Daisuke Nakayama

Long-Delayed Expression of the Immediate Early Gene Arc/Arg3.1 Refines Neuronal Circuits to Perpetuate Fear Memory

Fear memories typically persist for long time periods, and persistent fear memories contribute to post-traumatic stress disorder. However, little is known about the cellular and synaptic mechanisms that perpetuate long-term memories. Here, we find that mouse hippocampal CA1 neurons exhibit biphasic Arc (also known as Arg3.1) elevations after fear experience and that the late Arc expression regulates the perpetuation of fear memoires. An early Arc increase returned to the baseline after 6 h, followed by a second Arc increase after 12 h in the same neuronal subpopulation; these elevations occurred via distinct mechanisms. Antisense-induced blockade of late Arc expression disrupted memory persistence but not formation. Moreover, prolonged fear memories were associated with the delayed, specific elimination of dendritic spines and the reactivation of neuronal ensembles formed during fear experience, both of which required late Arc expression. We propose that late Arc expression refines functional circuits in a delayed fashion to prolong fear memory.

Late Arc/Arg3.1 expression in the basolateral amygdala is essential for persistence of newly-acquired and reactivated contextual fear memories

A feature of fear memory is its persistence, which could be a factor for affective disorders. Memory retrieval destabilizes consolidated memories, and then rapid molecular cascades contribute to early stabilization of reactivated memories. However, persistence of reactivated memories has been poorly understood. Here, we discover that late Arc (also known as Arg3.1) expression in the mouse basolateral amygdala (BLA) is involved in persistence of newly-acquired and reactivated fear memories. After both fear learning and retrieval, Arc levels increased at 2 h, returned to basal levels at 6 h but increased again at 12 h. Inhibiting late Arc expression impaired memory retention 7 d, but not 2 d, after fear learning and retrieval. Moreover, blockade of NR2B-containing N-methyl-D-aspartate receptors (NMDARs) prevented memory destabilization and inhibited late Arc expression. These findings indicate that NR2B-NMDAR and late Arc expression plays a critical role in the destabilization and persistence of reactivated memories.

Post-retrieval late process contributes to persistence of reactivated fear memory

Several studies have demonstrated the mechanisms involved in memory persistence after learning. However, little is known about memory persistence after retrieval. In this study, a protein synthesis inhibitor, anisomycin, was infused into the basolateral amygdala of mice 9.5 h after retrieval of contextual conditioned fear. Anisomycin attenuated fear memory after 7 d, but not after 2 d. In contrast, infusion of anisomycin 5- or 24-h post-retrieval was ineffective. These findings indicate that anisomycin attenuates the persistence of reactivated fear memory in a time-dependent manner. We propose that late protein synthesis is required for memory persistence after retrieval.

Frontal association cortex is engaged in stimulus integration during associative learning.

The frontal association cortex (FrA) is implicated in higher brain function. Aberrant FrA activity is likely to be involved in dementia pathology. However, the functional circuits both within the FrA and with other regions are unclear. A recent study showed that inactivation of the FrA impairs memory consolidation of an auditory fear conditioning in young mice. In addition, dendritic spine remodeling of FrA neurons is sensitive to paired sensory stimuli that produce associative memory. These findings suggest that the FrA is engaged in neural processes critical to associative learning. Here we characterize stimulus integration in the mouse FrA during associative learning. We experimentally separated contextual fear conditioning into context exposure and shock, and found that memory formation requires protein synthesis associated with both context exposure and shock in the FrA. Both context exposure and shock trigger Arc, an activity-dependent immediate-early gene, expression in the FrA, and a subset of FrA neurons was dually activated by both stimuli. In addition, we found that the FrA receives projections from the perirhinal (PRh) and insular (IC) cortices and basolateral amygdala (BLA), which are implicated in context and shock encoding. PRh and IC neurons projecting to the FrA were activated by context exposure and shock, respectively. Arc expression in the FrA associated with context exposure and shock depended on PRh activity and both IC and BLA activities, respectively. These findings indicate that the FrA is engaged in stimulus integration and contributes to memory formation in associative learning.

Blockade of stimulus convergence in amygdala neurons disrupts taste associative learning.

Humans and non-human animals learn associations of temporally contingent stimuli to better cope with the changing environment. In animal models of classical conditioning, a neutral conditioned stimulus (CS) predicts an aversive unconditioned stimulus (US). Several lines of indirect evidence indicate that this learning may rely on stimulus convergence in a subset of neurons, but this hypothesis has not been directly tested. In the current study, we tested this hypothesis using a pharmacogenetic approach, the cAMP response element-binding protein (CREB)/Allatostatin Receptor system, to target a subset of amygdala neurons receiving convergent stimuli in mice during conditioned taste aversion. Virally infected basolateral amygdala neurons with higher CREB levels were predominantly active during CS presentation. Blocking stimulus convergence in infected neurons by silencing them during US disrupted taste associative memory. Moreover, silencing infected neurons only during CS also disrupted associative memory formation. These results provide support for the notion that convergent inputs of CS and US in a subpopulation of neurons are critical for associative memory formation.

Ion Transport in Mesoporous Silica Thin Films

Mesoporous silica SBA-16 thin films were synthesized on a Si substrate via the dip-coating method. SEM analysis revealed that these films possess highly ordered 3D cubic structure. After these films were filled with either pure water or KCl aqueous solutions, the ionic current passing through the mesopores was measured by applying electric field to find out ion transport phenomena. If the ion transport phenomena in mesoporous silica are completely elucidated, this will enhance its use in applications where it is intended to be employed as a catalyst, filter, and adsorbent. The measured I-V curves were non-linear. This document discusses the relationship between the non-linear I-V curves and the ionic flow inside the 3D cubic pore structure. The effect of the dimensions and surface properties of mesopores on the I-V curves are also discussed.© 2011 ASME