During past decades, the formation and storage principle of memory have received much attention in the neuroscience field. Although some studies have attempted to demonstrate the nature of the engram, elucidating the memory engram allocation mechanism was not possible because of the limitations of existing methods, which cannot specifically modulate the candidate neuronal population. Recently, the development of new techniques, which offer ways to mark and control specific populations of neurons, may accelerate solving this issue. Here, we review the recent advances, which have provided substantial evidence showing that both candidates (neuronal population that is activated by learning, and that has increased CREB level/excitability at learning) satisfy the criteria of the engram, which are necessary and sufficient for memory expression.
Nerve injury-induced protein-1 (Ninjurin-1, Ninj1) was initially identified as a novel adhesion molecule in rat sciatic nerve and to be up-regulated in neurons and Schwann cells of distal nerve segments after nerve transection or crush injury. Recently, Ninj1 was found to act as a modulator of cell migration, angiogenesis, and apoptosis. Accumulating evidence indicates that innate immune response plays beneficial and deleterious roles in brain ischemia, and the trans-endothelial migration of blood-derived immune cells is key initiator of this response. In the present study, we examined the expression profile and cellular distribution of Ninj1 in rat brain after transient focal cerebral ischemia. Ninj1 expression was found to be significantly induced in cortical penumbras 1 day after 60 min of middle cerebral artery occlusion (MCAO) and to increase gradually for 8 days and then declined. In infarction cores of cortices, patterns of Ninj1 expression were similar to those observed in cortical penumbras, except induction was maintained for 10 days. At 1 day post-MCAO, Ninj1 inductions were detected mainly in neutrophils and endothelial cells in both infarction cores and penumbras, but reactive macrophages were the major cellular expressers of Ninj1 at 4 days post-MCAO. Expressional induction in reactive macrophages was maintained in infarction cores after 12 days post-MCAO but not in penumbras. These dynamic expressions of Ninj1 in different immune cells at different times suggest that this protein performs various, critical roles in the modulation of acute and delayed immune responses in the postischemic brain.
Regulation of cell volume is an important aspect of cellular homeostasis during neural activity. This volume regulation is thought to be mediated by activation of specific transporters, aquaporin, and volume regulated anion channels (VRAC). In cultured astrocytes, it was reported that swelling-induced mitogen-activated protein (MAP) kinase activation is required to open VRAC, which are thought to be important in regulatory volume decrease and in the response of CNS to trauma and excitotoxicity. It has been also described that sodium fluoride (NaF), a recognized G-protein activator and protein phosphatase inhibitor, leads to a significant MAP kinase activation in endothelial cells. However, NaF's effect in volume regulation in the brain is not known yet. Here, we investigated the mechanism of NaF-induced volume change in rat and mouse hippocampal slices using intrinsic optical signal (IOS) recording, in which we measured relative changes in intracellular and extracellular volume as changes in light transmittance through brain slices. We found that NaF (1~5 mM) application induced a reduction in light transmittance (decreased volume) in CA1 hippocampus, which was completely reversed by MAP kinase inhibitor U0126 (10 µM). We also observed that NaF-induced volume reduction was blocked by anion channel blockers, suggesting that NaF-induced volume reduction could be mediated by VRAC. Overall, our results propose a novel molecular mechanism of NaF-induced volume reduction via MAP kinase signaling pathway by activation of VRAC.
Adenylyl cyclase type-5 (AC5) is preferentially expressed in the dorsal striatum. Recently, we reported that AC5 knockout (KO) mice preferred food pellets carrying an olfactory cue produced by AC5 KO mice during food consumption (AC5 KO pellets) over food pellets that had been taken by wildtype (WT) mice. In the present study, we demonstrated that whisker trimming on the right side of the face but not the left in AC5 KO mice blocked the behavioral preference for AC5 KO pellets. Conversely, whisker trimming on the right but not the left in WT mice induced a behavioral preference for AC5 KO pellets. Mice lacking D2 dopamine receptor (D2 KO mice) also showed a behavioral preference for AC5 KO pellets. In D2 mice, whisker trimming on the right side of the face but not the left blocked a behavioral preference for AC5 KO food pellets. AC5 KO mice had increased level of phospho-CaMKIIα in the dorsal striatum, and WT mice with whiskers cut on either side also showed increased p-CaMKIIα level in the dorsal striatum. The siRNA-mediated inhibition of CaMKIIα in the dorsal striatum in either the right or the left hemisphere in AC5 KO mice and D2 KO mice blocked the behavioral preference for AC5 KO pellets. However, behavioral changes induced by this inhibition on each side showed asymmetrical time courses. These results suggest that an unconditioned behavioral preference for specific food pellets can be switched on or off based on the balance of states of neural activity in the dorsal striatum regulated by a signaling pathway centered on AC5 and D2 and the sensory inputs of whiskers from the right side of the face.
In neuronal recording studies on anesthetized animals, reliable measures for the transitional moment of consciousness are frequently required. Previous findings suggest that pupil fluctuations reflect the neuronal states during quiet wakefulness, whose correlation was unknown for the anesthetized condition. Here, we investigated the pupillary changes under isoflurane anesthesia simultaneously with the electroencephalogram (EEG) and electromyogram (EMG). The pupil was tracked by using a region-based active contour model. The dose was given to the animal in a stepwise increasing mode (simulating induction of anesthesia) or in a stepwise decreasing mode (simulating emergence of anesthesia). We found that the quickly widening pupil action (mydriasis) characterizes the transitional state in anesthesia. Mydriasis occurred only in the light dose in the emergence phase, and the events were accompanied by an increase of burst activity in the EEG followed by EMG activity in 47% of the mydriasis events. Our findings suggest that recording such pupil changes may offer a noncontact monitoring tool for indexing the transitional state of the brain, particularly when a lower threshold dose is applied.
An 18-year-old left-handed male harbored intractable medial temporal lobe epilepsy (MTLE) underwent fractionated gamma knife surgery (GKS) instead of open surgery, considering the mental retardation and diffuse cerebral dysfunction. GKS treatment parameters were: target volume, 8.8 cm3; total marginal dose, 24 Gy in 3 fractionations at the 50% isodose line. The patient has been free from seizures since 9 months after GKS, with notable improvement in cognitive outcome. Fractionated GKS could be considered as a safe tool for seizure control and neuropsychological improvement in patients with MTLE.