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Tsien J.Z.,Georgia Regents University | Tsien J.Z.,Banna Biomedical Research Institute
Frontiers in Systems Neuroscience | Year: 2016

Humans and animals may encounter numerous events, objects, scenes, foods and countless social interactions in a lifetime. This means that the brain is constructed by evolution to deal with uncertainties and various possibilities. What is the architectural abstraction of intelligence that enables the brain to discover various possible patterns and knowledge about complex, evolving worlds? Here, I discuss the Theory of Connectivity–a “power-of-two” based, operational principle that can serve as a unified wiring and computational logic for organizing and constructing cell assemblies into the microcircuit-level building block, termed as functional connectivity motif(FCM). Defined by the power-of-two based equation, N = 2i−1, each FCM consists of the principal projection neuron cliques (N), ranging from those specific cliques receiving specific information inputs (i) to those general and sub-general cliques receiving various combinatorial convergent inputs. As the evolutionarily conserved logic, its validation requires experimental demonstrations of the following three major properties: (1) Anatomical prevalence—FCMs are prevalent across neural circuits, regardless of gross anatomical shapes; (2) Species conservancy—FCMs are conserved across different animal species; and (3) Cognitive universality—FCMs serve as a universal computational logic at the cell assembly level for processing a variety of cognitive experiences and flexible behaviors. More importantly, this Theory of Connectivity further predicts that the specific-to-general combinatorial connectivity pattern within FCMs should be preconfigured by evolution, and emerge innately from development as the brain’s computational primitives. This proposed design-principle can also explain the general purpose of the layered cortex and serves as its core computational algorithm. © 2016 Tsien. Source

Wang D.,Banna Biomedical Research Institute | Jacobs S.A.,Georgia Regents University | Tsien J.Z.,Georgia Regents University
Expert Opinion on Therapeutic Targets | Year: 2014

Introduction: Age-related memory loss is believed to be a result of reduced synaptic plasticity, including changes in the NR2 subunit composition of the NMDA receptor. It is known that endogenous NR2B subunits decrease as the brain ages, whereas transgenic upregulation of NR2B enhances synaptic plasticity and learning and memory in several animal species. Accumulating evidence suggests that elevated brain magnesium levels, via dietary supplementation, can boost NR2B in the brain, consequently reversing memory deficits and enhancing cognitive abilities.Areas covered: This review highlights the convergent molecular mechanisms via the NR2B pathway as a useful strategy for treating age-related memory loss. A dietary approach, via oral intake of a novel compound, magnesium L-threonate (MgT), to boost NR2B expression in the brain is highlighted.Expert opinion: Direct upregulation of the NR2B subunit expression can enhance synaptic plasticity and memory functions in a broad range of behavioral tasks in rodents. Other upregulation approaches, such as targeting the NR2B transporter or surface recycling pathway via cyclin-dependent kinase 5, are highly effective in improving memory functions. A dietary supplemental approach by optimally elevating the [Mg2+] in the brain is surprisingly effective in upregulating NR2B expression and improving memories in preclinical studies. MgT is currently under clinical trials. © Informa UK, Ltd. Source

Jacobs S.,Georgia Regents University | Cui Z.,Georgia Regents University | Feng R.,Georgia Regents University | Wang H.,East China Normal University | And 2 more authors.
PLoS ONE | Year: 2014

The opening-duration of the NMDA receptors implements Hebb's synaptic coincidence-detection and is long thought to be the rate-limiting factor underlying superior memory. Here, we investigate the molecular and genetic determinants of the NMDA receptors by testing the "synaptic coincidence-detection time-duration" hypothesis vs. "GluN2B intracellular signaling domain" hypothesis. Accordingly, we generated a series of GluN2A, GluN2B, and GluN2D chimeric subunit transgenic mice in which C-terminal intracellular domains were systematically swapped and overexpressed in the forebrain excitatory neurons. The data presented in the present study supports the second hypothesis, the "GluN2B intracellular signaling domain" hypothesis. Surprisingly, we found that the voltage-gated channel opening-durations through either GluN2A or GluN2B are sufficient and their temporal differences are marginal. In contrast, the C-terminal intracellular domain of the GluN2B subunit is necessary and sufficient for superior performances in long-term novel object recognition and cued fear memories and superior flexibility in fear extinction. Intriguingly, memory enhancement correlates with enhanced longterm potentiation in the 10-100 Hz range while requiring intact long-term depression capacity at the 1-5 Hz range. © 2014 Jacobs et al. Source

Mei B.,East China Normal University | Mei B.,University of Georgia | Li F.,Shanghai JiaoTong University | Li F.,University of Georgia | And 4 more authors.
PLoS ONE | Year: 2011

Pattern completion, the ability to retrieve complete memories initiated by subsets of external cues, has been a major focus of many computation models. A previously study reports that such pattern completion requires NMDA receptors in the hippocampus. However, such a claim was derived from a non-inducible gene knockout experiment in which the NMDA receptors were absent throughout all stages of memory processes as well as animal's adult life. This raises the critical question regarding whether the previously described results were truly resulting from the requirement of the NMDA receptors in retrieval. Here, we have examined the role of the NMDA receptors in pattern completion via inducible knockout of NMDA receptors limited to the memory retrieval stage. By using two independent mouse lines, we found that inducible knockout mice, lacking NMDA receptor in either forebrain or hippocampus CA1 region at the time of memory retrieval, exhibited normal recall of associative spatial reference memory regardless of whether retrievals took place under full-cue or partial-cue conditions. Moreover, systemic antagonism of NMDA receptor during retention tests also had no effect on full-cue or partial-cue recall of spatial water maze memories. Thus, both genetic and pharmacological experiments collectively demonstrate that pattern completion during spatial associative memory recall does not require the NMDA receptor in the hippocampus or forebrain. © 2011 Mei et al. Source

Zhang H.,Georgia Regents University | Chen G.,Georgia Regents University | Kuang H.,Georgia Regents University | Kuang H.,Banna Biomedical Research Institute | Tsien J.Z.,Georgia Regents University
PLoS ONE | Year: 2013

Mapping and decoding brain activity patterns underlying learning and memory represents both great interest and immense challenge. At present, very little is known regarding many of the very basic questions regarding the neural codes of memory: are fear memories retrieved during the freezing state or non-freezing state of the animals? How do individual memory traces give arise to a holistic, real-time associative memory engram? How are memory codes regulated by synaptic plasticity? Here, by applying high-density electrode arrays and dimensionality-reduction decoding algorithms, we investigate hippocampal CA1 activity patterns of trace fear conditioning memory code in inducible NMDA receptor knockout mice and their control littermates. Our analyses showed that the conditioned tone (CS) and unconditioned footshock (US) can evoke hippocampal ensemble responses in control and mutant mice. Yet, temporal formats and contents of CA1 fear memory engrams differ significantly between the genotypes. The mutant mice with disabled NMDA receptor plasticity failed to generate CS-to-US or US-to-CS associative memory traces. Moreover, the mutant CA1 region lacked memory traces for "what at when" information that predicts the timing relationship between the conditioned tone and the foot shock. The degraded associative fear memory engram is further manifested in its lack of intertwined and alternating temporal association between CS and US memory traces that are characteristic to the holistic memory recall in the wild-type animals. Therefore, our study has decoded real-time memory contents, timing relationship between CS and US, and temporal organizing patterns of fear memory engrams and demonstrated how hippocampal memory codes are regulated by NMDA receptor synaptic plasticity. © 2013 Zhang et al. Source

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