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• W2324343487 abstract "It is now well accepted that new neurons continue to be generated in the adult hippocampus. By visualizing and manipulating new neurons in behaving mice, Danielson et al., 2016Danielson N.B. Kaifosh P. Zaremba J.D. Lovett-Barron M. Tsai J. Denny C.A. Balough E.M. Goldberg A.R. Drew L.J. Hen R. et al.Neuron. 2016; (Published online March 8, 2016)https://doi.org/10.1016/j.neuron.2016.02.019Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar begin to define how new neurons contribute to hippocampal function. It is now well accepted that new neurons continue to be generated in the adult hippocampus. By visualizing and manipulating new neurons in behaving mice, Danielson et al., 2016Danielson N.B. Kaifosh P. Zaremba J.D. Lovett-Barron M. Tsai J. Denny C.A. Balough E.M. Goldberg A.R. Drew L.J. Hen R. et al.Neuron. 2016; (Published online March 8, 2016)https://doi.org/10.1016/j.neuron.2016.02.019Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar begin to define how new neurons contribute to hippocampal function. In the 1960s a young neurobiologist from MIT discovered a subpopulation of proliferative cells in the dentate gyrus (DG) that appeared to generate new neurons well into adulthood (Altman, 1963Altman J. Anat. Rec. 1963; 145: 573-591Crossref PubMed Scopus (384) Google Scholar). Although Joseph Altman’s claims were initially met with skepticism (Altman, 2011Altman J. The discovery of adult mammalian neurogenesis.in: Neurogenesis in the Adult Brain I. Springer, 2011: 3-46Crossref Google Scholar), the introduction of more definitive methods for labeling and phenotyping newborn neurons in the 1990s led to broad acceptance of this phenomenon. With acceptance, attention swiftly shifted away from whether hippocampal neurogenesis persists in the adult brain to how the continued addition of new neurons contributes to hippocampal function. Given the role of the hippocampus in memory, initial studies focused largely on how adult-born granule cells (abGCs) impact hippocampal memory function: finding, for example, that global suppression of neurogenesis impairs encoding of some hippocampus-dependent memories (Shors et al., 2001Shors T.J. Miesegaes G. Beylin A. Zhao M. Rydel T. Gould E. Nature. 2001; 410: 372-376Crossref PubMed Scopus (1719) Google Scholar). More recently, however, the focus has narrowed. Motivated by the idea that the DG is important for pattern separation (Leutgeb et al., 2007Leutgeb J.K. Leutgeb S. Moser M.B. Moser E.I. Science. 2007; 315: 961-966Crossref PubMed Scopus (1099) Google Scholar, Treves and Rolls, 1994Treves A. Rolls E.T. Hippocampus. 1994; 4: 374-391Crossref PubMed Scopus (889) Google Scholar)—the process of transforming overlapping input representations into less overlapping or distinct output representations—current studies have asked how hippocampal neurogenesis regulates this process (Sahay et al., 2011bSahay A. Wilson D.A. Hen R. Neuron. 2011; 70: 582-588Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar). These studies report that increasing or decreasing hippocampal neurogenesis, respectively, improves or worsens rodents’ ability to encode fine spatial discriminations—a behavioral analog of pattern separation (Niibori et al., 2012Niibori Y. Yu T.S. Epp J.R. Akers K.G. Josselyn S.A. Frankland P.W. Nat. Commun. 2012; 3: 1253Crossref PubMed Scopus (129) Google Scholar, Sahay et al., 2011aSahay A. Scobie K.N. Hill A.S. O’Carroll C.M. Kheirbek M.A. Burghardt N.S. Fenton A.A. Dranovsky A. Hen R. Nature. 2011; 472: 466-470Crossref PubMed Scopus (1112) Google Scholar). However, these types of studies are not without limitations. First, the interventions chronically alter levels of hippocampal neurogenesis, allowing for the possibility of compensatory circuit-level changes that may muddy the interpretation. Second, while brain slice preparations have identified unique physiological features of abGCs (Marín-Burgin et al., 2012Marín-Burgin A. Mongiat L.A. Pardi M.B. Schinder A.F. Science. 2012; 335: 1238-1242Crossref PubMed Scopus (276) Google Scholar), it is challenging to know how these properties relate to alterations in behavior following global alteration of hippocampal neurogenesis. In the current issue of Neuron, a study by Danielson and colleagues begins to bridge this divide. Combining sophisticated transgenic and imaging strategies, Danielson et al., 2016Danielson N.B. Kaifosh P. Zaremba J.D. Lovett-Barron M. Tsai J. Denny C.A. Balough E.M. Goldberg A.R. Drew L.J. Hen R. et al.Neuron. 2016; (Published online March 8, 2016)https://doi.org/10.1016/j.neuron.2016.02.019Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar simultaneously monitor the activity of abGC and mature granule cell (mGC) populations in the DG as mice explore virtual contexts and test whether abGCs are necessary for context discrimination. Accordingly, the authors directly compare abGC and mGC activity in vivo and, in so doing, begin to reveal how abGCs uniquely contribute to behavioral pattern separation. Danielson et al., 2016Danielson N.B. Kaifosh P. Zaremba J.D. Lovett-Barron M. Tsai J. Denny C.A. Balough E.M. Goldberg A.R. Drew L.J. Hen R. et al.Neuron. 2016; (Published online March 8, 2016)https://doi.org/10.1016/j.neuron.2016.02.019Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar used two-photon calcium imaging in awake, behaving mice to record the activity of DG granule cells expressing the genetically encoded calcium indicator, GCaMP6f. By using transgenic mice in which abGCs were indelibly labeled with a red fluorophore (tdTomato), they directly compared calcium signals emitted from abGCs and mGCs. As these head-fixed mice traversed virtual linear environments (composed of different visual, auditory, and olfactory stimuli), the authors observed that abGCs were more active than their more mature counterparts: Calcium transients (a proxy for neuronal firing) were detected at higher rates in abGCs, and proportionately fewer abGCs were silent. Previous in vitro studies established that abGCs are more excitable than their mature neighbors (Marín-Burgin et al., 2012Marín-Burgin A. Mongiat L.A. Pardi M.B. Schinder A.F. Science. 2012; 335: 1238-1242Crossref PubMed Scopus (276) Google Scholar). The current study shows that the same holds true in vivo. Moreover, it suggests that abGCs—by virtue of their heightened excitability—more readily respond to stimuli during encoding. How might this promiscuous activity influence how abGCs encode and represent information? The major subdivisions of the hippocampus (including CA1, CA3, and DG) contain spatially modulated neurons, or place cells, that preferentially fire in one or more spatial locations in a given environment. Although it is clear that spatial information is carried by DG population activity, it is unclear whether immature and mGCs differentially contribute to this signal. To answer this question, Danielson et al., 2016Danielson N.B. Kaifosh P. Zaremba J.D. Lovett-Barron M. Tsai J. Denny C.A. Balough E.M. Goldberg A.R. Drew L.J. Hen R. et al.Neuron. 2016; (Published online March 8, 2016)https://doi.org/10.1016/j.neuron.2016.02.019Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar first examined to what extent GC activity was modulated by location in the virtual environments. While the activity of both abGCs and mGCs was spatially modulated, this modulation tended to be less precise in abGCs. New neurons were less spatially tuned. Might poorer spatial tuning reduce the ability of abGCs to discriminate similar environments? Danielson and colleagues next monitored GC activity as they altered the virtual environments. While mGCs “remapped” when environments were altered, this remapping appeared to be less efficient for abGCs (although this depended to some extent on how spatial tuning was assessed). Interestingly, though, the authors noted a subpopulation of abGCs that were as discerning as their mature counterparts, showing no difficulty discriminating efficiently between contexts. A more detailed analysis of this subpopulation is necessary to determine what particular properties support their superior discrimination ability. Nevertheless, these findings emphasize the utility of the imaging techniques employed by Danielson et al., 2016Danielson N.B. Kaifosh P. Zaremba J.D. Lovett-Barron M. Tsai J. Denny C.A. Balough E.M. Goldberg A.R. Drew L.J. Hen R. et al.Neuron. 2016; (Published online March 8, 2016)https://doi.org/10.1016/j.neuron.2016.02.019Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar in monitoring subpopulation-specific activity in the DG. The current findings that mGCs more efficiently discriminate contexts than abGCs extends previous research by allowing researchers to classify neuronal activity by cell age (Leutgeb et al., 2007Leutgeb J.K. Leutgeb S. Moser M.B. Moser E.I. Science. 2007; 315: 961-966Crossref PubMed Scopus (1099) Google Scholar). Although the present study finds that abGCs are relatively poor discriminators, paradoxically, elimination of this population of cells results in impaired behavioral pattern separation (Niibori et al., 2012Niibori Y. Yu T.S. Epp J.R. Akers K.G. Josselyn S.A. Frankland P.W. Nat. Commun. 2012; 3: 1253Crossref PubMed Scopus (129) Google Scholar, Sahay et al., 2011aSahay A. Scobie K.N. Hill A.S. O’Carroll C.M. Kheirbek M.A. Burghardt N.S. Fenton A.A. Dranovsky A. Hen R. Nature. 2011; 472: 466-470Crossref PubMed Scopus (1112) Google Scholar). In these studies, neurogenesis levels were typically manipulated prior to training, making it impossible to dissect the role of abGCs in distinct memory processes (e.g., encoding, consolidation, retrieval). Using a transgenic strategy to “tag” abGCs with the inhibitory opsin Arch, Danielson et al., 2016Danielson N.B. Kaifosh P. Zaremba J.D. Lovett-Barron M. Tsai J. Denny C.A. Balough E.M. Goldberg A.R. Drew L.J. Hen R. et al.Neuron. 2016; (Published online March 8, 2016)https://doi.org/10.1016/j.neuron.2016.02.019Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar gained temporal control over when abGCs could be inhibited during different stages of a contextual fear discrimination task. In this kind of task, mice are repeatedly exposed to a fearful (shock-paired) context and similar neutral context over the course of several days and start to show more fearful behavior (e.g., freezing) in the aversive context. Optogenetically silencing abGCs during initial exposures to the neutral, but not the aversive, context impaired this behavioral discrimination. However, silencing abGCs after context discrimination was already acquired, or during exposure to a neutral but dissimilar context, did not impair pattern separation. These data extend previous studies and suggest that abGC activity is necessary during the initial encoding of conflicting contextual stimuli to support pattern separation. But how might this happen? One possibility is that similar contexts are sparsely encoded by non-overlapping ensembles of abGCs, and this might help to reduce interference during memory retrieval. However, in light of the present study’s finding that abGCs more ambiguously represent context information (Danielson et al., 2016Danielson N.B. Kaifosh P. Zaremba J.D. Lovett-Barron M. Tsai J. Denny C.A. Balough E.M. Goldberg A.R. Drew L.J. Hen R. et al.Neuron. 2016; (Published online March 8, 2016)https://doi.org/10.1016/j.neuron.2016.02.019Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar), this interpretation seems unlikely. Instead, abGCs may act as “pattern integrators.” By virtue of their increased excitability, information from distinct experiences might be co-allocated to ensembles of abGCs that partially overlap in their spatial distributions. This idea is supported by computational modeling that predicts that distinct events may be encoded by largely overlapping ensembles of highly excitable abGCs but non-overlapping ensembles of mGCs (Aimone et al., 2009Aimone J.B. Wiles J. Gage F.H. Neuron. 2009; 61: 187-202Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar) and would explain why in the current study neuronal activity in new neuron population less efficiently disambiguated context experiences. The small percentage of abGCs that could discriminate contexts may represent a cohort of neurons on the cusp of maturity and therefore display the mGC phenotype, but more temporally precise labeling of immature granule cells is needed to test this possibility. Such experiments will determine whether a specific cohort of abGCs in the heterogeneous immature neuron population can support pattern separation. Why would the elimination of a population of “pattern integrators” lead to deficits in context discrimination? One idea is that abGCs help “sparsify” the DG code. Immature granule cells form connections with hilar and CA3 interneurons which exert inhibitory drive on mGC and CA3 pyramidal neuron populations to effectively constrain principal cell activation during encoding (Drew et al., 2015Drew L.J. Kheirbek M.A. Luna V.M. Denny C.A. Cloidt M.A. Wu M.V. Jain S. Scharfman H.E. Hen R. Hippocampus. 2015; https://doi.org/10.1002/hipo.22557Crossref PubMed Scopus (98) Google Scholar, Ikrar et al., 2013Ikrar T. Guo N. He K. Besnard A. Levinson S. Hill A. Lee H.K. Hen R. Xu X. Sahay A. Front. Neural Circuits. 2013; 7: 204Crossref PubMed Scopus (135) Google Scholar, Restivo et al., 2015Restivo L. Niibori Y. Mercaldo V. Josselyn S.A. Frankland P.W. J. Neurosci. 2015; 35: 10600-10612Crossref PubMed Scopus (60) Google Scholar). Consistent with this idea, increased levels of neurogenesis are associated with reduced DG activation both in vitro (Ikrar et al., 2013Ikrar T. Guo N. He K. Besnard A. Levinson S. Hill A. Lee H.K. Hen R. Xu X. Sahay A. Front. Neural Circuits. 2013; 7: 204Crossref PubMed Scopus (135) Google Scholar) and in vivo (Drew et al., 2015Drew L.J. Kheirbek M.A. Luna V.M. Denny C.A. Cloidt M.A. Wu M.V. Jain S. Scharfman H.E. Hen R. Hippocampus. 2015; https://doi.org/10.1002/hipo.22557Crossref PubMed Scopus (98) Google Scholar). Conversely, reduced levels of neurogenesis are associated with elevated DG activation both in vitro (Ikrar et al., 2013Ikrar T. Guo N. He K. Besnard A. Levinson S. Hill A. Lee H.K. Hen R. Xu X. Sahay A. Front. Neural Circuits. 2013; 7: 204Crossref PubMed Scopus (135) Google Scholar) and in vivo (Drew et al., 2015Drew L.J. Kheirbek M.A. Luna V.M. Denny C.A. Cloidt M.A. Wu M.V. Jain S. Scharfman H.E. Hen R. Hippocampus. 2015; https://doi.org/10.1002/hipo.22557Crossref PubMed Scopus (98) Google Scholar). Therefore, pattern separation deficits stemming from optogenetic inhibition of abGCs (Danielson et al., 2016Danielson N.B. Kaifosh P. Zaremba J.D. Lovett-Barron M. Tsai J. Denny C.A. Balough E.M. Goldberg A.R. Drew L.J. Hen R. et al.Neuron. 2016; (Published online March 8, 2016)https://doi.org/10.1016/j.neuron.2016.02.019Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar) could be attributed to unrestrained mGC activity during encoding of similar environments and poor separation of memory traces in CA3 (see also Niibori et al., 2012Niibori Y. Yu T.S. Epp J.R. Akers K.G. Josselyn S.A. Frankland P.W. Nat. Commun. 2012; 3: 1253Crossref PubMed Scopus (129) Google Scholar). What new neurons do in the adult hippocampus has been the subject of much conjecture and debate (Cameron and Glover, 2015Cameron H.A. Glover L.R. Annu. Rev. Psychol. 2015; 66: 53-81Crossref PubMed Scopus (180) Google Scholar). However, just as improved techniques allowed the field to move on from questioning whether neurogenesis persists in the adult hippocampus to acceptance of this phenomenon, improved techniques for imaging new neurons in behaving animals—in essence allowing researchers to watch thought in real time at a cellular level of resolution—will accelerate progress toward defining their function. Distinct Contribution of Adult-Born Hippocampal Granule Cells to Context EncodingDanielson et al.NeuronMarch 10, 2016In BriefDanielson et al. monitored and controlled the activity of adult-born and mature dentate gyrus neurons in vivo. They show that as a population, young adult-born neurons are more active and less sharply spatially tuned than their mature counterparts and that these cells contribute to context encoding. Full-Text PDF Open Archive" @default.
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• W2324343487 title "The Young and the Promiscuous" @default.
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