Welcome to Molecular Brain

We are delighted to announce the arrival of a brand new journal dedicated to the ever-expanding field of neuroscience. Molecular Brain is a peer-reviewed, open-access online journal that aims at publishing high quality articles as rapidly as possible. The journal will cover a broad spectrum of neuroscience ranging from molecular/cellular to behavioral/cognitive neuroscience and from basic to clinical research. Molecular Brain will publish not only research articles, but also methodology articles, editorials, reviews, and short reports. It will be a premier platform for neuroscientists to exchange their ideas with researchers from around the world to help improve our understanding of the molecular mechanisms of the brain and mind.     

In memoriam: John Lisman – commentaries on CaMKII as a memory molecule

Shortly before he died in October 2017, John Lisman submitted an invited review to Molecular Brain on ‘Criteria for identifying the molecular basis of the engram (CaMKII, PKMζ)’. John had no opportunity to read the referees’ comments, and as a mark of the regard in which he was held by the neuroscience community the Editors decided to publish his review as submitted. This obituary takes the form of a series of commentaries on Lisman’s review. At the same time we are publishing as a separate article a longer response by Todd Sacktor and André Fenton entitled ‘What does LTP tell us about the roles of CaMKII and PKMζ in memory?’ which presents the case for a rival memory molecule, PKMζ.     

Hydrogen peroxide-induced cell death in cultured Aplysia sensory neurons

Widespread neuronal cell death occurs during normal development and as a result of pathological conditions in the nervous system of many organisms. In this study, we investigated the cytotoxicity induced by H(2)O(2) in Aplysia mechanosensory neurons, which serve as a useful model in the study of learning and memory. Treatment with hydrogen peroxide (10(-2)-10 mM) for 3 h produced a nuclear DNA breakage in Aplysia sensory neurons, as revealed by TdT-mediated dUTP nick end labeling (TUNEL) staining, in a dose-dependent manner. Prolonged treatment (6-18 h) of Aplysia sensory neurons with 1 mM hydrogen peroxide produced dramatic morphological changes, such as neurite fragmentation, disintegration of the cell body, and a change in the resting membrane potential. This change in the resting potential was biphasic, and was initially hyperpolarized about 6 h after hydrogen peroxide treatment, but this later shifted to a depolarization some 13-18 h after treatment. Electron microscopic analysis also showed that this hydrogen peroxide-induced cell death was associated with apoptotic nuclear shrinkage, chromatin condensation, and necrotic swelling of organelles. Our results demonstrate that Aplysia sensory neurons show both apoptotic and necrotic characteristics as well as biphasic changes in resting potential during hydrogen peroxide-induced cell death.     

Identification of nuclear/nucleolar localization signal in Aplysia learning associated protein of slug with a molecular mass of 18 kDa homologous protein

We isolated a learning associated protein of slug with a molecular mass of 18 kDa (LAPS18) homologue from the expressed sequence tag database of Aplysia kurodai and named it Aplysia LAPS18-like protein (ApLLP). ApLLP encodes 120 amino acids and has 57% identity with LAPS18. To examine the subcellular expression pattern of ApLLP we constructed an EGFP-tagged ApLLP fusion protein and overexpressed it in both Aplysia neurons and COS-7 cells. In contrast to the previous findings, which showed that LAPS18 is secreted by COS-7 cells, ApLLP-EGFP was localized to the nucleus, and most of it to nucleoli. Analysis of deletion mutants of ApLLP-EGFP showed that the N-terminal and the C-terminal nucleolar and nucleus localization signal sequences are important for localization to the nucleus and the nucleoli.     

Plasticity of Metabotropic Glutamate Receptor-Dependent Long-Term Depression in the Anterior Cingulate Cortex after Amputation

Long-term depression (LTD) is a key form of synaptic plasticity important in learning and information storage in the brain. It has been studied in various cortical regions, including the anterior cingulate cortex (ACC). ACC is a crucial cortical region involved in such emotion-related physiological and pathological conditions as fear memory and chronic pain. In the present study, we used a multielectrode array system to map cingulate LTD in a spatiotemporal manner within the ACC. We found that low-frequency stimulation (1 Hz, 15 min) applied onto deep layer V induced LTD in layers II/III and layers V/VI. Cingulate LTD requires activation of metabotropic glutamate receptors (mGluRs), while L-type voltage-gated calcium channels and NMDA receptors also contribute to its induction. Peripheral amputation of the distal tail impaired ACC LTD, an effect that persisted for at least 2 weeks. The loss of LTD was rescued by priming ACC slices with activation of mGluR1 receptors by coapplying (RS)-3,5-dihydroxyphenylglycine and MPEP, a form of metaplasticity that involved the activation of protein kinase C. Our results provide in vitro evidence of the spatiotemporal properties of ACC LTD in adult mice. We demonstrate that tail amputation causes LTD impairment within the ACC circuit and that this can be rescued by activation of mGluR1.     

A cellular model of memory reconsolidation involves reactivation-induced destabilization and restabilization at the sensorimotor synapse in Aplysia

The memory reconsolidation hypothesis suggests that a memory trace becomes labile after retrieval and needs to be reconsolidated before it can be stabilized. However, it is unclear from earlier studies whether the same synapses involved in encoding the memory trace are those that are destabilized and restabilized after the synaptic reactivation that accompanies memory retrieval, or whether new and different synapses are recruited. To address this issue, we studied a simple nonassociative form of memory, long-term sensitization of the gill- and siphon-withdrawal reflex in Aplysia, and its cellular analog, long-term facilitation at the sensory-to-motor neuron synapse. We found that after memory retrieval, behavioral long-term sensitization in Aplysia becomes labile via ubiquitin/proteasome-dependent protein degradation and is reconsolidated by means of de novo protein synthesis. In parallel, we found that on the cellular level, long-term facilitation at the sensory-to-motor neuron synapse that mediates long-term sensitization is also destabilized by protein degradation and is restabilized by protein synthesis after synaptic reactivation, a procedure that parallels memory retrieval or retraining evident on the behavioral level. These results provide direct evidence that the same synapses that store the long-term memory trace encoded by changes in the strength of synaptic connections critical for sensitization are disrupted and reconstructed after signal retrieval.     

Two major gate-keepers in the self-renewal of neural stem cells: Erk1/2 and PLCγ1 in FGFR signaling

Neural stem cells are undifferentiated precursor cells that proliferate, self-renew, and give rise to neuronal and glial lineages. Understanding the molecular mechanisms underlying their self-renewal is an important aspect in neural stem cell biology. The regulation mechanisms governing self-renewal of neural stem cells and the signaling pathways responsible for the proliferation and maintenance of adult stem cells remain largely unknown. In this issue of Molecular Brain [Ma DK et al. Molecular genetic analysis of FGFR1 signaling reveals distinct roles of MAPK and PLCγ1 activation for self-renewal of adult neural stem cells. Molecular Brain 2009, 2:16], characterized the different roles of MAPK and PLCγ1 in FGFR1 signaling in the self-renewal of neural stem cells. These novel findings provide insights into basic neural stem cell biology and clinical applications of potential stem-cell-based therapy.     

Synaptic facilitation by ectopic octopamine and 5-HT receptors in Aplysia

The cAMP pathway plays a critical role in synaptic plasticity. We assessed using the ectopic expression of octopamine (OA) receptor, the contribution of the cAMP pathway to short-term facilitation of sensory-motor synapses in Aplysia. When synaptic connections were depressed to 20-30% of their initial EPSP amplitude, the application of OA to sensory cells expressing OA receptor showed significant synaptic facilitation, but this was less than the synaptic facilitation shown by 5-HT treatment. We also found that synaptic facilitation was further enhanced when OA was treated in the presence of 5-HT at non-depressed synapses, but not at depressed synapses. These results imply that the role of cAMP in synaptic facilitation is reduced as the synapse becomes depressed due to repeated activity.     

Thiol oxidation-mediated cell death in Aplysia cultured sensory neurons

Cellular thiol groups modulate various aspects of cellular function, including cell death. In this study, we found that a thiol oxidant, diamide, induced morphological changes such as cell swelling, membrane blebbing, and chromatin condensation in Aplysia cultured sensory neurons. Furthermore, diamide induced biphasic changes in the membrane potential, where hyperpolarization was followed by depolarization. Moreover, these diamide-induced cytotoxic effects were completely blocked by the equimolar addition of the disulfide reducing agent dithiothreitol (DTT). We also found that during H(2)O(2)-induced cell death, DTT attenuated cell swelling and membrane blebbing, but not DNA breakage, whereas the vitamin E analogue trolox attenuated DNA breakage, but not cell swelling and membrane blebbing. These results demonstrate that during H(2)O(2)-induced cell death, apoptotic features such as DNA breakage are mediated in part by free radical generation, whereas necrotic features such as cell swelling and membrane blebbing are primarily mediated by the oxidation of cellular thiol groups.