Sparse, environmentally selective expression ofArc RNA in the upper blade of the rodent fascia dentata by brief spatial experience

Chawla, Monica K.; Guzowski, John F.; Ramírez‐Amaya, Víctor; Lipa, P.; Hoffman, Kari L.; Marriott, Lisa K.; Worley, Paul F.; McNaughton, Bruce L.; Barnes, Carol A.

doi:10.1002/hipo.20091

Cited by 350 publications

(394 citation statements)

References 37 publications

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“…In that respect, it is interesting that earlier studies have shown distinct strain-specific patterns of MF lamination in mice, which were associated with an altered distribution of MFTs (42) and correlated with performance in cognitive tasks, including some spatial WM tasks (17,18). There is also evidence of differential activation of the SPBs and IPBs of the DG (43), and altered segregation of the SP and IP blades may change the respective connectivities of these blades with CA3. Although the pattern of MF lamination has not been explicitly probed in patients with SCHZ, one study has reported lower numerical density of MFTs in CA3 (44), and another study showed lighter overall staining with an MF specific marker (45) consistent with changes occurring in this pathway.…”

Section: Discussionmentioning

confidence: 90%

Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice

Kvajo

McKellar

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

106

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Carefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the endogenous Disc1 ortholog designed to model the effects of a schizophreniapredisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippocampal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that cAMP levels are elevated as a result of the Disc1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growthpromoting and premature maturation effects inferred from previous RNAi-based Disc1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations. psychiatric disease | rare mutation | mouse model T he schizophrenia (SCHZ) susceptibility gene DISC1 was identified through a balanced chromosomal translocation (1;11)(q42.1;q14.3) segregating with SCHZ and mood disorders in a large Scottish pedigree. This is the only confirmed disease risk allele within the DISC1 locus. The biology of DISC1 is being interrogated with a variety of approaches, such as acute RNAimediated gene knockdown (1-4), overexpression of truncated forms of the human DISC1 (5, 6), and chemical mutagenesis (7). Although they provide information about potential pathways related to DISC1, these approaches are not meant to recapitulate the integrated effects of the pathogenic translocation, and the relevance of these findings to SCHZ pathogenesis remains uncertain.We used a disease-focused knockin approach to introduce a truncating lesion in the endogenous murine Disc1 ortholog designed to model the effects of the (1;11) translocation (Mouse Genome Informatics nomenclature Disc1 Tm1Kara ) (8, 9). Although the divergence in the human and mouse Disc1 gene does not allow an exact replication of the human translocation, this mouse model approximates very closely the Scottish mutation. One advantage of our approach is that it retains endogenous levels as well as spatial and temporal patterns of Disc1 expression, and it preserves short N-terminal isoforms that are presumably unaffected by the Scottish translocation and seem to be expressed at relatively higher levels in the hippocampus (HPC) of patients with SCHZ (10). A comprehensive behavioral analysis has shown that Disc1 Tm1Kara mice display a unique profile of cognitive impairments, including specific and robust deficiencies in working memory (WM) tests (8, 9), which may relate to similar cognitive deficits prominent in psychotic disorders.DISC1 is...

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Section: Discussionmentioning

confidence: 90%

Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice

Kvajo

McKellar

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

106

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“…Multiple theories have hypothesized that the hippocampus serves to reduce interference via a process referred to as pattern separation (Marr 1971;Shapiro and Olton 1994;McClelland et al 1995;Rolls 1996). Given its sparse pattern of activity (Barnes et al 1990;Chawla et al 2005), particular attention has been paid to the DG as a potential mediator of pattern separation (Gilbert et al 2001;Lee et al 2004;Leutgeb et al 2007;Clelland et al 2009). A failure in pattern separation may provide an alternative explanation for the deficits we observe in our ADX rats.…”

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confidence: 79%

Object/context-specific memory deficits associated with loss of hippocampal granule cells after adrenalectomy in rats

Spanswick¹,

Sutherland²

2010

Learn. Mem.

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Chronic adrenalectomy (ADX) causes a gradual and selective loss of granule cells in the dentate gyrus (DG) of the rat. Here, we administered replacement corticosterone to rats beginning 10 wk after ADX. We then tested them in three discrimination tasks based on object novelty, location, or object/context association. Only during testing of the object/context association did ADX rats demonstrate deficits. These findings add to a body of evidence that the hippocampus is necessary when contextual information is important. We also confirm that memory deficits after chronic adrenalectomy are not a result of loss of corticosterone per se.Research with rats (Sutherland and McDonald 1990;Kim and Faneslow 1992;Anagnostaras et al. 2001;Lehmann et al. 2009), nonhuman primates (Machado and Bachevalier 2006;Pascalis et al. 2009), and humans (Alvarez et al. 2008;Marschner et al. 2008) shows that hippocampal damage can disrupt the ability to recall or express information about context. Furthermore, several reports suggest that the hippocampus is important for creating flexible representations of context and object associations. Studies in rats (Mumby et al. 2002;O'Brien et al. 2006) and humans (Pascalis et al. 2009) show that lesions specific to the hippocampus produce deficits in object recognition only when contextual information is altered.Within the hippocampus, the dentate gyrus (DG) is important for certain aspects of memory (Xavier et al. 1999;Garthe et al. 2009). Chronic adrenalectomy (ADX) causes a gradual and selective loss of granule cells in the DG of the rat (Sloviter et al. 1989). This loss of cells is attributed to a lack of circulating corticosterone (CORT) (Sloviter et al. 1989;Woolley et al. 1991). Behavioral deficits as a result of chronic ADX have been reported in the Morris water task (Armstrong et al. 1993;Roozendaal et al. 1998;Spanswick et al. 2007) and open-field task (Islam et al. 1995). There has been debate as to whether the deficits experienced by ADX rats are a result of lost CORT or due to the depletion of the granule cell layer itself. Conrad and Roy (1995) and McCormick et al. (1997) report that acute CORT replacement is sufficient to alleviate some of the deficits in spatial tasks associated with chronic ADX. These findings have led some to conclude that the removal of CORT is responsible for the behavioral deficits experienced by ADX rats and not the loss of granule cells per se. In direct contrast to these findings, Spanswick et al. (2007) report that administration of CORT after 6 wk of ADX does not alleviate spatial deficits in a moving-platform version of the Morris water task. Also in opposition to Conrad and Roy (1995) and McCormick et al. (1997), studies utilizing colchicine as a method to remove granule cells report spatial deficits as a result of cell loss (Sutherland et al. 1983;Xavier et al. 1999;Jeltsch et al. 2001).Here, we show using three versions of a novelty-preference task (novel object, novel place, and object/context mismatch) that lesions limited to the granule cell layer...

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“…Evidence from electrophysiological and immediate-early gene imaging experiments suggests that only a small portion of neurons within a region encodes any one memory (Guzowski et al, 1999;Vazdarjanova et al, 2006;Reijmers et al, 2007). This seems particularly true in the dentate gyrus (DG) layer of the hippocampus, which exhibits strikingly sparse activity patterns during experiences (Chawla et al, 2005;Leutgeb et al, 2007). The DG is important in hippocampal dependent learning, including contextual fear memory (Hernańdez-Rabaza et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Neuronal Allocation to a Hippocampal Engram

Park

Kramer

Mercaldo

et al. 2016

Neuropsychopharmacol

155

113

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The dentate gyrus (DG) is important for encoding contextual memories, but little is known about how a population of DG neurons comes to encode and support a particular memory. One possibility is that recruitment into an engram depends on a neuron's excitability. Here, we manipulated excitability by overexpressing CREB in a random population of DG neurons and examined whether this biased their recruitment to an engram supporting a contextual fear memory. To directly assess whether neurons overexpressing CREB at the time of training became critical components of the engram, we examined memory expression while the activity of these neurons was silenced. Chemogenetically (hM4Di, an inhibitory DREADD receptor) or optogenetically (iC++, a light-activated chloride channel) silencing the small number of CREB-overexpressing DG neurons attenuated memory expression, whereas silencing a similar number of random neurons not overexpressing CREB at the time of training did not. As post-encoding reactivation of the activity patterns present during initial experience is thought to be important in memory consolidation, we investigated whether post-training silencing of neurons allocated to an engram disrupted subsequent memory expression. We found that silencing neurons 5 min (but not 24 h) following training disrupted memory expression. Together these results indicate that the rules of neuronal allocation to an engram originally described in the lateral amygdala are followed in different brain regions including DG, and moreover, that disrupting the post-training activity pattern of these neurons prevents memory consolidation.

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Sparse, environmentally selective expression ofArc RNA in the upper blade of the rodent fascia dentata by brief spatial experience

Cited by 350 publications

References 37 publications

Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice

Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice

Object/context-specific memory deficits associated with loss of hippocampal granule cells after adrenalectomy in rats

Neuronal Allocation to a Hippocampal Engram

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