure- function relationships of the light-gated pore. [ABSTRACT FROM AUTHOR]

Published
2016
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192. Contextual fear conditioning in zebrafish

Author

Kenney, Justin W., Scott, Ian C., Josselyn, Sheena A., and Frankland, Paul W.

Abstract

Zebrafish are a genetically tractable vertebrate that hold considerable promise for elucidating the molecular basis of behavior. Although numerous recent advances have been made in the ability to precisely manipulate the zebrafish genome, much less is known about many aspects of learning and memory in adult fish. Here, we describe the development of a contextual fear conditioning paradigm using an electric shock as the aversive stimulus. We find that contextual fear conditioning is modulated by shock intensity, prevented by an established amnestic agent (MK-801), lasts at least 14 d, and exhibits extinction. Furthermore, fish of various background strains (AB, Tu, and TL) are able to acquire fear conditioning, but differ in fear extinction rates. Taken together, we find that contextual fear conditioning in zebrafish shares many similarities with the widely used contextual fear conditioning paradigm in rodents. Combined with the amenability of genetic manipulation in zebrafish, we anticipate that our paradigm will prove to be a useful complementary system in which to examine the molecular basis of vertebrate learning and memory.

Published
2017
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200. Selective Erasure of a Fear Memory

Author

Han, Jin-Hee, primary, Kushner, Steven A., additional, Yiu, Adelaide P., additional, Hsiang, Hwa-Lin (Liz), additional, Buch, Thorsten, additional, Waisman, Ari, additional, Bontempi, Bruno, additional, Neve, Rachael L., additional, Frankland, Paul W., additional, and Josselyn, Sheena A., additional

Published
2009
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