Following initial encoding, memories undergo a prolonged period of reorganization. While such reorganization may occur in many different memory systems, its purpose is not clear. Previously, we have shown that recall of recent contextual fear memories engages the dorsal hippocampus (dHPC). In contrast, recall of remote contextual fear memories engages a number of different cortical regions, including the anterior cingulate cortex (ACC). To examine whether this reorganization leads to greater memory stability, we examined reconsolidation of 1 d-old (recent) and 36 d-old (remote) contextual fear memory in mice. We infused the protein synthesis inhibitor, anisomycin (ANI), into either the dHPC or ACC immediately following retrieval of either a recent or remote contextual fear memory. In the dHPC, ANI infusions disrupted subsequent expression of recent, but not remote, contextual fear memory. Similar infusions into the ACC had no effect on either recent or remote contextual fear memories, whereas systemically applied ANI blocked subsequent remote memory expression when long re-exposure durations were used. Together, these data suggest that as memories mature they become increasingly stable. Furthermore, the dissociation between the effects of systemically and centrally administered ANI on remote memory suggests that stability is due, in part, to the distributed nature of remote contextual fear memories.Memories are not formed instantaneously. Instead, following initial encoding, memories appear to undergo a prolonged period of reorganization (McClelland et al. 1995;Squire and Alvarez 1995;Dudai 2004;Wiltgen et al. 2004;Frankland and Bontempi 2005). The result of this reorganization is that circuits underlying encoding or initial storage may differ from those required for permanent storage. This type of reorganization has most often been studied in cortico-hippocampal circuits (Squire et al. 2004;Frankland and Bontempi 2005). However, time-dependent reorganization is observed across many different memory systems (Shadmehr and Holcomb 1997;Tronel and Sara 2002;Bahar et al. 2004) and in many different species, including invertebrates (McBride et al. 1999;Menzel 2001;Keller et al. 2005). While these studies indicate that reorganization might be a somewhat ubiquitous process during memory maturation, its exact purpose is still not clear. Because behavioral expression of memory doesn't necessarily change over time, one possibility is that reorganization leads to greater memory stability ( One way to probe memory stability is to apply consolidation blockers (e.g., protein synthesis inhibitors) during or immediately following memory retrieval. Such manipulations interfere with the restabilization (or reconsolidation) of memories, leading to amnesia (Nader 2003). While reconsolidation has now been demonstrated across species and memory paradigms (Nader 2003;Dudai and Eisenberg 2004), post-reactivation protein synthesis blockade does not always lead to amnesia (Vianna et al. 2001;Kraus et al. 2002;Biedenkapp and Rudy 2004;Cam...

Neat1 is a non-protein-coding RNA that serves as an architectural component of the nuclear bodies known as paraspeckles. Although cell-based studies indicate that Neat1 is a crucial regulator of gene expression, its physiological relevance remains unclear. Here, we find that Neat1 knockout (KO) mice stochastically fail to become pregnant despite normal ovulation. Unilateral transplantation of wild-type ovaries or the administration of progesterone partially rescued the phenotype, suggesting that corpus luteum dysfunction and concomitant low progesterone were the primary causes of the decreased fertility. In contrast to the faint expression observed in most of the adult tissues, Neat1 was highly expressed in the corpus luteum, and the formation of luteal tissue was severely impaired in nearly half of the Neat1 KO mice. These observations suggest that Neat1 is essential for the formation of the corpus luteum and for the subsequent establishment of pregnancy under a suboptimal condition that has not yet been identified.

Autophagy is mostly a nonselective bulk degradation system within cells. Recent reports indicate that autophagy can act both as a protector and killer of the cell depending on the stage of the disease or the surrounding cellular environment (for review see Cuervo, A.M. 2004. Trends Cell Biol. 14:70–77). We found that cytoplasmic vacuoles induced in pancreatic acinar cells by experimental pancreatitis were autophagic in origin, as demonstrated by microtubule-associated protein 1 light chain 3 expression and electron microscopy experiments. To analyze the role of macroautophagy in acute pancreatitis, we produced conditional knockout mice lacking the autophagy-related 5 gene in acinar cells. Acute pancreatitis was not observed, except for very mild edema in a restricted area, in conditional knockout mice. Unexpectedly, trypsinogen activation was greatly reduced in the absence of autophagy. These results suggest that autophagy exerts devastating effects in pancreatic acinar cells by activation of trypsinogen to trypsin in the early stage of acute pancreatitis through delivering trypsinogen to the lysosome.

The NR2B subunit of the NMDA receptor interacts with several prominent proteins in the postsynaptic density, including calcium/ calmodulin-dependent protein kinase II (CaMKII). To determine the function of these interactions, we derived transgenic mice expressing a ligand-activated carboxy-terminal NR2B fragment (cNR2B) by fusing this fragment to a tamoxifen (TAM)-dependent mutant of the estrogen receptor ligand-binding domain LBD G521R . Here, we show that induction by TAM allows the transgenic cNR2B fragment to bind to endogenous CaMKII in neurons. Activation of the LBD G521R -cNR2B transgenic protein in mice leads to the disruption of CaMKII/NR2B interactions at synapses. The disruption decreases Thr286 phosphorylation of ␣CaMKII, lowers phosphorylation of a key CaMKII substrate in the postsynaptic membrane (AMPA receptor subunit glutamate receptor 1), and produces deficits in hippocampal long-term potentiation and spatial learning. Together our results demonstrate the importance of interactions between CaMKII and NR2B for CaMKII activity, synaptic plasticity, and learning.