Showing papers by "Susumu Tonegawa published in 2008"

Transgenic Inhibition of Synaptic Transmission Reveals Role of CA3 Output in Hippocampal Learning

Abstract: The hippocampus is an area of the brain involved in learning and memory. It contains parallel excitatory pathways referred to as the trisynaptic pathway (which carries information as follows: entorhinal cortex --> dentate gyrus --> CA3 --> CA1 --> entorhinal cortex) and the monosynaptic pathway (entorhinal cortex --> CA1 --> entorhinal cortex). We developed a generally applicable tetanus toxin-based method for transgenic mice that permits inducible and reversible inhibition of synaptic transmission and applied it to the trisynaptic pathway while preserving transmission in the monosynaptic pathway. We found that synaptic output from CA3 in the trisynaptic pathway is dispensable and the short monosynaptic pathway is sufficient for incremental spatial learning. In contrast, the full trisynaptic pathway containing CA3 is required for rapid one-trial contextual learning, for pattern completion-based memory recall, and for spatial tuning of CA1 cells.

Brain-derived Neurotrophic Factor Over-expression in the Forebrain Ameliorates Huntington’s Disease Phenotypes in Mice

Abstract: Huntington's disease (HD), a dominantly inherited neurodegenerative disorder characterized by relatively selective degeneration of striatal neurons, is caused by an expanded polyglutamine tract of the huntingtin (htt) protein. The htt mutation reduces levels of brain-derived neurotrophic factor (BDNF) in the striatum, likely by inhibiting cortical BDNF gene expression and anterograde transport of BDNF from cortex to striatum. However, roles of the BDNF reduction in HD pathogenesis have not been established conclusively. We reasoned that increasing striatal BDNF through over-expression would slow progression of the disease if BDNF reduction plays a pivotal role in HD pathogenesis. We employed a Bdnf transgene driven by the promoter for the alpha subunit of Ca(2+)/calmodulin-dependent kinase II to over-express BDNF in the forebrain of R6/1 mice which express a fragment of mutant htt with a 116-glutamine tract. The Bdnf transgene increased BDNF levels and TrkB signaling activity in the striatum, ameliorated motor dysfunction, and reversed brain weight loss in R6/1 mice. Furthermore, it normalized DARPP-32 expression of the 32 kDa dopamine and cAMP-regulated phosphoprotein, increased the number of enkephalin-containing boutons, and reduced formation of neuronal intranuclear inclusions in the striatum of R6/1 mice. These results demonstrate crucial roles of reduced striatal BDNF in HD pathogenesis and suggest potential therapeutic values of BDNF to HD.

Differential Gene Expression between Sensory Neocortical Areas: Potential Roles for Ten_m3 and Bcl6 in Patterning Visual and Somatosensory Pathways

Abstract: Adult neocortical areas are characterized by marked differences in cytoarchitecture and connectivity that underlie their functional roles. The molecular determinants of these differences are largely unknown. We performed a microarray analysis to identify molecules that define the somatosensory and visual areas during the time when afferent and efferent projections are forming. We identified 122 molecules that are differentially expressed between the regions and confirmed by quantitative polymerase chain reaction 95% of the 20 genes tested. Two genes were chosen for further investigation: Bcl6 and Ten_m3. Bcl6 was highly expressed in the superficial cortical plate corresponding to developing layer IV of somatosensory cortex at postnatal day (P) 0. This had diminished by P3, but strong expression was found in layer V pyramidal cells by P7 and was maintained until adulthood. Retrograde tracing showed that Bcl6 is expressed in corticospinal neurons. Ten_m3 was expressed in a graded pattern within layer V of caudal cortex that corresponds well with visual cortex. Retrograde tracing and immunostaining showed that Ten_m3 is highly expressed along axonal tracts of projection neurons of the developing visual pathway. Overexpression demonstrated that Ten_m3 promotes homophilic adhesion and neurite outgrowth in vivo. This suggests an important role for Ten_m3 in the development of the visual pathway.

The Network Collective: Rise and Fall of a Scientific Paradigm

Abstract: First-hand account of the rise and fall of a scientific paradigm Shows how scientific fiction turns to fact Highlights the origin of scientific hype Includes interviews with prominent scientists The network paradigm dominated immunological research from the early 1970s to the late 1980s. The originator, Niels Jerne, hypothesized that the vast diversity of antibodies in each individual forms a network of mutual "idiotypic" recognition, thus regulating the immune system. In context of emerging concepts of systems biology such as cybernetics and autopoesis, the "Eigenbehavior" of the immune system fascinated an entire generation of young immunologists. But fascination led to experimental errors and overinterpretation, eventually magnifying the immune system from a mere infection-fighting device to a substrate of personality and individuality. As a result, what initially appeared as an exciting new perspective of the immune system is now viewed as a scientific vagary, and is largely abandoned. The author, himself a participant in the network vagary, begins with a description of the leading theoretical concepts on fact finding in science. This is followed by a historical account of the rise and fall of the network paradigm, complemented by personal interviews with some of the prominent protagonists. By comparing the network paradigm to other, more lasting concepts in life science, the author develops a general perspective on how solid knowledge is derived from error-prone scientific methodology, namely by exposure of scientific notions to the scrutiny of reality.

Molecular and Circuit Mechanisms for Hippocampal Learning

Abstract: The hippocampus is crucial for the formation of memories of facts and episodes (Scoville and Milner 1957; Jarrard 1993; Squire et al. 2004; Burgess et al. 2002). In storing the contents of a specific episode, the hippocampus must rapidly form and maintain representations of the temporal and spatial relationship of events and keep these representations distinct, allowing similar episodes to be distinguished, a property termed pattern separation. Furthermore, because specific episodes are rarely replicated in full, the hippocampus must be capable of using partial cues to retrieve previously stored patterns of representations, a phenomenon referred to as pattern completion. Based primarily on the anatomy (Fig. 1) and physiology of the hippocampus and its associated cortical structures, computational neuroscientists have suggested specific hippocampal subregions and circuits thatmay subserve thesemnemonic requirements. These are the feedforward pathway from the entorhinal cortex (EC) to the dentate gyrus (DG) and on to CA3 for pattern separation, and the recurrent and highly plastic connections in CA3 for pattern completion (Marr 1971;McClelland and Goddard 1996; McNaughton and Nadel 1990; O’Reilly and McClelland 1994).