What is memory? The present state of the engram

The mechanism of memory remains one of the great unsolved problems of biology. Grappling with the question more than a hundred years ago, the German zoologist Richard Semon formulated the concept of the engram, lasting connections in the brain that result from simultaneous "excitations", whose precise physical nature and consequences were out of reach of the biology of his day. Neuroscientists now have the knowledge and tools to tackle this question, however, and this Forum brings together leading contemporary views on the mechanisms of memory and what the engram means today

Ontogenetic and Phylogenetic Approaches for Studying the Mechanisms of Cognitive Dysfunctions

This chapter summarizes the phylogenetic and ontogenetic approaches for studying cognitive disorders such as Alzheimer’s disease. It gives an extended example of evaluation of animal behavior and brain properties using an original model of prenatal hypoxia in rats by various physiological, behavioral, immunohistochemical, molecular biological, and biochemical techniques at different stages of postnatal development, which provide a better understanding of the pathological processes in the human brain during the development of neurodegeneration

Eligibility Traces and Plasticity on Behavioral Time Scales: Experimental Support of neoHebbian Three-Factor Learning Rules

Most elementary behaviors such as moving the arm to grasp an object or walking into the next room to explore a museum evolve on the time scale of seconds; in contrast, neuronal action potentials occur on the time scale of a few milliseconds. Learning rules of the brain must therefore bridge the gap between these two different time scales. Modern theories of synaptic plasticity have postulated that the co-activation of pre- and postsynaptic neurons sets a flag at the synapse, called an eligibility trace, that leads to a weight change only if an additional factor is present while the flag is set. This third factor, signaling reward, punishment, surprise, or novelty, could be implemented by the phasic activity of neuromodulators or specific neuronal inputs signaling special events. While the theoretical framework has been developed over the last decades, experimental evidence in support of eligibility traces on the time scale of seconds has been collected only during the last few years. Here we review, in the context of three-factor rules of synaptic plasticity, four key experiments that support the role of synaptic eligibility traces in combination with a third factor as a biological implementation of neoHebbian three-factor learning rules

Experience-driven formation of parts-based representations in a model of layered visual memory

Growing neuropsychological and neurophysiological evidence suggests that the visual cortex uses parts-based representations to encode, store and retrieve relevant objects. In such a scheme, objects are represented as a set of spatially distributed local features, or parts, arranged in stereotypical fashion. To encode the local appearance and to represent the relations between the constituent parts, there has to be an appropriate memory structure formed by previous experience with visual objects. Here, we propose a model how a hierarchical memory structure supporting efficient storage and rapid recall of parts-based representations can be established by an experience-driven process of self-organization. The process is based on the collaboration of slow bidirectional synaptic plasticity and homeostatic unit activity regulation, both running at the top of fast activity dynamics with winner-take-all character modulated by an oscillatory rhythm. These neural mechanisms lay down the basis for cooperation and competition between the distributed units and their synaptic connections. Choosing human face recognition as a test task, we show that, under the condition of open-ended, unsupervised incremental learning, the system is able to form memory traces for individual faces in a parts-based fashion. On a lower memory layer the synaptic structure is developed to represent local facial features and their interrelations, while the identities of different persons are captured explicitly on a higher layer. An additional property of the resulting representations is the sparseness of both the activity during the recall and the synaptic patterns comprising the memory traces.Comment: 34 pages, 12 Figures, 1 Table, published in Frontiers in Computational Neuroscience (Special Issue on Complex Systems Science and Brain Dynamics), http://www.frontiersin.org/neuroscience/computationalneuroscience/paper/10.3389/neuro.10/015.2009

An Operating Principle of the Cerebral Cortex, and a Cellular Mechanism for Attentional Trial-and-Error Pattern Learning and Useful Classification Extraction

A feature of the brains of intelligent animals is the ability to learn to respond to an ensemble of active neuronal inputs with a behaviorally appropriate ensemble of active neuronal outputs. Previously, a hypothesis was proposed on how this mechanism is implemented at the cellular level within the neocortical pyramidal neuron: the apical tuft or perisomatic inputs initiate "guess" neuron firings, while the basal dendrites identify input patterns based on excited synaptic clusters, with the cluster excitation strength adjusted based on reward feedback. This simple mechanism allows neurons to learn to classify their inputs in a surprisingly intelligent manner. Here, we revise and extend this hypothesis. We modify synaptic plasticity rules to align with behavioral time scale synaptic plasticity (BTSP) observed in hippocampal area CA1, making the framework more biophysically and behaviorally plausible. The neurons for the guess firings are selected in a voluntary manner via feedback connections to apical tufts in the neocortical layer 1, leading to dendritic Ca2+ spikes with burst firing, which are postulated to be neural correlates of attentional, aware processing. Once learned, the neuronal input classification is executed without voluntary or conscious control, enabling hierarchical incremental learning of classifications that is effective in our inherently classifiable world. In addition to voluntary, we propose that pyramidal neuron burst firing can be involuntary, also initiated via apical tuft inputs, drawing attention towards important cues such as novelty and noxious stimuli. We classify the excitations of neocortical pyramidal neurons into four categories based on their excitation pathway: attentional versus automatic and voluntary/acquired versus involuntary. Additionally, we hypothesize that dendrites within pyramidal neuron minicolumn bundles are coupled via depolarization...Comment: 20 pages, 13 figure

Deletion of BDNF in Pax2 Lineage-Derived Interneuron Precursors in the Hindbrain Hampers the Proportion of Excitation/Inhibition, Learning, and Behavior

© 2021 Eckert, Marchetta, Manthey, Walter, Jovanovic, Savitska, Singer, Jacob, Rüttiger, Schimmang, Milenkovic, Pilz and Knipper.Numerous studies indicate that deficits in the proper integration or migration of specific GABAergic precursor cells from the subpallium to the cortex can lead to severe cognitive dysfunctions and neurodevelopmental pathogenesis linked to intellectual disabilities. A different set of GABAergic precursors cells that express Pax2 migrate to hindbrain regions, targeting, for example auditory or somatosensory brainstem regions. We demonstrate that the absence of BDNF in Pax2-lineage descendants of BdnfPax2KOs causes severe cognitive disabilities. In BdnfPax2KOs, a normal number of parvalbumin-positive interneurons (PV-INs) was found in the auditory cortex (AC) and hippocampal regions, which went hand in hand with reduced PV-labeling in neuropil domains and elevated activity-regulated cytoskeleton-associated protein (Arc/Arg3.1; here: Arc) levels in pyramidal neurons in these same regions. This immaturity in the inhibitory/excitatory balance of the AC and hippocampus was accompanied by elevated LTP, reduced (sound-induced) LTP/LTD adjustment, impaired learning, elevated anxiety, and deficits in social behavior, overall representing an autistic-like phenotype. Reduced tonic inhibitory strength and elevated spontaneous firing rates in dorsal cochlear nucleus (DCN) brainstem neurons in otherwise nearly normal hearing BdnfPax2KOs suggests that diminished fine-grained auditory-specific brainstem activity has hampered activity-driven integration of inhibitory networks of the AC in functional (hippocampal) circuits. This leads to an inability to scale hippocampal post-synapses during LTP/LTD plasticity. BDNF in Pax2-lineage descendants in lower brain regions should thus be considered as a novel candidate for contributing to the development of brain disorders, including autism.We acknowledge grants from the Deutsche Forschungsgemeins-chaft FOR 2060 project RU 713/3-2 (WS and LR), GRK 2381 (PM), SPP 1608 RU 316/12-1 (PE and LR), MI 954/3-1 (IM and SJ), KN 316/12-1 (MM and MK), BFU2016-76580-P (TS), and NIH NIMH 1R01MH106623 (MJ)

Lateralization of the developing rat hippocampal formation

Differences between the left and right hemisphere of the brain have been observed in humans and rodents (Broca, 1861; Wernicke, 1881), including the hippocampal formation, a region of the brain that is necessary for some forms of learning and memory (Olton and Samuelson, 1976; deToledo-Morrell et al., 1988; Bernasconi-Guastalla et al., 1994; Tabibnia et al., 1994; Poe et al., 2000; Lister et al., 2006; Hanlon et al., 2005; Sommer et al., 2005; Moskal et al., 2006; Thompson et al., 2008; Klur et al., 2009). Although lateralization of the hippocampal formation has been studied in the adult, few have sought to directly examine the development of hippocampal lateralization (Moskal et al., 2006) and none have examined hippocampal lateralization in the embryo. The objective of the study outlined in this dissertation was to characterize the development of hippocampal lateralization in the rat. To achieve this objective, a rat CNS microarray with 1,178 genes representing the majority of ontological categories within the rat genome (Kroes et al., 2006) was used to examine lateralized gene expression in the embryonic rat hippocampal formation: 14 genes were all more highly expressed in the right hippocampus at E18 (Gross et al., 2008; Gross et al., 2010). Database for Annotation Visualization and Integrated Discovery (DAVID) and Gene Set Enrichment Analysis (GSEA) were also used to further investigate whether specific genes differentially expressed at E18 comprised pathways known to be important in the development of the hippocampal formation. Results demonstrated that genes related to structure, transcription and translation, cellular metabolism, glycolysis, and gap junction signaling were more highly expressed in the right hippocampus at E18. Expression of genes corresponding to proteins that comprise the gap junction signaling pathway were further examined using qRT-PCR. Results showed that alpha1a-tubulin, beta3-tubulin, and connexin43 were more highly expressed in the right hippocampus at E18. Using Western blot analysis, alpha1a-tubulin protein levels were also shown to be higher in the right hippocampus at E18. These results indicated that genes related to hippocampal growth and development were more highly expressed in the right hippocampus at E18, and furthermore they suggested that gap junctions may play a critical role in the development of hippocampal lateralization in the embryo. To further characterize the lateralized development of the rat hippocampal formation, the effect of N-methyl-D-aspartate glutamate receptor (NMDAR) mediated synaptic activity lateralized gene expression in the hippocampal formation during early postnatal development in the rat. During normal development, the pattern of lateralized gene expression displays a right-to-left shift in preferential expression between P6 and P9 (Moskal et al., 2006). A reduction in NMDA receptor (NMDAR) mediated synaptic activity using the selective NMDAR antagonist CPP, altered this pattern of lateralized gene expression at P9 (Rahimi et al., 2006, Gross et al., 2007; Claiborne et al., 2010). These data were then analyzed using Significance Analysis for Microarrays, DAVID, and GSEA analyses. The MAPK signaling pathway was enriched in the right hippocampal formation at P9 following CPP injections: these data were corroborated and extended using qRT-PCR. Expression of MAPK14 mRNA was not significantly different between the left and right hippocampal formation at postnatal day 6, nor was it greater in the right HF as compared to the left in saline treated rats at P9; however, MAPK14 mRNA was more highly expressed in the right hippocampal formation at P9 following a reduction in NMDAR activity between P6 and P9. c-Myc was more highly expressed in the right hippocampal formation at P6, and it was not differentially expressed during normal development or following saline control injections between P6 and P9. However, cMyc mRNA expression was significantly greater in the right hippocampal formation in CPP treated rats. These findings indicated that genes involved in the MAPK signaling pathway were upregulated in the right hippocampal formation during early postnatal development following a reduction in NMDAR-mediated synaptic activity. The findings presented in this dissertation are both novel and important: they are the first to demonstrate that lateralized gene expression is present in the embryonic rat hippocampal formation. Furthermore, these findings are the first to show the effect of early experience on the development of hippocampal lateralization in the first postnatal week. The results support the idea that differential gene expression patterns in the hippocampus are likely developmentally regulated and play a key role in the formation and function of that region and that the gene expression patterns can be significantly influenced by factors that modulate synapse plasticity

Microfluidics based techniques for electrophysiological studies of cells

This thesis work investigates the application of microfluidics to perform electrophysiological studies on cells, including investigations of the effect of cholesterol on the dynamic ion permeability of TRPV1 ion channels, and the application of a microfluidic device, the multifunctional pipette, in electrophysiological studies on brain slices. In the first part of this thesis, Chinese hamster ovary (CHO) cells overexpressing the TRPV1 ion channel were used in a dynamic ion permeability study, where the activation properties of the TRPV1 ion channel were investigated using the patch clamp technique after depletion of membrane cholesterol. The dynaflow system, an open-volume multichannel microfluidic system, and the multifunctional pipette, a freestanding microfluidic device utilizing hydrodynamically confined flow for spatially confined solution exchange, were used to deliver chemical stimuli exclusively to the patched cell. The result showed that the depletion of membrane cholesterol impaired the dynamic permeability of large cations in TRPV1 in low calcium solutions. The second project focused on the application of the multifunctional pipette in neuropharmacological studies of the brain slices. We developed an experimental setup, performed feasibility studies, characterized the device performance and compared it with common superfusion techniques, using extra- and intracellular electrophysiological recordings of pyramidal cells in hippocampal and prefrontal cortex brain slices from rats. The multifunctional pipette was used in these experiments for highly localized delivery of the competitive AMPA receptor antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) to selected locations on the slices. By applying multifunctional pipette, we achieved a multifold gain in solution exchange time and more efficient drug delivery compared to whole slice perfusion. The amount of drugs required in the microfluidics-supported experiments was by several orders of magnitude smaller. The multifunctional pipette enabled selective perfusion of a single dendritic layer in the CA1 region of hippocampus with CNQX, without affecting other layers in this region

State-dependencies of learning across brain scales

Learning is a complex brain function operating on different time scales, from milliseconds to years, which induces enduring changes in brain dynamics. The brain also undergoes continuous “spontaneous” shifts in states, which, amongst others, are characterized by rhythmic activity of various frequencies. Besides the most obvious distinct modes of waking and sleep, wake-associated brain states comprise modulations of vigilance and attention. Recent findings show that certain brain states, particularly during sleep, are essential for learning and memory consolidation. Oscillatory activity plays a crucial role on several spatial scales, for example in plasticity at a synaptic level or in communication across brain areas. However, the underlying mechanisms and computational rules linking brain states and rhythms to learning, though relevant for our understanding of brain function and therapeutic approaches in brain disease, have not yet been elucidated. Here we review known mechanisms of how brain states mediate and modulate learning by their characteristic rhythmic signatures. To understand the critical interplay between brain states, brain rhythms, and learning processes, a wide range of experimental and theoretical work in animal models and human subjects from the single synapse to the large-scale cortical level needs to be integrated. By discussing results from experiments and theoretical approaches, we illuminate new avenues for utilizing neuronal learning mechanisms in developing tools and therapies, e.g., for stroke patients and to devise memory enhancement strategies for the elderly

Neto1 Is a Novel CUB-Domain NMDA Receptor–Interacting Protein Required for Synaptic Plasticity and Learning

The N-methyl-D-aspartate receptor (NMDAR), a major excitatory ligand-gated ion channel in the central nervous system (CNS), is a principal mediator of synaptic plasticity. Here we report that neuropilin tolloid-like 1 (Neto1), a complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing transmembrane protein, is a novel component of the NMDAR complex critical for maintaining the abundance of NR2A-containing NMDARs in the postsynaptic density. Neto1-null mice have depressed long-term potentiation (LTP) at Schaffer collateral-CA1 synapses, with the subunit dependency of LTP induction switching from the normal predominance of NR2A- to NR2B-NMDARs. NMDAR-dependent spatial learning and memory is depressed in Neto1-null mice, indicating that Neto1 regulates NMDA receptor-dependent synaptic plasticity and cognition. Remarkably, we also found that the deficits in LTP, learning, and memory in Neto1-null mice were rescued by the ampakine CX546 at doses without effect in wild-type. Together, our results establish the principle that auxiliary proteins are required for the normal abundance of NMDAR subunits at synapses, and demonstrate that an inherited learning defect can be rescued pharmacologically, a finding with therapeutic implications for humans