Rehebbilitating Memory

Amnesia is a deficit of memory function that can result from trauma, stress, disease, drug use, or ageing. Though efforts are made to prevent and treat the various causes of amnesia, there remains no treatment for the symptom of memory loss itself. Because the defining feature of amnesia is an inability recall memory, any given case may be due to the possibility that the memory is damaged, or the alternative that it is present but irretrievable (Squire, 1982). Discriminating between these two scenarios would be of scientific value, because the neurobiology of memory formation is anchored in experimental amnesia. Pathological cases of amnesia that are due to retrieval deficits may in principal be treatable rather than merely preventable. Amnesia could be attributed to a retrieval deficit if the ostensible ‘lost’ memory could be evoked through brain stimulation. The challenge here is to identify exactly where in the brain a particular memory is stored.JPB FoundationRIKEN Brain Science Institut

Evolution of NMDA receptor cytoplasmic interaction domains: implications for organisation of synaptic signalling complexes

<p>Abstract</p> <p>Background</p> <p>Glutamate gated postsynaptic receptors in the central nervous system (CNS) are essential for environmentally stimulated behaviours including learning and memory in both invertebrates and vertebrates. Though their genetics, biochemistry, physiology, and role in behaviour have been intensely studied <it>in vitro </it>and <it>in vivo</it>, their molecular evolution and structural aspects remain poorly understood. To understand how these receptors have evolved different physiological requirements we have investigated the molecular evolution of glutamate gated receptors and ion channels, in particular the <it>N</it>-methyl-<it>D</it>-aspartate (NMDA) receptor, which is essential for higher cognitive function. Studies of rodent NMDA receptors show that the C-terminal intracellular domain forms a signalling complex with enzymes and scaffold proteins, which is important for neuronal and behavioural plasticity</p> <p>Results</p> <p>The vertebrate NMDA receptor was found to have subunits with C-terminal domains up to 500 amino acids longer than invertebrates. This extension was specific to the NR2 subunit and occurred before the duplication and subsequent divergence of NR2 in the vertebrate lineage. The shorter invertebrate C-terminus lacked vertebrate protein interaction motifs involved with forming a signaling complex although the terminal PDZ interaction domain was conserved. The vertebrate NR2 C-terminal domain was predicted to be intrinsically disordered but with a conserved secondary structure.</p> <p>Conclusion</p> <p>We highlight an evolutionary adaptation specific to vertebrate NMDA receptor NR2 subunits. Using <it>in silico </it>methods we find that evolution has shaped the NMDA receptor C-terminus into an unstructured but modular intracellular domain that parallels the expansion in complexity of an NMDA receptor signalling complex in the vertebrate lineage. We propose the NR2 C-terminus has evolved to be a natively unstructured yet flexible hub organising postsynaptic signalling. The evolution of the NR2 C-terminus and its associated signalling complex may contribute to species differences in behaviour and in particular cognitive function.</p

The Subtype of GluN2 C-terminal Domain Determines the Response to Excitotoxic Insults

It is currently unclear whether the GluN2 subtype influences NMDA receptor (NMDAR) excitotoxicity. We report that the toxicity of NMDAR-mediated Ca(2+) influx is differentially controlled by the cytoplasmic C-terminal domains of GluN2B (CTD(2B)) and GluN2A (CTD(2A)). Studying the effects of acute expression of GluN2A/2B-based chimeric subunits with reciprocal exchanges of their CTDs revealed that CTD(2B) enhances NMDAR toxicity, compared to CTD(2A). Furthermore, the vulnerability of forebrain neurons in vitro and in vivo to NMDAR-dependent Ca(2+) influx is lowered by replacing the CTD of GluN2B with that of GluN2A by targeted exon exchange in a mouse knockin model. Mechanistically, CTD(2B) exhibits stronger physical/functional coupling to the PSD-95-nNOS pathway, which suppresses protective CREB activation. Dependence of NMDAR excitotoxicity on the GluN2 CTD subtype can be overcome by inducing high levels of NMDAR activity. Thus, the identity (2A versus 2B) of the GluN2 CTD controls the toxicity dose-response to episodes of NMDAR activity

Effects Of Length, Complexity, And Grammatical Correctness On Stuttering In Spanish-Speaking Preschool Children

Purpose: To explore the effects of utterance length, syntactic complexity, and grammatical correctness on stuttering in the spontaneous speech of young, monolingual Spanish-speaking children. Method: Spontaneous speech samples of 11 monolingual Spanish-speaking children who stuttered, ages 35 to 70 months, were examined. Mean number of syllables, total number of clauses, utterance complexity (i.e., containing no clauses, simple clauses, or subordinate and/or conjoined clauses), and grammatical correctness (i.e., the presence or absence of morphological and syntactical errors) in stuttered and fluent utterances were compared. Results: Findings revealed that stuttered utterances in Spanish tended to be longer and more often grammatically incorrect, and contain more clauses, including more subordinate and/or conjoined clauses. However, when controlling for the interrelatedness of syllable number and clause number and complexity, only utterance length and grammatical incorrectness were significant predictors of stuttering in the spontaneous speech of these Spanish-speaking children. Use of complex utterances did not appear to contribute to the prediction of stuttering when controlling for utterance length. Conclusions: Results from the present study were consistent with many earlier reports of English-speaking children. Both length and grammatical factors appear to affect stuttering in Spanish-speaking children. Grammatical errors, however, served as the greatest predictor of stuttering.Communication Sciences and Disorder

The Tidal Disruption Event AT 2018hyz II: Light Curve Modeling of a Partially Disrupted Star

AT 2018hyz (=ASASSN-18zj) is a tidal disruption event (TDE) located in the nucleus of a quiescent E+A galaxy at a redshift of $z = 0.04573$, first detected by the All-Sky Automated Survey for Supernovae (ASAS-SN). We present optical+UV photometry of the transient, as well as an X-ray spectrum and radio upper limits. The bolometric light curve of AT 2018hyz is comparable to other known TDEs and declines at a rate consistent with a $t^{-5/3}$ at early times, emitting a total radiated energy of $E = 9\times10^{50}$ erg. An excess bump appears in the UV light curve about 50 days after bolometric peak, followed by a flattening beyond 250 days. The light curve shows an excess bump in the UV about 50 days after bolometric peak lasting for at least 100 days, which may be related to an outflow. We detect a constant X-ray source present for at least 86 days. The X-ray spectrum shows a total unabsorbed flux of $\sim 4\times10^{-14}$ erg cm$^{-2}$ s$^{-1}$ and is best fit by a blackbody plus power-law model with a photon index of $\Gamma = 0.8$. A thermal X-ray model is unable to account for photons $> 1$ keV, while the radio non-detection favors inverse-Compton scattering rather than a jet for the non-thermal component. We model the optical and UV light curves using the Modular Open-Source Fitter for Transients (MOSFiT) and find a best fit for a black hole of $5.2\times10^6$ M$_\odot$ partially disrupting a $0.1$ M$_\odot$ star (stripping a mass of $\sim 0.01$ M$_\odot$ for the inferred impact parameter, $\beta=0.6$). The low optical depth implied by the small debris mass may explain how we are able to see hydrogen emission with disk-like line profiles in the spectra of AT 2018hyz (see our companion paper, Short et al.~2020).Comment: 10 pages, 10 figures, published in MNRA

SN 2021zny: an early flux excess combined with late-time oxygen emission suggests a double white dwarf merger event

We present a photometric and spectroscopic analysis of the ultra-luminous and slowly evolving 03fg-like Type Ia SN 2021zny. Our observational campaign starts from $\sim5.3$ hours after explosion (making SN 2021zny one of the earliest observed members of its class), with dense multi-wavelength coverage from a variety of ground- and space-based telescopes, and is concluded with a nebular spectrum $\sim10$ months after peak brightness. SN 2021zny displayed several characteristics of its class, such as the peak brightness ($M_{B}=-19.95$ mag), the slow decline ($\Delta m_{15}(B) = 0.62$ mag), the blue early-time colours, the low ejecta velocities and the presence of significant unburned material above the photosphere. However, a flux excess for the first $\sim1.5$ days after explosion is observed in four photometric bands, making SN 2021zny the third 03fg-like event with this distinct behavior, while its $+313$ d spectrum shows prominent [O I] lines, a very unusual characteristic of thermonuclear SNe. The early flux excess can be explained as the outcome of the interaction of the ejecta with $\sim0.04\:\mathrm{M_{\odot}}$ of H/He-poor circumstellar material at a distance of $\sim10^{12}$ cm, while the low ionization state of the late-time spectrum reveals low abundances of stable iron-peak elements. All our observations are in accordance with a progenitor system of two carbon/oxygen white dwarfs that undergo a merger event, with the disrupted white dwarf ejecting carbon-rich circumstellar material prior to the primary white dwarf detonation.Comment: 19 pages, 16 figures, accepted for publication in MNRA

Evolution of GluN2A/B cytoplasmic domains diversified vertebrate synaptic plasticity and behavior

Two genome duplications early in the vertebrate lineage expanded gene families, including GluN2 subunits of the NMDA receptor. Diversification between the four mammalian GluN2 proteins occurred primarily at their intracellular C−terminal domains (CTDs). To identify shared ancestral functions and diversified subunit−specific functions, we exchanged the exons encoding the GluN2A (also known as Grin2a) and GluN2B (also known as Grin2b) CTDs in two knock−in mice and analyzed the mice's biochemistry, synaptic physiology, and multiple learned and innate behaviors. The eight behaviors were genetically separated into four groups, including one group comprising three types of learning linked to conserved GluN2A/B regions. In contrast, the remaining five behaviors exhibited subunit−specific regulation. GluN2A/B CTD diversification conferred differential binding to cytoplasmic MAGUK proteins and differential forms of long−term potentiation. These data indicate that vertebrate behavior and synaptic signaling acquired increased complexity from the duplication and diversification of ancestral GluN2 gene

Revealing the progenitor of SN 2021zby through analysis of the TESSTESS shock-cooling light curve

We present early observations and analysis of the double-peaked Type IIb supernova (SN IIb) 2021zby. $TESS$ captured the prominent early shock cooling peak of SN 2021zby within the first $\sim$10 days after explosion with a 30-minute cadence. We present optical and near-infrared spectral series of SN 2021zby, including three spectra during the shock cooling phase. Using a multi-band model fit, we find that the inferred properties of its progenitor are consistent with a red supergiant or yellow supergiant, with an envelope mass of $\sim$0.3-3.0 M$_\odot$ and an envelope radius of $\sim$50-350$R_\odot$. These inferred progenitor properties are similar to those of other SNe IIb with double-peak feature, such as SNe 1993J, 2011dh, 2016gkg and 2017jgh. This study further validates the importance of the high cadence and early coverage in resolving the shape of the shock cooling light curve, while the multi-band observations, especially UV, is also necessary to fully constrain the progenitor properties.Comment: 12 pages, 5 figures, 2 tables, submitted to ApJ