The molecular and cellular biology of enhanced cognition

Department of Neurobiology, Brain Research Institute, University of California, Los Angeles, California 90095, USA.
Nature Reviews Neuroscience (Impact Factor: 31.43). 03/2009; 10(2):126-40. DOI: 10.1038/nrn2572
Source: PubMed


Most molecular and cellular studies of cognitive function have focused on either normal or pathological states, but recent research with transgenic mice has started to address the mechanisms of enhanced cognition. These results point to key synaptic and nuclear signalling events that can be manipulated to facilitate the induction or increase the stability of synaptic plasticity, and therefore enhance the acquisition or retention of information. Here, we review these surprising findings and explore their implications to both mechanisms of learning and memory and to ongoing efforts to develop treatments for cognitive disorders. These findings represent the beginning of a fundamental new approach in the study of enhanced cognition.

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Available from: Yong-Seok Lee, Jun 11, 2014
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    • "an electric shock to develop conditioned responses (Kim & Fanselow 1992; Lee & Silva 2009). During the training sessions, mice were subjected to a tone paired with a mild foot shock in a conditioning chamber. "
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    ABSTRACT: The C57BL/6 is one of the most frequently used mouse strains in neuroscience. Although it is well recognized that genetic background has a critical impact on the behavior and physiology of different strains of mice, the differences among substrains of C57BL/6 are not well appreciated. Here, we compared three substrains of C57BL/6 (C57BL/6NCrljOri, C57BL/6NTacSam, and C57BL/6JBomTac) in a series of behavioral tasks examining both general behavior, and learning and memory. In addition, we have also performed electrophysiological analyses including long-term potentiation (LTP) in the hippocampus, which is considered a cellular mechanism for learning and memory. We found that there are significant differences between C57BL/6JBomTac and the other two substrains in their behavioral phenotypes, including motor coordination, anxiety, and freezing in classical fear conditioning. However, the three substrains show comparable levels of hippocampal LTP. Our findings provide guidelines for choosing the most appropriate substrain for the intended studies.
    Animal cells and systems the official publication of the Zoological Society of Korea 04/2015; 19(3):1-7. DOI:10.1080/19768354.2015.1023830 · 0.44 Impact Factor
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    • "Viewed as an adaptive information-processing system, AMPAR exocytosis is one of several negative-feedback loops in CREB-based E-T signaling that modulate synaptic strength, thereby facilitating network updates. Other loops would include HDAC1 (histone deacetylase 1)-and HDAC8-associated protein phosphatase 1 (PP1) which de-phosphorylates CREB at Ser-133 (Lee and Silva, 2009), endogenous inducible cAMP early repressor (ICER) which competes with CREB for CRE binding sites (Mioduszewska et al., 2003), and CREB phosphorylation at Ser-142 via CaMKII which blocks CREBmediated transcription (Wu and McMurray, 2001). New studies of phenotypic correlates of CREB signaling in the amygdala reflect a revised functional interpretation which in turn appears consistent with brain evolutionary studies. "
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    ABSTRACT: Neurologically-complex species utilize two intricately-coupled information–processing systems to adapt to their social and natural environments. Action potentials (APs) facilitate rapid responses to the nearly continuous fluctuations in the animal's surroundings. By contrast, genetic encodings comprise a molecular memory of ancient adaptive responses expressed as cognitive, emotional, or behavioral phenotypes. The linking of the two systems via intracellular Ca2+ networks which address transcription factors---e.g., cAMP response element-binding protein (CREB)---is an appropriate focus for the biology of human behavior. Computational modeling utilizing Boolean networks (BNs) is a suitable qualitative method, requiring no kinetic information, for eliciting the systems’ architectural properties. In particular, BNs can reveal critical intracellular regimes of possible evolutionary significance. As a platform for future research, we propose that those networks sufficiently robust to attenuate damaging intracellular noise and deleterious mutations, yet sufficiently close to chaos to permit or amplify adaptive noise and favorable mutations, would be favored by natural selection. Critical regimes of this type would be, literally, “poised for survival”, and would stabilize and promote the survival of their correlated cultural phenotypes.
    The International Journal of Biochemistry & Cell Biology 01/2015; 61. DOI:10.1016/j.biocel.2015.01.013 · 4.05 Impact Factor
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    • "Factors that globally impact cognition may provide an alternate therapeutic approach for treating dementia, for which genetic heterogeneity and environmental risk factors may be further complicating risk factors [Lee and Silva, 2009]. "
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    ABSTRACT: Objective Identify genetic factors associated with cognitive maintenance in late life and assess their association with gray matter (GM) volume in brain networks affected in aging. Methods We conducted a genome-wide association study of ∼2.4 M markers to identify modifiers of cognitive trajectories in Caucasian participants (N = 7,328) from two population-based cohorts of non-demented elderly. Standardized measures of global cognitive function (z-scores) over 10 and 6 years were calculated among participants and mixed model regression was used to determine subject-specific cognitive slopes. “Cognitive maintenance” was defined as a change in slope of ≥ 0 and was compared with all cognitive decliners (slope < 0). In an independent cohort of cognitively normal older Caucasians adults (N = 122), top association findings were then used to create genetic scores to assess whether carrying more cognitive maintenance alleles was associated with greater GM volume in specific brain networks using voxel-based morphometry. ResultsThe most significant association was on chromosome 11 (rs7109806, P = 7.8 × 10−8) near RIC3. RIC3 modulates activity of α7 nicotinic acetylcholine receptors, which have been implicated in synaptic plasticity and beta-amyloid binding. In the neuroimaging cohort, carrying more cognitive maintenance alleles was associated with greater volume in the right executive control network (RECN; PFWE = 0.01). Conclusions These findings suggest that there may be genetic loci that promote healthy cognitive aging and that they may do so by conferring robustness to GM in the RECN. Future work is required to validate top candidate genes such as RIC3 for involvement in cognitive maintenance. Hum Brain Mapp, 2014. © 2014 Wiley Periodicals, Inc.
    Human Brain Mapping 09/2014; 35(9). DOI:10.1002/hbm.22494 · 5.97 Impact Factor
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