Memory: looking back and looking forward

This review brings together past and present achievements in memory research, ranging from molecular to psychological discoveries. Despite some false starts, major advances include our growing understanding of learning-related neural plasticity and the characterisation of different classes of memory. One striking example is the ability to reactivate targeted neuronal ensembles so that an animal will seemingly re-experience a particular memory, with the further potential to modify such memories. Meanwhile, human functional imaging studies can distinguish individual episodic memories based on voxel activation patterns. While the hippocampus continues to provide a rich source of information, future progress requires broadening our research to involve other sites. Related challenges include the need to understand better the role of glial-neuron interactions and to look beyond the synapse as the sole site of experience-dependent plasticity. Unmet goals include translating our neuroscientific knowledge in order to optimise learning and memory, especially amongst disadvantaged populations

Synaptic tagging and capture : differential role of distinct calcium/calmodulin kinases in protein synthesis-dependent long-term potentiation

Weakly tetanized synapses in area CA1 of the hippocampus that ordinarily display long-term potentiation lasting ~3 h (called early-LTP) will maintain a longer-lasting change in efficacy (late-LTP) if the weak tetanization occurs shortly before or after strong tetanization of an independent, but convergent, set of synapses in CA1. The synaptic tagging and capture hypothesis explains this heterosynaptic influence on persistence in terms of a distinction between local mechanisms of synaptic tagging and cell-wide mechanisms responsible for the synthesis, distribution, and capture of plasticity-related proteins (PRPs). We now present evidence that distinct CaM kinase (CaMK) pathways serve a dissociable role in these mechanisms. Using a hippocampal brain-slice preparation that permits stable long-term recordings in vitro for >10 h and using hippocampal cultures to validate the differential drug effects on distinct CaMK pathways, we show that tag setting is blocked by the CaMK inhibitor KN-93 (2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)amino-N-(4-chlorocinnamyl)-N-methylbenzylamine) that, at low concentration, is more selective for CaMKII. In contrast, the CaMK kinase inhibitor STO-609 [7H-benzimidazo(2,1-a)benz(de)isoquinoline-7-one-3-carboxylic acid] specifically limits the synthesis and/or availability of PRPs. Analytically powerful three-pathway protocols using sequential strong and weak tetanization in varying orders and test stimulation over long periods of time after LTP induction enable a pharmacological dissociation of these distinct roles of the CaMK pathways in late-LTP and so provide a novel framework for the molecular mechanisms by which synaptic potentiation, and possibly memories, become stabilized

Anterior cingulate cortex in schema assimilation and expression

In humans and in animals, mental schemas can store information within an associative framework that enables rapid and efficient assimilation of new information. Using a hippocampal-dependent paired-associate task, we now report that the anterior cingulate cortex is part of a neocortical network of schema storage with NMDA receptor-mediated transmission critical for information updating, and AMPA receptor-mediated transmission required for the expression and updating of stored information

Effects of negative energy balance on liver gene and protein expression during the early postpartum period and its impacts on dairy cow fertility

End of project reportNegative energy balance (NEB) is a severe metabolic affecting high yielding dairy cows early post partum with both concurrent and latent negative effects on cow fertility as well as on milk production and cow health. The seasonal nature of Irish dairy production necessitates high cow fertility and a compact spring calving pattern in order to maximise grass utilisation. Poor dairy cow reproductive performance currently costs the Irish cattle industry in excess of €400 million annually. High milk yields have been associated with lower reproductive efficiency, and it has been suggested that this effect is probably mediated through its effects on the energy balance of the cow during lactation. The modern high genetic merit dairy cow prioritises nutrient supply towards milk production in early lactation and this demand takes precedence over the provision of optimal conditions for reproduction. In this study we used the bovine Affymetrix 23,000 gene microarray, which contains the most comprehensive set of bovine genes to be assembled and provides a means of investigating the modifying influences of energy balance on liver gene expression. Cows in severe negative energy balance (SNEB) in early lactation showed altered hepatic gene expression in metabolic processes as well as a down regulation of the insulin-like growth factor (IGF) system, where insulin like growth factor-1 (IGF-1), growth hormone receptor variant 1A (GHR1A) and insulin-like growth factor binding protein-acid labile subunit (IGFBP-ALS) were down regulated compared to the cows in the moderate negative energy balance MNEB group, consistent with a five-fold reduction in systemic concentrations of IGF1 in the SNEB group.Cows in SNEB showed elevated expression of key genes involved in the inflammatory response such as interleukin-8 (IL-8). There was a down regulation of genes involved in cellular growth in SNEB cows and moreover a negative regulator of cellular proliferation (HGFIN) was up regulated in SNEB cows, which is likely to compromise adaptation and recovery from NEB. The puma method of analysis revealed that 417 genes were differentially regulated by EB (P<0.05), of these genes 190 were up-regulated while 227 were down-regulated, with 405 genes having known biological functions. From Ingenuity Pathway Analysis (IPA), lipid catabolism was found to be the process most affected by differences in EB status

Analysis of gene expression in the bovine corpus luteum through generation and characterisation of 960 ESTs

To gain new insights into gene identity and gene expression in the bovine corpus luteum (CL) a directionally cloned CL cDNA library was constructed, screened with a total CL cDNA probe and clones representing abundant and rare mRNA transcripts isolated. The 5Vterminal DNA sequence of 960 cDNA clones, composed of 192 abundant and 768 rare mRNA transcripts was determined and clustered into 351 non-redundant expressed sequence tag (EST) groups. Bioinformatic analysis revealed that 309 (88%) of the ESTs showed significant homology to existing sequences in the protein and nucleotide public databases. Several previously unidentified bovine genes encoding proteins associated with key aspects of CL function including extracellular matrix remodelling, lipid metabolism/steroid biosynthesis and apoptosis, were identified. Forty-two (12%) of the ESTs showed homology with human or with other uncharacterised ESTs, some of these were abundantly expressed and may therefore play an important role in primary CL function. Tissue-specificity and temporal CL gene expression of selected clones previously unidentified in bovine CL tissue was also examined. The most interesting finds indicated that mRNA encoding squalene epoxidase was constitutively expressed in CL tissue throughout the oestrous cycle and 7-fold down-regulated ( P < 0.05)in late luteal tissue, concomitant with the disappearance of systemic progesterone, suggesting that de novo cholesterol biosynthesis plays an important role in steroidogenesis. The mRNA encoding the growth factor, insulin-like growth factor-binding protein-related protein 1 (IGFBP-rP1), remained constant during the oestrous cycle and was 1.8-fold up-regulated ( P < 0.05) in late luteal tissue implying a role in CL regression

Natural Wormholes as Gravitational Lenses

Visser has suggested traversable 3-dimensional wormholes that could plausibly form naturally during Big Bang inflation. A wormhole mouth embedded in high mass density might accrete mass, giving the other mouth a net *negative* mass of unusual gravitational properties. The lensing of such a gravitationally negative anomalous compact halo object (GNACHO) will enhance background stars with a time profile that is observable and qualitatively different from that recently observed for massive compact halo objects (MACHOs) of positive mass. We recommend that MACHO search data be analyzed for GNACHOs.Comment: 4 pages; plus 4 figures; ReV_TeX 3.0; DOE/ER/40537-001/NPL94-07-01

A Markov Chain based method for generating long-range dependence

This paper describes a model for generating time series which exhibit the statistical phenomenon known as long-range dependence (LRD). A Markov Modulated Process based upon an infinite Markov chain is described. The work described is motivated by applications in telecommunications where LRD is a known property of time-series measured on the internet. The process can generate a time series exhibiting LRD with known parameters and is particularly suitable for modelling internet traffic since the time series is in terms of ones and zeros which can be interpreted as data packets and inter-packet gaps. The method is extremely simple computationally and analytically and could prove more tractable than other methods described in the literatureComment: 8 pages, 2 figure

Brain region networks for the assimilation of new associative memory into a schema

Alterations in long-range functional connectivity between distinct brain regions are thought to contribute to the encoding of memory. However, little is known about how the activation of an existing network of neocortical and hippocampal regions might support the assimilation of relevant new information into the preexisting knowledge structure or ‘schema’. Using functional mapping for expression of plasticity-related immediate early gene products, we sought to identify the long-range functional network of paired-associate memory, and the encoding and assimilation of relevant new paired-associates. Correlational and clustering analyses for expression of immediate early gene products revealed that midline neocortical-hippocampal connectivity is strongly associated with successful memory encoding of new paired-associates against the backdrop of the schema, compared to both (1) unsuccessful memory encoding of new paired-associates that are not relevant to the schema, and (2) the mere retrieval of the previously learned schema. These findings suggest that the certain midline neocortical and hippocampal networks support the assimilation of newly encoded associative memories into a relevant schema. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13041-022-00908-9